BioDEX/raw_dataset · Datasets at Hugging Face

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{ "abstract": "Fetal supraventricular tachycardia (SVT), characterized by a fetal ventricular heart rate faster than 200 beats per minute (bpm), is often diagnosed during routine fetal heart monitoring or prenatal ultrasound examinations. Clinical guidelines for management of fetal SVT have not been determined in standardized trials, nor do we have a clear sense regarding the long-term developmental outcomes and side effects of in utero antiarrhythmic therapy. We describe our approach to the treatment of refractory SVT in a fetus with hydrops using direct umbilical vein treatment with amiodarone coupled with effusion evacuation. We successfully achieved in utero resolution of SVT. There was transient amiodarone-induced hypothyroidism, which we screened for early and treated with Synthroid. Ultimately our patient had normal long-term growth and development as measured by modified Denver office checklists and Ages and Stages questionnaires. Our experience advocates for vigilant screening and management of hypothyroidism in fetuses exposed to in utero amiodarone and suggests that it is possible to achieve good outcomes in high-acuity refractory cases of SVT.", "affiliations": "Department of Pediatrics, Division of Pediatric Cardiology, The Children's Hospital at Montefiore-Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Obstetrics, Gynecology & Women's Health, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Obstetrics, Gynecology & Women's Health, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Pediatrics, Division of Pediatric Cardiology, The Children's Hospital at Montefiore-Albert Einstein College of Medicine, Bronx, NY, USA.", "authors": "Capone\|C A\|CA\|;Gebb\|J\|J\|;Dar\|P\|P\|;Shenoy\|R U\|RU\|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone; D013974:Thyroxine", "country": "Netherlands", "delete": false, "doi": "10.3233/NPM-14814017", "fulltext": null, "fulltext_license": null, "issn_linking": "1878-4429", "issue": "7(4)", "journal": "Journal of neonatal-perinatal medicine", "keywords": "Fetal arrhythmias; amiodarone-induced hypothyroidism; cardioversion; hydrops fetalis; neurodevelopment", "medline_ta": "J Neonatal Perinatal Med", "mesh_terms": "D000328:Adult; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D005260:Female; D005315:Fetal Diseases; D006801:Humans; D015160:Hydrops Fetalis; D007037:Hypothyroidism; D007231:Infant, Newborn; D011247:Pregnancy; D013617:Tachycardia, Supraventricular; D013974:Thyroxine; D016896:Treatment Outcome; D016216:Ultrasonography, Prenatal", "nlm_unique_id": "101468335", "other_id": null, "pages": "305-9", "pmc": null, "pmid": "25468615", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Favorable neurodevelopmental outcome in a hypothyroid neonate following intracordal amiodarone for cardioversion of refractory supraventricular tachycardia in a fetus.", "title_normalized": "favorable neurodevelopmental outcome in a hypothyroid neonate following intracordal amiodarone for cardioversion of refractory supraventricular tachycardia in a fetus" }	[ { "companynumb": "PHHY2015US008620", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", 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"drugtreatmentdurationunit": null, "medicinalproduct": "SEROQUEL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GLYBURIDE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLYBURIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROPRANOLOL\\PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "70663", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUPRAVENTRICULAR TACHYCARDIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLECAINIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLECAINIDE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUPRAVENTRICULAR TACHYCARDIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLECAINIDE" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "3.41", "reaction": [ { "reactionmeddrapt": "Wolff-Parkinson-White syndrome congenital", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Congenital hypothyroidism", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pericardial effusion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Supraventricular tachycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hydrops foetalis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardioactive drug level below therapeutic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CAPONE C.A, GEBB J, DAR P, SHENOY RU. FAVORABLE NEURODEVELOPMENTAL OUTCOME IN A HYPOTHYROID NEONATE FOLLOWING INTRACORDAL AMIODARONE FOR CARDIOVERSION OF REFRACTORY SUPRAVENTRICULAR TACHYCARDIA IN A FETUS. 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FAVORABLE NEURODEVELOPMENTAL OUTCOME IN A HYPOTHYROID NEONATE FOLLOWING INTRACORDAL AMIODARONE FOR CARDIOVERSION OF REFRACTORY SUPRAVENTRICULAR TACHYCARDIA IN A FETUS.. J-NEONATAL-PERINATAL-MED. 2014?7(4):305-309", "literaturereference_normalized": "favorable neurodevelopmental outcome in a hypothyroid neonate following intracordal amiodarone for cardioversion of refractory supraventricular tachycardia in a fetus", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151228", "receivedate": "20150527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11142200, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "PHHY2015US007445", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { 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FAVORABLE NEURODEVELOPMENTAL OUTCOME IN A HYPOTHYROID NEONATE FOLLOWING INTRACORDAL AMIODARONE FOR CARDIOVERSION OF REFRACTORY SUPRAVENTRICULAR TACHYCARDIA IN A FETUS.. 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{ "abstract": "Cutaneous alternariosis is an uncommon fungal infection that most commonly presents in organ transplant patients on immunosuppressive therapy. There are no clinical trials or guidelines to guide treatment of this condition, however itraconazole is the most commonly used antifungal in published cases. Here we report on a case of cutaneous alternariosis in a renal transplant recipient treated with a newer antifungal, posaconazole. A review of published reports of cutaneous alternariosis since 2008 is also discussed.", "affiliations": "Niagara Falls Memorial Medical Center, 621 10th Street, Niagara Falls, NY 14302, USA.;Niagara Falls Memorial Medical Center, 621 10th Street, Niagara Falls, NY 14302, USA; D'Youville College School of Pharmacy, 320 Porter Avenue, Buffalo, NY 14201, USA.;Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212, USA.", "authors": "Bajwa\|Rajinder\|R\|;Wojciechowski\|Amy L\|AL\|;Hsiao\|Chiu-Bin\|CB\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.mmcr.2017.01.003", "fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(17)30002-710.1016/j.mmcr.2017.01.003Case ReportCutaneous alternariosis in a renal transplant patient successfully treated with posaconazole: Case report and literature review Bajwa Rajinder aWojciechowski Amy L. [email protected]@nfmmc.orgab⁎Hsiao Chiu-Bin ca Niagara Falls Memorial Medical Center, 621 10th Street, Niagara Falls, NY 14302, USAb D’Youville College School of Pharmacy, 320 Porter Avenue, Buffalo, NY 14201, USAc Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212, USA⁎ Corresponding author at: Niagara Falls Memorial Medical Center, 621 10th Street, Niagara Falls, NY 14302, USA. [email protected]@nfmmc.org21 1 2017 3 2017 21 1 2017 15 16 20 1 12 2016 12 1 2017 17 1 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cutaneous alternariosis is an uncommon fungal infection that most commonly presents in organ transplant patients on immunosuppressive therapy. There are no clinical trials or guidelines to guide treatment of this condition, however itraconazole is the most commonly used antifungal in published cases. Here we report on a case of cutaneous alternariosis in a renal transplant recipient treated with a newer antifungal, posaconazole. A review of published reports of cutaneous alternariosis since 2008 is also discussed.\n\nKeywords\nAlternaria spp.AlternariosisFungal infectionPosaconazole\n==== Body\n1 Introduction\nSkin lesions are common in organ transplant recipients who are on immunosuppressive therapy. Almost all cases require a biopsy to confirm the etiology, as there are a variety of infectious and non-infectious causes of the skin lesions in this patient population. We recently saw a pancreatic-renal transplant patient who presented with cutaneous alternariosis. Infection with Alternaria spp. is relatively uncommon and has been primarily described in case reports and small case series, with the last major review reported in 2008 [1]. Therefore, in this report we summarize the clinical findings from reports since 2008. Further, there are no randomized trials that address treatment of cutaneous alternariosis. Although itraconazole has been used most commonly, there have been case reports of failure or relapse with that agent [2]. Newer antifungal agents have started to gain popularity in treating cutaneous alternariosis [3], [4], [5], [6], including our case which was successfully treated with posaconazole.\n\n2 Case\nA 56 year old male with end stage renal disease secondary to type 1 diabetes mellitus (DM) and history of renal and pancreatic transplant presented to the clinic (day 0) with complaints of multiple non-pruritic lesions on his lower extremities. The patient stated that he first noticed the lesion three weeks prior to presentation as a single lesion on his left ankle with then progressed and spread to both lower extremities. The patient had undergone a cadaveric renal and pancreatic transplant five months prior to presentation. The transplanted kidney underwent acute rejection and was removed four months prior to presentation, necessitating reinstitution of hemodialysis. He was continued on his immunosuppressive therapy because of well-functioning pancreatic transplant. His immunosuppressive regimen included tacrolimus 2 mg in morning and 3 mg in evening, mycophenolate mofetil 540 mg twice daily and prednisone 5 mg daily. He was also on trimethoprim-sulfamethoxazole double-strength tablet three times a week as prophylaxis against opportunistic infections. Other medications included metoprolol for hypertension and erythropoietin injections for anemia.\n\nOn the day of presentation to the clinic, the patient's physical examination was only remarkable for onychomycosis involving the toenails and multiple nodular, violaceous mildly tender skin lesions on both lower extremities up to the level of his knees. Some of these lesions had scabs associated with them (Fig. 1). Laboratory findings on day 0 revealed a white blood cell count of 3600/mm3 with a normal differential, a hemoglobin of 11.2 g/dL, a platelet count of 145,000/mm3, a creatinine of 5.4 mg/dL, a blood urea nitrogen of 21.1 mg/dL, normal liver function tests, and an erythrocyte sedimentation rate of 26 mm/h. His HIV serology was negative. A chest X-ray revealed clear lung fields.Fig. 1 Violaceous indurated nodules and ulcers on right lower extremity.\n\nFig. 1.\n\nOne of the lesions was biopsied and the histopathology revealed a few fungal hyphae. Routine, fungal and mycobacterial cultures were requested. Fungal culture grew Alternaria that was not speciated (Fig. 2, Fig. 3). As there was no evidence of systemic infection, a diagnosis of cutaneous alternariosis was made on day 14, and antifungal treatment was initiated with posaconazole 200 mg three times a day. By week 6, follow up visit revealed significant improvement, with complete resolution by week 14. The patient was continued on posaconazole due to continued immunosuppression for the functioning pancreatic graft. The patient died 18 months after the diagnosis of cutaneous alternariosis because of unrelated causes without relapse of cutaneous fungal infection.Fig. 2 Skin biopsy showing fungal hyphae with occasional branching (Gomori Methenamine stain, 200× original magnification).\n\nFig. 2.Fig. 3 Multicellular ovoid macroconidia arising on septate hyphae (Lactophenol Cotton Blue mount, 400× original magnification).\n\nFig. 3.\n\n3 Discussion\nAlternaria spp. are dematiaceous fungi, which are ubiquitous in nature. They infrequently cause human infection in immunocompetent patients [7]. However, as the number of immunocompromised patients has increased, so has the reported cases of alternariosis [8], [9]. Since the first case report in 1933 [10], over 200 cases have been reported in the literature. Cutaneous infections represent the overwhelming majority of cases [1], [11].\n\nWe have reviewed the literature published in English from 2008 to 2016 for case reports or case series on cutaneous alternariosis. Our search yielded 55 cases that are summarized in Table 1. This will supplement the comprehensive reviews of cases published by Lyke et al. in 2001 and Pastor and Guarro in 2008 [1], [2]. In our review there are 15 females and 40 males with ages ranging from 13 to 85 years. Consistent with previous reports [1], [2], cutaneous alternariosis of the extremities was the most common site of involvement.Table 1 Published cases of cutaneous Alternariosis from 2008–2016.\n\nTable 1Year\tAuthor\tSex\tAge\tUnderlying Conditiona\tSpecies\tPrimary Therapyb\tOutcome for Primary therapyc\t\n2008\tC Williams [25]\tM\t85\tNone\tAlternaria spp.\tITZ\tCure\t\n2008\tJ Brasch [26]\tM\t68\tRenal Tx\tAlternaria infectoria\tITZ\tCure\t\n2008\tL Podda [27]\tM\t24\tALL\tAlternaria infectoria\tVori\tCure\t\n2008\tG Calabro [28]\tM\t53\tRenal Tx\tAlternaria alternata\tITZ\tCure\t\n2009\tS Segner [29]\tM\t73\tRenal Tx\tAlternaria infectoria\tITZ\tImproved\t\n2010\tRD Boyce [30]\tF\t45\tCardiac Tx\tAlternaria spp.\tSx+CSP+ITZ\tFailure\t\n2010\tRD Boyce [30]\tM\t62\tCardiac Tx\tAlternaria spp.\tSx+Vori\tCure\t\n2010\tRD Boyce [30]\tM\t51\tRenal & Pancreas Tx\tAlternaria spp.\tITZ\tFailure\t\n2010\tRD Boyce [30]\tF\t60\tLung & Renal Tx\tAlternaria spp.\tSx+Vori\tImproved\t\n2010\tRD Boyce [30]\tM\t41\tRenal & Pancreas Tx\tAlternaria spp.\tSx\tFailure\t\n2010\tRD Boyce [30]\tM\t36\tRenal Tx\tAlternaria spp.\tITZ\tFailure\t\n2010\tRD Boyce [30]\tM\t40\tRenal & Pan Tx\tAlternaria spp.\tSx+ITZ\tCure\t\n2010\tRD Boyce [30]\tF\t63\tPancreas Tx\tAlternaria spp.\tSx+ITZ\tCure\t\n2010\tAM Morales [31]\tM\t63\tCardiac Tx\tAlternaria spp.\tCryotherapy+ITZ\tCure\t\n2010\tF Santiago [32]\tM\t55\tRenal Tx\tAlternaria alternata\tITZ\tFailure\t\n2010\tSEM Vermeire [21]\tF\t51\tRenal Tx\tAlternaria alternata\tSx+Vori\tCure\t\n2010\tTR Leahy [19]\tF\t14\tAML\tAlternaria infectoria\tLamB+Vori\tCure\t\n2010\tM Yasui [33]\tM\t68\tNone\tAlternaria alternata\tThermotherapy\tCure\t\n2010\tDR Matson [34]\tM\t17\tNone\tAlternaria spp.\tITZ\tImproved\t\n2011\tGW Osmond [35]\tM\t57\tCardiac Tx\tAlternaria spp.\tSx+Vori\tImproved\t\n2011\tDS Kpodzo [6]\tM\t58\tCLL\tAlternaria alternata\tSx+Posa\tCure\t\n2012\tT Robert [36]\tF\t73\tDM\tAlternaria infectoria\tITZ\tImproved\t\n2012\tT Robert [36]\tM\t54\tRenal Tx\tAlternaria infectoria\tFLU\tImproved\t\n2012\tT Robert [36]\tF\t75\tRenal Tx\tAlternaria infectoria\tVori\tDied of unrelated cause\t\n2012\tT Robert [36]\tM\t56\tCardiac & Lung Tx\tAlternaria infectoria\tSx+Vori\tImproved\t\n2012\tT Robert [36]\tM\t77\tCMML\tAlternaria infectoria\tITZ\tDied of unrelated cause\t\n2012\tT Robert [36]\tF\t41\tNone\tAlternaria infectoria\tITZ\tFailure\t\n2012\tD Cunha [37]\tM\t53\tRenal Tx\tAlternaria infectoria\tITZ\tCure\t\n2012\tB Rammaert [38]\tF\t64\tCardiac Tx\tAlternaria infectoria\tITZ\tFailure\t\n2012\tD Tambasco [39]\tF\t64\tRenal Tx\tAlternaria infectoria\tTerb\tCure\t\n2012\tRA Lavergne [40]\tM\t63\tCardiac Tx\tAlternaria alternata\tVori\tImproved\t\n2012\tL Rudnicka [41]\tM\t13\tAlopecia areata\tAlternaria chlamydospora\tUnknown\tOutcome not known\t\n2012\tVSM Saegeman [5]\tF\t52\tLung Tx\tAlternaria infectoria\tSx+Vori\tImproved\t\n2012\tF Seyfarth [42]\tF\t65\tRenal Tx\tAlternaria infectoria\tCiclo+Vori\tFailure\t\n2013\tB Sharifkashani [43]\tM\t37\tHeart Tx\tAlternaria spp.\tVori\tCure\t\n2013\tL Lopes [4]\tM\t61\tRenal Tx\tAlternaria infectoria\tITZ\tCure\t\n2013\tL Lopes [4]\tM\t63\tRenal Tx\tAlternaria infectoria\tCryotherapy+Posa\tImproved\t\n2013\tL Lopes [4]\tM\t56\tRenal Tx\tAlternaria infectoria\tSx+ITZ\tCure\t\n2013\tB Kleker [44]\tM\t55\tALL\tAlternaria alternata\tVori\tFailure\t\n2013\tN Alhmali [45]\tF\t65\tLiver Tx\tAlternaria infectoria\tCiclo+FLU\tCure\t\n2013\tC Dessinioti [46]\tM\t58\tNone\tAlternaria alternata\tBIF+ITZ\tFailure\t\n2013\tZ Secnikova [3]\tM\t60\tHeart Tx\tAlternaria alternata\tSx+Vori\tImproved\t\n2013\tMC Gonzalez-Vela [47]\tM\t60\tLung Tx\tAlternaria triticina\tITZ\tImproved\t\n2014\tN Essabbah [48]\tF\t33\tRenal Tx\tAlternaria tenuissima\tdecrease IS\tImproved\t\n2014\tM Michelon [49]\tM\t70\tRenal Tx\tAlternaria spp.\tITZ\tImproved\t\n2014\tE Coussens [50]\tM\t65\tLiver Tx\tAlternaria infectoria\tFLU\tCure\t\n2014\tD Daglar [51]\tM\t33\tRenal Tx\tAlternaria infectoria\tITZ\tFailure\t\n2014\tSH Sohng [52]\tM\t76\tNone\tAlternaria alternata\tKET\tImproved\t\n2015\tM Demirci [53]\tF\t32\tRenal Tx\tAlternaria spp.\tITZ\tCure\t\n2015\tW Hu [54]\tM\t28\tNone\tAlternaria arborescens\tITZ+LamB\tCure\t\n2015\tCC Hsu [55]\tM\t61\tRenal Tx\tAlternaria spp.\tITZ\tFailure\t\n2015\tS Bras [56]\tM\t65\tLiver Tx\tAlternaria alternata+Alternaria infectoria\tSx+ITZ\tCure\t\n2016\tCL Simpson [57]\tM\t60's\tHeart Tx\tAlternaria spp.\tITZ\tFailure\t\n2016\tRC Patel [58]\tM\t13\tNone\tAlternaria spp.\teconazole+ITZ\tCure\t\n2016\tC O'Meara [59]\tM\t80\tMDS\tAlternaria spp.\tsilver chloride gel\tCure\t\na ALL=acute lymphoblastic leukemia, AML=acute myelogenous leukemia, CLL=chronic lymphoid leukemia, CMML=chronic myelomonocytic leukemia, DM=diabetes mellitus, MDS=myelodysplastic syndrome, Tx=transplant.\n\nb BIF=bifonazole, Ciclo=ciclopiroxolamine, CSP=caspofungin, FLU=fluconazole, IS=immunosuppressive therapy, ITZ=itraconazole, KET=ketoconazole, LamB=liposomal amphotericin B, Posa=posaconazole, Sx=surgery, Terb=terbinafine, Vori=voriconazole.\n\nc Cure=complete resolution, Improved=Improvement but not complete resolution, Failure=worsening or no improvement.\n\n\n\n3.1 Agent\nThe genus Alternaria is comprised of over 80 species. A. alternata, A. infectoria, A. tenuissima and A. chartarum cause the majority of infections. Alternaria alternata (59/156, 38%) followed by A. tenuissima (23/156, 15%) were the most frequent isolates described in a previous review (Pastor, 2008), however, in 55/156 (35%) cases a speciation was not performed. In our review of 55 cases since 2008, species determination was done in 36/55 (65%) cases with Alternaria infectoria implicated in 22/55 (40%) followed by Alternaria alternata in 11/55 (20%) and Alternaria tenuissima in 1/55 (1.8%) of cases, suggesting a possible shift in prevalence of each species over the past decade.\n\n3.2 Risk factors\nMost patients with cutaneous alternariosis have an immunocompromising condition, such as transplantation [12], collagen vascular disease (e.g. systemic lupus erythematous (SLE)) [13], hematological malignancy [2], endogenous hypercortisolism and diabetes [2], [12]. Rare cases have been described in hosts with no known immunocompromising conditions [14].\n\nIn our review of cases from 2008 to present, 39/55 (71%) patients had an organ transplant and were on multiple immunosuppressive agents when lesion/lesions occurred, six (11%) patients had hematological malignancies, and several had other conditions affecting the immune system. In seven (13%) patients no obvious immunosuppression was noted. This is in contrast to cases earlier than 2008, where only 51 out of 156 (33%) cases had an organ transplant, potentially due to the increasing number of organ transplant patients living today leading to a greater percentage of infected patients falling into this category.\n\n3.3 Mode of acquisition and clinical features\nAlternaria spp. are ubiquitous in distribution and are common soil saprophytes. The mode of acquisition is not always established, although minor skin trauma and subsequent inoculation appears to be a plausible route of entry [15]. The most common presentation is skin lesions [1], [11]. Cutaneous alternariosis exists in two forms: epidermal type or dermal type depending on the depth of fungal invasion. In both types, the lesion usually appears on the exposed sites such as the dorsum of hands, forearms, knees and legs. Scaly infiltrated erythematous or ulcerative are seen with the epidermal type. The dermal type has been described as plaques with papules, pustules, crusts, and with the surface being more or less granular and atrophic. In some cases, pain is associated with the lesions [16]. Less common clinical syndromes reported with alternariosis include allergic sinusitis, hypersensitivity pneumonitis, osteomyelitis, keratitis, endophthalmitis, rhinosinusitis, onychomycosis, and peritonitis [1], [2], [7], [17].\n\n3.4 Diagnosis\nThe establishment of Alternaria spp. infection requires demonstration of fungal tissue invasion or recovery of the fungi from a sterile site. This is important, as Alternaria spp. is ubiquitously present in the environment and thereby could contaminate the culture or could be colonizing, but not infecting, superficial tissue. Alternaria spp. usually, but not always, appear dark-walled on standard histopathologic stains. Cell wall melanin may be visible as a brownish-yellow color on hematoxylin-eosin (H&E) stain. If melanin is not evident on H&E stain, it can be identified using the Fontana-Masson method. However, culture is essential for the identification of Alternaria spp., since histologic findings are not pathognonic. Morphology of the conidia is used for speciation of Alternaria spp. However clinically important species often lose their ability to sporulate and, thus, cannot be identified by microscopic examination. For this reason, molecular techniques are increasingly used to identify Alternaria spp\n[1], [18], [19].\n\n3.5 Treatment\nThere are no randomized controlled trials that have assessed the treatment of Alternaria spp. infections. In absence of any guidance from controlled data, multiple therapeutic options have been used. Review of literature has identified itraconazole as the most commonly used antimicrobial. Outcomes appear to be satisfactory. Some series report its efficacy above 90% [2], [17]. Doses ranging from 100 mg/day to 600 mg/day have been used, with the duration of therapy usually being in excess of two months. However, there have been reports of failure with itraconazole, even when in vitro data demonstrates susceptibility in vitro\n[2]. Voriconazole [19], [20], [21], fluconazole [22], Amphotericin B [16], [19], and terbinafine [22] have been used in few cases. Surgery alone has been reported to be successful in the case of localized, superficial lesions [23], [24].\n\nIn our review, itraconazole was used alone as primary therapy in 20 of 55 patients, with eight of these patients failing therapy and requiring use of additional agents. This 40% failure rate is much higher than previously reported, suggesting a possible increase in resistance to itraconazole [2], [17]. The increase in reported failures may, however, be due to a reporting bias because unexpected failures are more likely to be reported than expected cures. In our series, initial combination therapy with itraconazole plus either surgery, cryotherapy, or another antifungal agent resulted in cure in seven of nine patients (78%). Initial use of other azole antifungals, either alone or in combination with other treatment modalities, had generally positive results. Voriconazole monotherapy or in combination with surgery or topical antifungals resulted in cure or improvement in 11 of 14 patients (79%). Fluconazole monotherapy or in combination with topical ciclopiroxolamine led to improvement or cure in all three reported cases. Posaconazole use was reported in two patients, in combination with either surgery or cryotherapy, and led to cure or improvement in both cases. Additionally, in two of the cases that saw initial improvement, but not cure, with voriconazole-based therapy, a change in antifungal to posaconazole yielded improvement in the skin lesions [3], [5].\n\nCutaneous infection with Alternaria spp. is a well-described, though still relatively rare, complication in patients on immunosuppressive therapy due to solid organ transplant. Historically, itraconazole has been used most frequently to treat this infection. However it is not universally effective and it has certain disadvantages such as significant drug-drug interactions mediated by inhibition of cytochrome P450 enzymes. Posaconazole is another potential antifungal option that overcomes some of the disadvantages of itraconazole, particularly with regard to drug-drug interactions. Our case demonstrates that posaconazole can be used successfully as a first line treatment of cutaneous alternariosis, however additional clinical data are needed to determine the place in therapy for this agent.\n\nConflict of interest\nThere are none.\n\nAcknowledgements\nWe thank Dr. Thomas A. Russo for discussion and critical review of this manuscript.\n==== Refs\nReferences\n1 Pastor F.J. Guarro J. Alternaria infections: laboratory diagnosis and relevant clinical features Clin. Microbiol. Infect. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 14 8 2008 734 746 \n2 Lyke K.E. Miller N.S. Towne L. Merz W.G. 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Parma A. Naldi L. Goglio A. Pheohyphomycotic soft tissue disease caused by Alternaria alternata in a kidney transplant patient: a case report and literature review Transpl. Proc. 39 5 2007 1655 1659 \n13 Akman A. Sakalli Cakcak D. Ozhak Baysan B. Yazisiz V. Terzioglu E. Ciftcioglu M.A. Cutaneous alternariosis in a patient with systemic lupus erythematosus Lupus 16 12 2007 993 996 18042595 \n14 Sood N. Gugnani H.C. Guarro J. Paliwal-Joshi A. Vijayan V.K. Subcutaneous phaeohyphomycosis caused by Alternaria alternata in an immunocompetent patient Int. J. Dermatol. 46 4 2007 412 413 17442087 \n15 Kazory A. Ducloux D. Reboux G. Blanc D. Faivre B. Chalopin J.-M. Cutaneous Alternaria infection in renal transplant recipients: a report of two cases with an unusual mode of transmission Transpl. Infect. Dis. J. Transpl. Soc. 6 1 2004 46 49 \n16 Henn S.L. Forrest G.N. Febrile neutropenia associated with painful lesions of the palms and digits Clin. Infect. Dis. Publ. Infect. Dis. Soc. Am. 43 6 2006 791 792 \n17 Sharkey P.K. Graybill J.R. Rinaldi M.G. Stevens D.A. Tucker R.M. Peterie J.D. Itraconazole treatment of phaeohyphomycosis J. Am. Acad. Dermatol. 23 3 Pt 2 1990 577 586 2170477 \n18 Romano C. Vanzi L. Massi D. Difonzo E.M. Subcutaneous alternariosis Mycoses 48 6 2005 408 412 16262877 \n19 Leahy T.R. Punnett A.S. Richardson S.E. Gharabaghi F. Wadhwa A. Molecular identification of phaeohyphomycosis due to Alternaria infectoria in a patient with acute myeloid leukemia--a case report Diagn. Microbiol. Infect. Dis. 66 3 2010 318 321 19896319 \n20 Luque P. García-Gil F.A. Larraga J. Jiménez B. Tomé-Zelaya E. Serrano M.T. Treatment of cutaneous infection by Alternaria alternata with voriconazole in a liver transplant patient Transpl. Proc. 38 8 2006 2514 2515 \n21 Vermeire S.E.M. de Jonge H. Lagrou K. Kuypers D.R.J. Cutaneous phaeohyphomycosis in renal allograft recipients: report of 2 cases and review of the literature Diagn. Microbiol. Infect. Dis. 68 2 2010 177 180 20846592 \n22 Gilaberte M. Bartralot R. Torres J.M. Reus F.S. Rodríguez V. Alomar A. Cutaneous alternariosis in transplant recipients: clinicopathologic review of 9 cases J. Am. Acad. Dermatol. 52 4 2005 653 659 15793517 \n23 Nulens E. De Laere E. Vandevelde H. Hilbrands L.B. Rijs A.J.M.M. Melchers W.J.G. Alternaria infectoria phaeohyphomycosis in a renal transplant patient Med. Mycol. 44 4 2006 379 382 16772234 \n24 Cardoso S.V. Campolina S.S. Guimarães A.L.S. Faria P.R. da C. Costa E.M. Gomez R.S. Oral phaeohyphomycosis J. Clin. Pathol. 60 2 2007 204 205 17264246 \n25 Williams C. Layton A.M. Kerr K. Kibbler C. Barton R.C. Cutaneous infection with an Alternaria sp. in an immunocompetent host Clin. Exp. Dermatol. 33 4 2008 440 442 18312460 \n26 Brasch J. Busch J.-O. de Hoog G.S. Cutaneous phaeohyphomycosis caused by Alternaria infectoria Acta Derm. Venereol. 88 2 2008 160 161 18311446 \n27 Podda L. Fozza C. Nieddu R. Sanna S. Paglietti B. Vacca A. Breakthrough cutaneous alternariosis in a patient with acute lymphoblastic leukemia: clinical features and diagnostic issues Leuk. Lymphoma 49 1 2008 154 155 18203025 \n28 Calabrò G. Nino M. Gallo L. Scalvenzi M. Cutaneous alternariosis in a kidney transplantation recipient: report of a case J. Dermatol. Treat. 19 4 2008 246 248 \n29 Segner S. Jouret F. Durant J.-F. Marot L. Kanaan N. Cutaneous infection by Alternaria infectoria in a renal transplant patient Transpl. Infect. Dis. J. Transpl. Soc. 11 4 2009 330 332 \n30 Boyce R.D. Deziel P.J. Otley C.C. Wilhelm M.P. Eid A.J. Wengenack N.L. Phaeohyphomycosis due to Alternaria species in transplant recipients Transpl. Infect. Dis. J. Transpl. Soc. 12 3 2010 242 250 \n31 Morales A.M. Charlez L. Remón L. Sanz P. Aspiroz C. Cutaneous alternariosis in a heart transplant recipient Actas Dermosifiliogr. 101 4 2010 370 372 20487700 \n32 Santiago F. Serra D. Vieira R. Brites M.M. Figueiredo A. Successful cryotherapy for a cutaneous alternariosis in a renal transplant recipient Eur. J. Dermatol. EJD 20 6 2010 841 20937586 \n33 Yasui M. Hattori M. Ikegami N. Kaga M. Ogawa Y. Hiruma M. A case of alternariosis successfully treated with local hyperthermia Mycoses 54 5 2011 e623 e626 21910761 \n34 Matson D.R. Eudy J.D. Matson S.C. Cutaneous alternariosis in an adolescent patient Pedia. Dermatol. 27 1 2010 98 100 \n35 Osmond G.W. Walters R.W. Puri P.K. Cutaneous alternariosis microscopically mimicking blastomycosis J. Cutan. Pathol. 38 11 2011 923 925 21752048 \n36 Robert T. Talarmin J.-P. Leterrier M. Cassagnau E. Le Pape P. Danner-Boucher I. Phaeohyphomycosis due to Alternaria infectoria : a single-center experience with utility of PCR for diagnosis and species identification Med. Mycol. 50 6 2012 594 600 22404860 \n37 Cunha D. Amaro C. Vieira M.R. Martins M. da L. Maduro A.P. Inácio J. Phaeohyphomycosis caused by Alternaria infectoria presenting as multiple vegetating lesions in a renal transplant patient Rev. Ibero. Micol. 29 1 2012 44 46 \n38 Rammaert B. Aguilar C. Bougnoux M.-E. Noël N. Charlier C. Denis B. Success of posaconazole therapy in a heart transplanted patient with Alternaria infectoria cutaneous infection Med. Mycol. 50 5 2012 518 521 22142219 \n39 Tambasco D. D’Ettorre M. Bracaglia R. Massi G. Posteraro B. Torelli R. A suspected squamous cell carcinoma in a renal transplant recipient revealing a rare cutaneous phaeohyphomycosis by Alternaria infectoria J. Cutan. Med. Surg. 16 2 2012 131 134 22513067 \n40 Lavergne R.A. Cassaing S. Nocera T. Pauwels C. Cointault O. Basse G. Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Transpl. Infect. Dis. J. Transpl. Soc. 14 6 2012 E156 E160 \n41 Rudnicka L. Lukomska M. Alternaria scalp infection in a patient with alopecia areata. Coexistence or causative relationship? J. Dermatol. Case Rep. 6 4 2012 120 124 23329992 \n42 Seyfarth F. Goetze S. Gräser Y. Kaatz M. Ott U. Rüster C. Successful treatment of cutaneous alternariosis with caspofungin in a renal transplant recipient Mycoses 55 5 2012 457 462 22329778 \n43 Sharifkashani B. Farshidpour M. Droudinia A. Marjani M. Ahmadi Z. Ansari Z. Cutaneous alternariosis with trichosporon infection in a heart transplant recipient: a case report Exp. Clin. Transplant. 11 5 2013 464 466 23530868 \n44 Kleker B. Endo J. Bennett D. Snow S. Mohs micrographic surgery for the treatment of localized cutaneous alternariosis J. Am. Acad. Dermatol. 68 2 2013 e55 e56 23317992 \n45 Alhmali N. Lindenlaub P. Ghebremedhin B. Franke I. Gollnick H. Bonnekoh B. Deep cutaneous mycosis due to Alternaria infectoria after liver transplantation: successful treatment with fluconazole Eur. J. Dermatol. 1–2 1 2013 100 102 \n46 Dessinioti C. Soumalevris A. Papadogeorgaki E. Athanasopoulou V. Christofidou E. Antoniou C. Cutaneous alternariosis in an immunocompetent patient successfully treated with oral fluconazole Eur. J. Dermatol. 7–8 4 2013 545 547 \n47 González-Vela M.C. Armesto S. Unda-Villafuerte F. Val-Bernal J.F. Cutaneous infection with Alternaria triticina in a Bilateral lung transplant recipient Actas Dermosifiliogr. 105 8 2014 e51 e54 24440281 \n48 Essabbah N. Gorsane I. Youssef M. Hadhri R. Aloui S. Gorcii M. Cutaneous alternariosis in a renal transplant recipient Cutis 93 5 2014 237 240 24897135 \n49 Michelon M. Greenlaw S. O’Donnell P. Geist D. Levin N.A. Multifocal cutaneous alternariosis in a 70-year-old Kenyan renal transplant patient Dermatol. Online J. 20 2014 7 \n50 Coussens E. Rogge S. Haspeslagh M. Geerts A. Verhelst X. Van Vlierberghe H. Cutaneous infection by Alternaria infectoria in a liver transplant recipient: a case report Acta Gastro-Enterol. Belg. 77 2 2014 256 258 \n51 Daglar D. Akman-Karakas A. Ozhak-Baysan B. Gunseren F. Ciftcioglu M.A. Buitrago M.J. Cutaneous Alternaria infectoria infection diagnosed by molecular techniques in a renal transplant patient Clin. Lab. 60 9 2014 1569 1572 25291955 \n52 Sohng S. Kim Y. Kim B. Choi J. Shin D. Choi J. A case of cutaneous infection by Alternaria alternata Korean J. Med. Mycol. 19 3 2014 76 81 \n53 Demirci M. Baran N. Uzum A. Calli A.O. Gul-Yurtsever S. Demirdal T. Cutaneous Alternariasis in a patient with renal transplant Jundishapur J. Microbiol. 8 5 2015 (Available from) 〈http://www.jjmicrobiol.com/?page=article&article_id=19082〉 \n54 Hu W. Ran Y. Zhuang K. Lama J. Zhang C. Alternaria arborescens infection in a healthy individual and literature review of cutaneous alternariosis Mycopathologia 179 1–2 2015 147 152 25370461 \n55 Hsu C.-C. Chang S.-S. Lee P.-C. Chao S.-C. Cutaneous alternariosis in a renal transplant recipient: a case report and literature review Asian J. Surg. 38 1 2015 47 57 25554667 \n56 Brás S. Sabino R. Laureano A. Simões H. Fernandes C. Marques-Pinto G. Cutaneous infection by different Alternaria species in a liver transplant recipient Med. Mycol. Case Rep. 8 2015 1 4 25750855 \n57 Simpson C.L. Craig-Muller S. Sobanko J.F. Weikert B.C. Micheletti R.G. Refractory cutaneous alternariosis successfully treated with Mohs surgery and full-thickness skin grafting Dermatol. Surg. Publ. Am. Soc. Dermatol Surg. 42 3 2016 426 429 \n58 Patel R.C. Helm M. Shimizu I. Cutaneous alternariosis in an immunocompetent patient Dermatol. Online J. 22 10 2016 12 \n59 OʼMeara C. Boyanton B.L. Spurlin D. Carpenter C.F. Cutaneous fungal infection with Alternaria in a patient With myelodysplastic syndrome: successful treatment With Topical silver chloride gel Infect. Dis. Clin. Pract. 24 2 2016 112 114\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2211-7539", "issue": "15()", "journal": "Medical mycology case reports", "keywords": "Alternaria spp.; Alternariosis; Fungal infection; Posaconazole", "medline_ta": "Med Mycol Case Rep", "mesh_terms": null, "nlm_unique_id": "101598259", "other_id": null, "pages": "16-20", "pmc": null, "pmid": "28180057", "pubdate": "2017-03", "publication_types": "D016428:Journal Article", "references": "22142219;23530868;23329992;16772234;20487700;26945322;15793517;22897073;11283807;22329778;18608728;20199426;27429134;20937586;18311446;2497012;18203025;23317992;15225228;20002611;16262877;28329593;25370461;25554667;24440281;20319289;23075226;20846592;19896319;25046464;25291955;22513067;8914373;21910761;10817234;21787876;24897135;23477761;2170477;17580210;21299373;18312460;26060568;24112410;25750855;24001697;19594865;17097985;22404860;18042595;21752048;16912950;25090825;17264246;18727797;17442087", "title": "Cutaneous alternariosis in a renal transplant patient successfully treated with posaconazole: Case report and literature review.", "title_normalized": "cutaneous alternariosis in a renal transplant patient successfully treated with posaconazole case report and literature review" }	[ { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2020-05533", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "208591", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALTERNARIA INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BAJWA R, WOJCIECHOWSKI AL, HSIAO CB. 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{ "abstract": "OBJECTIVE\nTo evaluate the feasibility of transarterial therapy (transcatheter arterial chemoembolization and transcatheter arterial infusion) for patients with hepatocellular carcinoma and chronic kidney disease (CKD).\n\n\nMETHODS\nThe study enrolled 35 patients who received transarterial therapy. The patients were classified into a CKD group (n = 10 nondialysis chronic kidney disease [NDCKD] and n = 9 end-stage renal disease [ESRD]) or a non-CKD group (n = 16). The survival rates between the two groups were compared using two different starting points: (a) from initial diagnosis of hepatocellular carcinoma and (b) from enrollment in the study. The tolerance of transarterial therapy in patients with CKD was evaluated by comparing the incidence of major adverse events.\n\n\nRESULTS\nThe 2-year and 5-year survival rates from initial diagnosis were 83.9% and 53.8% in the CKD group and 70.1% and 40.4% in the non-CKD group (P = .478). The corresponding 3-year survival rate from enrollment in the two groups was 25.6% and 41.2%, respectively (P = .995). The 2-year and 5-year survival rates from initial diagnosis were 70.1% and 40.4% in the non-CKD group, 90.0% and 39.4% in NDCKD patients, and 76.2% and 76.2% in ESRD patients (P = .380). The corresponding 2-year survival rates from enrollment in these groups were 54.9%, 48.0%, and 48.6% (P = .943). Severe contrast-induced nephropathy (n = 3) and late-onset death caused by cholesterol crystal embolism (n = 1) were observed in the NDCKD group.\n\n\nCONCLUSIONS\nTranscatheter arterial chemoembolization is feasible in patients with CKD by instituting periprocedural hemodialysis with similar 2-year and 5-year survival compared with patients without CKD.", "affiliations": "Department of Gastroenterology, Kitasato University Medical Center, 6-100 Arai, Kitamoto, Saitama, 364-8501, Japan. Electronic address: [email protected].;Department of Risk Management and Health Care Administration, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Nephrology in Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Gastroenterology, Kitasato University East Hospital, Sagamihara, Kanagawa, Japan.", "authors": "Watanabe\|Masaaki\|M\|;Shibuya\|Akitaka\|A\|;Minamino\|Tsutomu\|T\|;Murano\|Junya\|J\|;Matsunaga\|Keiji\|K\|;Fujii\|Kaoru\|K\|;Ogasawara\|Gou\|G\|;Irie\|Tsugumi\|T\|;Woodhams\|Reiko\|R\|;Koizumi\|Wasaburo\|W\|", "chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D015251:Epirubicin; C406530:miriplatin; D004998:Ethiodized Oil; D002945:Cisplatin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1051-0443", "issue": "25(12)", "journal": "Journal of vascular and interventional radiology : JVIR", "keywords": null, "medline_ta": "J Vasc Interv Radiol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D002945:Cisplatin; D015331:Cohort Studies; D003131:Combined Modality Therapy; D015251:Epirubicin; D004998:Ethiodized Oil; D005240:Feasibility Studies; D005260:Female; D005781:Gelatin Sponge, Absorbable; D006801:Humans; D007676:Kidney Failure, Chronic; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D015996:Survival Rate; D016896:Treatment Outcome", "nlm_unique_id": "9203369", "other_id": null, "pages": "1947-55; quiz 1955", "pmc": null, "pmid": "25306225", "pubdate": "2014-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Benefits and problems of transarterial therapy in patients with hepatocellular carcinoma and chronic kidney disease.", "title_normalized": "benefits and problems of transarterial therapy in patients with hepatocellular carcinoma and chronic kidney disease" }	[ { "companynumb": "JP-GE HEALTHCARE MEDICAL DIAGNOSTICS-OMPQ-PR-1410L-1316", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": 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"patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "53.2", "reaction": [ { "reactionmeddrapt": "Nephropathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WATANABE M,SHIBUYA A,MINAMINO T,MURANO J,MATSUNAGA K,FUJII K,OGASAWARA G,IRIE T,WOODHAMS R,WASABURO K. BENEFITS AND PROBLEMS OF TRANSARTERIAL THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AND CHRONIC KIDNEY DISEASE. J VASC INTERV RADIOL. 2014 JAN 01;1-9.", "literaturereference_normalized": "benefits and problems of transarterial therapy in patients with hepatocellular carcinoma and chronic kidney disease", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141205", "receivedate": "20141030", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10555764, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "JP-GE HEALTHCARE MEDICAL DIAGNOSTICS-OMPQ-PR-1410L-1317", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": 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null, "drugstartdateformat": null, "drugstructuredosagenumb": "157", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "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": "UNSPECIFIED DIURETIC" }, { "actiondrug": null, "activesubstance": null, "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": "MIRIPLATIN HYDRATE" } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "55", "reaction": [ { "reactionmeddrapt": "Nephropathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WATANABE M,SHIBUYA A,MINAMINO T,MURANO J,MATSUNAGA K,FUJII K,OGASAWARA G,IRIE T,WOODHAMS R,WASABURO K. BENEFITS AND PROBLEMS OF TRANSARTERIAL THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AND CHRONIC KIDNEY DISEASE. J VASC INTERV RADIOL. 2014 JAN 01;1-9.", "literaturereference_normalized": "benefits and problems of transarterial therapy in patients with hepatocellular carcinoma and chronic kidney disease", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141030", "receivedate": "20141030", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10556086, "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" } ]
{ "abstract": "Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of medications that target the transporter that reabsorbs ~90% of glucose in the S1 segment of the proximal convoluted tubule. As a result, SGLT2 inhibition increases urinary glucose excretion, effectively lowering plasma glucose levels. In addition to reducing hemoglobin A1c levels, these drugs also lower body weight, blood pressure, and uric acid levels in Type 2 diabetes mellitus (T2DM) patients. Importantly, empagliflozin has been observed to slow progression of kidney disease and reduce dialysis requirements in T2DM patients. However, the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) has collected over 100 cases of acute kidney injury (AKI) for canagloflozin and dapagliflozin since their approval. Of the 101 patients, 96 required hospitalization, 22 required intensive care unit admission, and 15 underwent hemodialysis. The FDA now requires that AKI be listed as a potential side effect of the SGLT2 inhibitors along with cautious prescription of these drugs with other medications, such as renin-angiotensin-system antagonists, diuretics, and NSAIDs. It is unclear, however, whether this FAERS reported \"AKI\" actually represents structural kidney injury, as randomized, controlled trials of these drugs do not describe AKI as an adverse event despite coprescription with RAS blockers and diuretics. As a result of this FDA warning, diabetic patients with early-stage CKD may not be prescribed an SGLT2 inhibitor for fear of AKI. Thus, it is imperative to ascertain whether the reported AKI represents true structural kidney injury or a functional decline in glomerular filtration rate. We propose using readily available clinical tools with experimental biomarkers of kidney injury and kidney-on-a-chip technology to resolve this question and provide solid evidence about the AKI risk of these drugs for healthcare providers.", "affiliations": "Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.;Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut [email protected].", "authors": "Saly\|Danielle L\|DL\|;Perazella\|Mark A\|MA\|", "chemical_list": "D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors", "country": "United States", "delete": false, "doi": "10.1152/ajprenal.00250.2017", "fulltext": null, "fulltext_license": null, "issn_linking": "1522-1466", "issue": "313(4)", "journal": "American journal of physiology. Renal physiology", "keywords": "SGLT2 inhibitors; acute kidney injury; biomarkers; nephrotoxicity; urine microscopy", "medline_ta": "Am J Physiol Renal Physiol", "mesh_terms": "D058186:Acute Kidney Injury; D000818:Animals; D006801:Humans; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors", "nlm_unique_id": "100901990", "other_id": null, "pages": "F951-F954", "pmc": null, "pmid": "28637789", "pubdate": "2017-10-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Harnessing basic and clinic tools to evaluate SGLT2 inhibitor nephrotoxicity.", "title_normalized": "harnessing basic and clinic tools to evaluate sglt2 inhibitor nephrotoxicity" }	[ { "companynumb": "US-JNJFOC-20171031255", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CANAGLIFLOZIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204042", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANAGLIFLOZIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SALY DL, PERAZELLA MA. HARNESSING BASIC AND CLINIC TOOLS TO EVALUATE SGLT2 INHIBITOR NEPHROTOXICITY. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 2017;313 (4):F951-F954.", "literaturereference_normalized": "harnessing basic and clinic tools to evaluate sglt2 inhibitor nephrotoxicity", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171031", "receivedate": "20171031", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14145617, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20180321" } ]
{ "abstract": "Herein, we aimed to report a diffuse large B cell lymphoma (DLBCL) case that had extensive cutaneous relapse with no skin involvement previously. A 59-year-old man presented to hospital in April 2014 with fatigue, anorexia, fever, and anemia. Cervical lymph node biopsy revealed CD20+, BCL2+, MUM1+, BCL6+ high grade B lymphoproliferative neoplasm. After FISH investigation, he was diagnosed as DLBCL. He was given 7 cycles of R-CHOP and achieved remission. However, in November 2014, he had emerging skin lesions that cover nearly all of his body. A control PET-CT revealed diffuse cutaneous involvement. CD20+, BCL2+, MUM1+, BCL6+ high grade B cell lymphoma infiltration was detected with skin biopsy. He was diagnosed as relapse lymphoma, so 2 cycles of R-DHAP were given. There was no treatment response; therefore, R-ICE regimen was started. The patient had achieved second complete remission and his skin lesions were completely regressed. The involvement of skin with CD20+ cells after 7 cycles of rituximab therapy favors that there is a rituximab resistant disease which tends to involve the skin. To conclude, DLBCL may relapse extensively with cutaneous involvement and the best treatment option in these patients is salvage chemotherapy followed by autologous peripheral blood stem cell transplantation.", "affiliations": "Department of Hematology, School of Medicine, Hacettepe University, 0100 Ankara, Turkey.;Department of Hematology, School of Medicine, Hacettepe University, 0100 Ankara, Turkey.;Department of Hematology, School of Medicine, Hacettepe University, 0100 Ankara, Turkey.;Department of Hematology, School of Medicine, Hacettepe University, 0100 Ankara, Turkey.", "authors": "Malkan\|Umit Yavuz\|UY\|;Gunes\|Gursel\|G\|;Yayar\|Okan\|O\|;Demiroglu\|Haluk\|H\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2015/137682", "fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2015/137682Case ReportDiffuse Large B Cell Lymphoma with Extensive Cutaneous Relapse Malkan Umit Yavuz \n\nGunes Gursel Yayar Okan Demiroglu Haluk Department of Hematology, School of Medicine, Hacettepe University, 0100 Ankara, TurkeyUmit Yavuz Malkan: [email protected] Editor: Jeffrey M. Weinberg\n\n2015 20 9 2015 2015 1376825 7 2015 10 9 2015 Copyright © 2015 Umit Yavuz Malkan 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.Herein, we aimed to report a diffuse large B cell lymphoma (DLBCL) case that had extensive cutaneous relapse with no skin involvement previously. A 59-year-old man presented to hospital in April 2014 with fatigue, anorexia, fever, and anemia. Cervical lymph node biopsy revealed CD20+, BCL2+, MUM1+, BCL6+ high grade B lymphoproliferative neoplasm. After FISH investigation, he was diagnosed as DLBCL. He was given 7 cycles of R-CHOP and achieved remission. However, in November 2014, he had emerging skin lesions that cover nearly all of his body. A control PET-CT revealed diffuse cutaneous involvement. CD20+, BCL2+, MUM1+, BCL6+ high grade B cell lymphoma infiltration was detected with skin biopsy. He was diagnosed as relapse lymphoma, so 2 cycles of R-DHAP were given. There was no treatment response; therefore, R-ICE regimen was started. The patient had achieved second complete remission and his skin lesions were completely regressed. The involvement of skin with CD20+ cells after 7 cycles of rituximab therapy favors that there is a rituximab resistant disease which tends to involve the skin. To conclude, DLBCL may relapse extensively with cutaneous involvement and the best treatment option in these patients is salvage chemotherapy followed by autologous peripheral blood stem cell transplantation.\n==== Body\n1. Introduction\nDiffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma [1]. The majority of relapses occur during the first two years after completion of treatment [2, 3]. Relapses are usually symptomatic and rarely identified solely on the basis of routine imaging [4–6]. Extra nodal involvement of B cell lymphoma generally appears in gastrointestinal system followed by skin [7]. Skin involvement of B cell lymphomas could be either primary or secondary. Herein, we aimed to report a DLBCL case that had extensive cutaneous relapse with no skin involvement previously.\n\n2. Case Report\nA 59-year-old man presented to our clinic in April 2014 with fatigue, anorexia, fever, and anemia. Clinical examination revealed splenomegaly and cervical lymphadenopathies. Laboratory tests were reported as hemoglobin 9.1 gr/dL, white blood cell 6.1 × 103/μL, and platelets 430 × 103/μL with normal other biochemical values. HIV test was negative. Spleen size was found as 160 × 90 mm and lymphadenopathies around portal hilus were detected by abdominal USG. Cervical lymph node biopsy revealed high grade B lymphoproliferative neoplasm. Conventional cytogenetic analysis was performed; however it resulted in no metaphases. The FISH investigation has resulted in BCL2−, BCL6−, and MYC−. Immunohistochemical study has resulted in CD20+, BCL2+, MUM1+, BCL6+, and Tdt−. Ki-67 proliferation index of the patient was 90%. No disease involvement was detected in the bone marrow biopsy investigation. PET-CT was performed for disease staging. Involvement in spleen, bone marrow, cervical lymph nodes, bilateral axillary lymph nodes, thoracal lymph nodes, portal, para-aortic, paracaval, and bilateral inguinal lymph nodes, sternum, C2 vertebra, clavicula, acromion, and left humerus was detected, with SUV max value above 4. The patient was diagnosed as stage 4 diffuse large B cell lymphoma and 4 cycles of R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone) regimen were given. In August 2014, cervical, thoracal, and abdominal CT revealed regression. R-CHOP regimen was given for 3 more cycles. The patient responded to the treatment well with complete resolution of all lymphadenopathies. However, 2 months after the completion of chemotherapy cycles in November 2014, the patient had emerging skin lesions that cover nearly all of his body. The lesions were painless and different in diameter with the biggest lesion reaching 5-6 cm (Figure 1). A control PET-CT revealed diffuse cutaneous involvement (SUV max 18.3) with axillary lymph node involvement (SUV max 14.8). Interestingly this time, spleen, inguinal nodes, and bone marrow involvement could not be detected. Biopsy was performed from skin lesion which was reported as CD20+, BCL2+, MUM1+, BCL6+ high grade B cell lymphoma infiltration. The patient also had foot drop which was considered to be secondary to vincristine. Electromyography revealed diffuse and severe axonal polyneuropathy and active myopathy in distal muscles. There was no involvement in cranial MR. He was diagnosed as relapsed lymphoma, so R-DHAP (rituximab, cisplatin, cytosine arabinoside, and dexamethasone) chemotherapy regimen was started. There was no treatment response after 2 cycles of R-DHAP; therefore, chemotherapy regimen has changed to R-ICE (rituximab, etoposide, carboplatin, and ifosfamide). With R-ICE treatment, the patient achieved second complete remission and his skin lesions were completely regressed (Figure 2). Autologous peripheral blood stem cell transplantation (PBSCT) was planned for our patient.\n\n3. Discussion\nPrimary cutaneous lymphomas have better clinical course and prognosis [8, 9]. However, extensive secondary cutaneous involvement in systemic B cell lymphomas has been also reported in the literature [10, 11]. Very significant improvements were recorded in the management of DLBCL; however, it is still not usual to achieve cure with conventional treatment. The outcome of relapsed DLBCL largely depends on several factors such as fitness and chemosensitivity of the patient, eligibility for stem cell transplantation (SCT), IPI score at relapse, and time interval from previous chemotherapy. In the literature, it was stated that after the relapse of DLBCL the response rate following second line therapy (R-ICE or R-DHAP) was 63% [12]. Disease-free survival is very low in cases who reach second remission [13]. However, performing SCT in these patients would extend treatment response to two years [14]. Non-Hodgkin lymphomas generally relapse in the same involvement sites. In the literature, there are reports of cases who relapsed with CD20− skin involvement after rituximab therapy [15, 16]. Our case differs from these reports with CD20+ relapse after 7 cycles treatment with R-CHOP regimen. At the beginning of the treatment, our patient did not have skin involvement that excludes the diagnosis of primary cutaneous lymphoma. The involvement of skin with CD20+ after 7 cycles of rituximab therapy suggests that there is a resistant disease to rituximab which tends to involve the skin. Interestingly, disease relapse was not present in our patients' primary involvement sites, except axillary region. Moreover, disease relapse occurred in cutaneous region which did not have disease involvement primarily. To conclude, diffuse large B cell lymphomas may relapse extensively with cutaneous involvement and the best treatment option in these patients is salvage chemotherapy followed by autologous PBSCT.\n\nConflict of Interests\nThe authors of this paper have no conflict of interests, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.\n\nFigure 1 Prior to salvage treatment.\n\nFigure 2 After salvage treatment.\n==== Refs\n1 Morton L. M. Wang S. S. Devesa S. S. Hartge P. Weisenburger D. D. Linet M. S. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001 Blood 2006 107 1 265 276 10.1182/blood-2005-06-2508 2-s2.0-30144443996 16150940 \n2 Larouche J.-F. Berger F. Chassagne-Clément C. Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome Journal of Clinical Oncology 2010 28 12 2094 2100 10.1200/jco.2009.24.5860 2-s2.0-77951629048 20308668 \n3 Maurer M. J. Ghesquières H. Jais J.-P. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy Journal of Clinical Oncology 2014 32 10 1066 1073 10.1200/JCO.2013.51.5866 2-s2.0-84901700388 24550425 \n4 Weeks J. C. Yeap B. Y. Canellos G. P. Shipp M. A. Value of follow-up procedures in patients with large-cell lymphoma who achieve a complete remission Journal of Clinical Oncology 1991 9 7 1196 1203 2-s2.0-0025736610 1710656 \n5 Liedtke M. Hamlin P. A. Moskowitz C. H. Zelenetz A. D. Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population Annals of Oncology 2006 17 6 909 913 10.1093/annonc/mdl049 2-s2.0-33646860107 16672295 \n6 El-Galaly T. Mylam K. J. Bøgsted M. Role of routine imaging in detecting recurrent lymphoma: a review of 258 patients with relapsed aggressive non-Hodgkin and Hodgkin lymphoma American Journal of Hematology 2014 89 6 575 580 10.1002/ajh.23688 2-s2.0-84900844110 24493389 \n7 Santucci M. Pimpinelli N. Primary cutaneous B-cell lymphomas. Current concepts. I Haematologica 2004 89 11 1360 1371 2-s2.0-9144226809 15531459 \n8 Kerl H. Fink-Puches R. Cerroni L. Diagnostic criteria of primary cutaneous B-cell lymphomas and pseudolymphomas The Keio Journal of Medicine 2001 50 4 269 273 10.2302/kjm.50.269 2-s2.0-0035751482 11806505 \n9 Thomas V. Dobson R. Mennel R. Primary cutaneous large B-cell lymphoma, leg type Proceedings of the Baylor University Medical Center 2011 24 350 353 \n10 Amo Y. Tanei R. Yonemoto K. Katsuoka K. Mori M. Diffuse large B-cell lymphoma associated with skin, muscle and cranial nerve involvement European Journal of Dermatology 2000 10 4 306 308 2-s2.0-0034032694 10846261 \n11 Shamsudin N. Chang C. C. Diffuse large B-cell lymphoma presenting with extensive cutaneous infiltration Singapore Medical Journal 2012 53 9 e198 e200 2-s2.0-84870048315 23023915 \n12 Gisselbrecht C. Glass B. Mounier N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era Journal of Clinical Oncology 2010 28 27 4184 4190 10.1200/jco.2010.28.1618 2-s2.0-77957965500 20660832 \n13 Singer C. R. J. Goldstone A. H. Clinical studies of ABMT in non-Hodgkin's lymphoma Clinics in Haematology 1986 15 1 105 150 10.1016/s0308-2261(86)80008-x 2-s2.0-0023039567 3516486 \n14 Cortelazzo S. Rambaldi A. Rossi A. Intensification of salvage treatment with high-dose sequential chemotherapy improves the outcome of patients with refractory or relapsed aggressive non-Hodgkin's lymphoma British Journal of Haematology 2001 114 2 333 341 10.1046/j.1365-2141.2001.02955.x 2-s2.0-0034882693 11529852 \n15 Iguchi T. Miyazawa K. Okabe S. Relapse of diffuse large B cell lymphoma to CD20-negative multiple cutaneous tumors immediately after anti-CD20 monoclonal antibody (rituximab) therapy Rinshō Ketsueki 2004 45 10 1129 1134 2-s2.0-16644363199 15553050 \n16 Massengale W. T. McBurney E. Gurtler J. CD20-negative relapse of cutaneous B-cell lymphoma after anti-CD20 monoclonal antibody therapy Journal of the American Academy of Dermatology 2002 46 3 441 443 10.1067/mjd.2002.108490 2-s2.0-0036123109 11862185\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "2015()", "journal": "Case reports in medicine", "keywords": null, "medline_ta": "Case Rep Med", "mesh_terms": null, "nlm_unique_id": "101512910", "other_id": null, "pages": "137682", "pmc": null, "pmid": "26457084", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "20660832;23023915;24550425;16150940;22046074;24493389;15553050;3516486;10846261;11529852;15531459;11806505;11862185;1710656;16672295;20308668", "title": "Diffuse Large B Cell Lymphoma with Extensive Cutaneous Relapse.", "title_normalized": "diffuse large b cell lymphoma with extensive cutaneous relapse" }	[ { "companynumb": "TR-PFIZER INC-2017495355", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { 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{ "abstract": "The objective of the study is to report a case of acute pancreatitis secondary to hypercalcemia induced by primary hyperparathyroidism in a pregnant woman at the end of the first trimester. The case included a 32-year-old woman who was diagnosed with acute pancreatitis and severe hypercalcemia refractory to many regimens of medical therapy in the first trimester of pregnancy. She was successfully treated with parathyroidectomy in the early second trimester with complete resolution of hypercalcemia and pancreatitis. Neonatal course was unremarkable. To our best knowledge, this is a rare case when primary hyperparathyroidism and its complications are diagnosed in the first trimester of pregnancy. In conclusion, primary hyperparathyroidism is a rare life-threatening condition to the fetus and mother especially when associated with complications such as pancreatitis. Early therapeutic intervention is important to reduce the morbidity and mortality. Parathyroidectomy performed in the second trimester can be the only solution.\nLearning how to make diagnosis of primary hyperparathyroidism in a woman during the first trimester of pregnancy.Understanding the complications of hypercalcemia and be aware of the high mortality and sequelae in both fetus and mother.Providing the adequate treatment in such complicated cases with coordinated care between endocrinologists and obstetricians to ensure optimal outcomes.", "affiliations": "Rafic Hariri University Hospital, Beirut, Lebanon.;Rafic Hariri University Hospital, Beirut, Lebanon.;Rafic Hariri University Hospital, Beirut, Lebanon.;Rafic Hariri University Hospital, Beirut, Lebanon.", "authors": "Richa\|Carine Ghassan\|CG\|;Saad\|Khadija Jamal\|KJ\|;Chaaban\|Ali Khaled\|AK\|;El Rawas\|Mohamad Souheil\|MS\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1530/EDM-17-0175", "fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-17-0175EDM170175Pregnant AdultFemaleWhiteLebanonParathyroidBonePTHCalcitoninHyperparathyroidism (Primary)HypercalcaemiaPancreatitisParathyroid AdenomaPancreatitisHypercalcaemiaAbdominal painNauseaVomitingLeukocytosisPruritusParaesthesiaKidney stonesAmylaseBilirubinAlanine aminotransferaseLipase (serum)Endoscopic ultrasoundCalcium (serum)MagnesiumPhosphate (serum)Urine 24-hour volumeCreatinineCalcium (urine)PTHUltrasound scan25-hydroxyvitamin-D3MRIHistopathologyParathyroidectomyFluid repletionCalcitoninSalineFurosemideZoledronic acidBisphosphonatesCalcium gluconateCalciumCalcitriolObstetricsUnique/Unexpected Symptoms or Presentations of a DiseaseUnique/Unexpected Symptoms or Presentations of a DiseaseA rare case of hypercalcemia-induced pancreatitis in a first trimester pregnant woman C G Richa and othersHyperparathyroidism in pregnancyRicha Carine Ghassan 123Saad Khadija Jamal 124Chaaban Ali Khaled 156El Rawas Mohamad Souheil 1271 Rafic Hariri University Hospital, Beirut, Lebanon2 Department of Medicine, Endocrinology Division, Lebanese University, Hadath, Lebanon3 Endocrinology Department, Rafic Hariri University Hospital, Beirut, Lebanon4 Endocrinology Department, Mount Lebanon Hospital, Beirut, Lebanon5 Department of Radiology, Beirut Governmental University Hospital, Beirut, Lebanon6 Diagnostic Radiology, Radiology Department7 Clinical Endocrinology, Endocrinology Department, Rafic Hariri University Hospital, Beirut, LebanonCorrespondence should be addressed to C G Richa Email: [email protected] 3 2018 2018 2018 17-017525 2 2018 08 3 2018 © 2018 The authors2018The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nThe objective of the study is to report a case of acute pancreatitis secondary to hypercalcemia induced by primary hyperparathyroidism in a pregnant woman at the end of the first trimester. The case included a 32-year-old woman who was diagnosed with acute pancreatitis and severe hypercalcemia refractory to many regimens of medical therapy in the first trimester of pregnancy. She was successfully treated with parathyroidectomy in the early second trimester with complete resolution of hypercalcemia and pancreatitis. Neonatal course was unremarkable. To our best knowledge, this is a rare case when primary hyperparathyroidism and its complications are diagnosed in the first trimester of pregnancy. In conclusion, primary hyperparathyroidism is a rare life-threatening condition to the fetus and mother especially when associated with complications such as pancreatitis. Early therapeutic intervention is important to reduce the morbidity and mortality. Parathyroidectomy performed in the second trimester can be the only solution.\n\nLearning points:\nLearning how to make diagnosis of primary hyperparathyroidism in a woman during the first trimester of pregnancy.\n\nUnderstanding the complications of hypercalcemia and be aware of the high mortality and sequelae in both fetus and mother.\n\nProviding the adequate treatment in such complicated cases with coordinated care between endocrinologists and obstetricians to ensure optimal outcomes.\n\nPatient Demographics\nPregnant adultFemaleWhiteLebanonClinical Overview\nParathyroidBonePTHCalcitoninHyperparathyroidism (primary)HypercalcaemiaPancreatitisParathyroid adenomaDiagnosis and Treatment\nPancreatitisHypercalcaemiaAbdominal painNauseaVomitingLeukocytosisPruritusParaesthesiaKidney stonesAmylaseBilirubinAlanine aminotransferaseLipase (serum)Endoscopic ultrasoundCalcium (serum)MagnesiumPhosphate (serum)Urine 24-hour volumeCreatinineCalcium (urine)PTHUltrasound scan25-hydroxyvitamin-D3MRIHistopathologyParathyroidectomyFluid repletionCalcitoninSalineFurosemideZoledronic acidBisphosphonatesCalcium gluconateCalciumCalcitriolRelated Disciplines\nObstetricsPublication Details\nUnique/unexpected symptoms or presentations of a diseaseMarch2018\n==== Body\nBackground\nMany reports describe the association\n between primary hyperparathyroidism and pancreatitis (3); however, others (7) showed that the rate of acute pancreatitis was not increased in patients with primary hyperparathyroidism. In pregnancy, few cases of primary hyperparathyroidism complicated by pancreatitis and preeclampsia have been reported mainly in the third trimester and in the postpartum period (Table 1). Herein, we present the case of a 32-year-old pregnant woman presenting with an acute pancreatitis secondary to a parathyroid adenoma at the end of the first trimester, with total remission after parathyroidectomy.\nTable 1 Cases of hyperparathyroidism and pancreatitis in pregnancy.\n\nAuthors\tPMH\tGA\tPresenting signs and symptoms\tCa\tMaternal outcomes\tFetal outcomes\tSurgery\t\nHong et al. (1)\tNephrolithiasis 3 consecutives miscarriages in the previous 4 years IVF performed\t30 + 4 weeks\tSevere epigastric pain, vomiting, fever, tachypnea, tachycardia, elevated blood pressure\t17.9a\tARF intubation\tC-section 31 weeks + 3 days MV for 2 days transient hypocalcemia\tDay 6 PP\t\nKryslak et al. (2)\tReccurent miscarriages due to pancreatitis\t8th week\tAbdominal pain, nausea, vomiting, anorexia\t10.4a\tHypercalcemia (12.8a) nephrolithiasis hypotension\tSVD 38 weeks hypercalcemia (11.6a)\tNot done medical therapy: calcitonin\t\nLee et al. (3)\t1 spontaneous abortion\tPP\tAcute abdominal pain\t11.5a\tIA abcess due to pancreatitis hydronephrosis due to nephrolithiasis neurologic complications\tHealthy baby 37 weeks\t11 weeks PP\t\nLiu et al. (4)\tIrrelevant\t31 weeks\tNausea, vomiting, irritability, high blood pressure\t15.16a\tPreeclampsia hypercalcemic crisis (13.12a) pancreatitis PP\tC-section 31 weeks hypercalcemia (12.56a)\tPP\t\nDale et al. (5)\tIrrelevant\t32 weeks\tHigh blood pressure, scotomata epigastric pain\t9.9a\tPreeclampsia hypercalcemia (10.2a)\tC-section 32 weeks\tPP\t\nBurks et al. (6)\tIrrelevant\t11 weeks\tRefractory nausea vomiting\t12.6a\tWorsening symptoms hypercalcemia (14.1a)\tHealthy baby\t12 weeks of gestation\t\nPresent case\t4 years infertility IVF performed\t11 weeks\tEpigastric pain, nausea, vomiting\t12.35a\tRefractory hypercalcemia (12.74a)\tC-section 36 weeks healthy baby\t13 weeks of gestation\t\n\naTotal serum calcium in mg/dL (normal value: 8.5–10.5).\n\nARF, acute respiratory failure; Ca, calcium level; C-section, cesarean section; GA, gestational age; IA, intra-abdominal; MV, mechanical ventilation; PMH, past medical history; PP, postpartum; SVG, spontaneous vaginal delivery.\n\n\n\n\nCase presentation\nA 32-year-old lady, Gravida 1 Para 0, who underwent in vitro fertilization (IVF) because of unexplained infertility, presented at her 11th week of gestation for epigastric pain, nausea and bilious vomiting. She noted recurrent hospitalization for the same complaints even prior to her pregnancy. Past medical history was significant for chronic pruritic rash and nephrolithiasis, which has never been investigated.\n\nInvestigation\nLaboratory tests showed leukocytosis with a left shift (14900/µL with 80% neutrophils), alanine aminotransferase of 116 (normal range: 7–56 IU/L), aspartate aminotransferase of 60 (normal range: 5–40 IU/L), alkaline phosphatase of 140 IU/L (normal range: 44–147 IU/L), gamma-glutamyl transpeptidase of 62 (normal range: 9–48 IU/L), direct bilirubin of 0.48 (normal range <0.3 mg/dL), total bilirubin of 0.74 (normal range: 0.1–1.2 mg/dL) and elevated amylase and lipase: four to five times the upper limits of normal, 340 and 820 IU/L respectively (normal range for amylase: 10–120 IU/L and normal range for lipase: 13–60 IU/L).\n\nPancreatitis was diagnosed based on the clinical presentation and the laboratory findings. The patient was kept null per os (NPO) for few days, with pain control medications (meperidine 50 mg intravenous three times per day), intravenous fluids and total parenteral nutrition (oliclinomel N4 1 L per daily) at a later stage in order to maintain the caloric needs necessary for fetal growth. Lipase levels decreased to 600 IU/L after 48 h, then to 491 IU/L after 72 h.\n\nWhile investigating the etiology of pancreatitis, an ultrasound of her abdomen showed biliary sludge with no signs of cholecystitis and an endoscopic ultrasound confirmed the absence of common bile duct dilatation. However, her calcium level was found to be significantly elevated with a value of 12.35 mg/dL (normal range: 8.5–10.2 mg/dL) with a low serum phosphorus and magnesium levels, 2.03 mg/dL and 1.35 mg/dL respectively (normal phosphorus range: 2.5–4.5 mg/dL and normal magnesium range: 1.7–2.2 mg/dL). A 24-h urine calcium collection showed markedly elevated levels, 380 mg/day (normal range from 100 to 300 mg/day) with a urine volume of 4700 mL/24 h and urine creatinine of 658 mg (normal range: 600–2000 mg/24 h). Parathyroid hormone (PTH) level was elevated, 301.8 pg/mL (normal range: 10–65 pg/mL) with a low 25-hydroxyvitamin D level of 4.2 ng/mL (normal range: 20–50 ng/mL). Based on the above mentioned results, primary hyperparathyroidism was identified and resulting hypercalcemia was thought to be the culprit behind this patient’s pancreatitis.\n\nA neck ultrasound revealed no parathyroid lesions. A subsequent magnetic resonance imaging (MRI) of the neck was preferred over a sestamibi scan view the fetal radiation exposure risk associated with the latter. Neck MRI revealed a 2.8 × 1.7 × 1 cm oval-shaped homogenous high intensity lesion, just inferior to the right thyroid lobe consistent with a parathyroid adenoma (Figs 1, 2 and 3). Thus, a multidisciplinary decision involving the gynecology, endocrinology and surgery teams was undergone and the patient was advised to have a parathyroidectomy in her early second trimester, which is considered the safest period for surgery during pregnancy.Figure 1 Brain magnetic resonance imaging of anterior neck. T2-weighted imaging sagittal view with the arrow showing the parathyroid adenoma.\n\n\nFigure 2 Brain magnetic resonance imaging of anterior neck. T2-weighted imaging axial view with the arrow showing the parathyroid adenoma.\n\n\nFigure 3 Brain magnetic resonance imaging of anterior neck. T2-weighted imaging coronal view demonstrating an oval shape mass inferior to the right lobe of the thyroid consistent with an enlarged right inferior parathyroid adenoma.\n\n\n\n\nTreatment\nAt the same time, the initial target to reduce the patient’s serum calcium level failed despite various attempts using aggressive saline infusion (up to 4 L per day), furosemide (60 mg intravenous daily), calcitonin 4 IU/kg twice daily, later increased to 8 IU/kg three times daily. Moreover, and despite its potential adverse effects in pregnancy, zoledronic acid was administered at a dose of 4 mg intravenously after discussing its risks and benefits with the patient and view the refractory hypercalcemia, but calcium level remained elevated (Figure 4).Figure 4 Variation of calcium level pre and post parathyroidectomy.\n\n\n\n\nSo, an uneventful minimally invasive parathyroidectomy was performed after 14 days of diagnosis, with a subsequent significant intraoperative drop in PTH (from 1332 to 150 pg/mL) indicating adequate adenoma removal. Pathology confirmed the presence of a 2.8 × 1.6 × 1 cm right inferior parathyroid adenoma.\n\nOutcome and follow-up\nThe patient experienced a rapid resolution of her acute pancreatitis with improvement in her abdominal pain and pruritic rash. On postoperative day 3, the calcium level dropped to 8.45 mg/dL, phosphorus level to 1.2 mg/dL and magnesium level to 1.41 mg/dL suggesting hungry bone syndrome. Simultaneously, the patient started complaining of perioral and upper extremity numbness that resolved after 2 g of intravenous calcium gluconate. Thereafter, calcium 600 mg twice daily and calcitriol 1 µg daily were started. The patient was successfully discharged home on day 4 post parathyroidectomy and a one-week follow-up noted the absence of symptoms with a calcium level of 9.2 mg/dL and phosphorus level of 3.8 mg/dL. Calcium and calcitriol replacement were therefore discontinued.\n\nThe patient was closely monitored and after around 6 months (at 36 weeks of gestation), she had an uneventful delivery.\n\nDiscussion\nPrimary hyperparathyroidism causing hypercalcemia, while uncommon during pregnancy, is concerning and requires special care for mother and fetus to prevent problems such as nephrolithiasis, pancreatitis or hypercalcemic crisis and more importantly, major fetal complications such as hypocalcemia and tetany, preterm delivery and fetal demise even when pregnancy and delivery are uneventful (5, 8). Diagnosis is challenging, as symptoms may mimic other features observed frequently in pregnancy. Timely diagnosis and early intervention are crucial in this condition.\n\nPrimary hyperparathyroidism (PHPT) during pregnancy is thought to occur in less than 1% of cases. However, many authors agree that the actual number of cases in pregnancy is underestimated especially that gestational hyperparathyroidism (HPT) remains undiagnosed in a significant number of patients and is often suggested after numerous unexplained miscarriages (9). Despite its rarity, PHPT is the third most common endocrine disease in pregnancy (10) with up to 200 cases reported in the literature (11). Primary adenoma is the most common etiology of PHPT. The majority of patients (23–80%) are asymptomatic (8).\n\nThe diagnosis of primary hyperparathyroidism is very challenging due to the non-specificity of symptoms, the clinical similarities to other obstetrical diseases including hyperemesis gravidarum, the decrease in total calcium levels secondary to gestational hemodilution, increase in glomerular filtration rate leading to hypercalciuria and hypoalbuminemia, transplacental transfer of calcium and elevated estrogen levels in pregnancy (8). Moreover, clinicians have limited radiological options in pregnant women view the risk of fetal radiation which limits the use of sestamibi scan (5). Alternative imaging modalities have been suggested including the99m Tc-MIBI scan (12) and the cervical ultrasound (11).\n\nDecreased fertility in pregnant women with hyperparathyroidism is controversial. Primary hyperparathyroidism can lead to higher rates of fetal complications. The most serious outcomes include neonatal tetany secondary to hypocalcemia and suppression of the fetal parathyroid glands, still birth and respiratory failure in newborns (5, 8).\n\nOn the other hand, obstetrical complications of PHPT are usually uncommon because calcium levels are only mildly elevated in the majority of cases. However, significant calcium elevations can lead to pancreatitis. Hypercalcemic crisis can occur in the postpartum period because of the decreased shunting of calcium to fetus (8).\n\nNorman et al. reported a higher incidence of miscarriages (3.5-fold) in pregnant women with PHPT who did not undergo parathyroidectomy, whereas Abood and Vestergaard, and Hirsh and coworkers found no difference in the outcomes (10).\n\nAbood and Vestergaard also reported no increase in abortion rate and no need for parathyroidectomy but increased risk of delivery by cesarean section in mild PHPT-associated pregnancy. Weight and length birth, and Apgar score are usually not affected in mild PHPT (13). Miscarriages occur most commonly between week 10 and 15, in patients with calcium levels exceeding 11.4 mg/dL and with history of previous miscarriages (9). Women diagnosed with hyperparathyroidism during pregnancy can report one or more miscarriages that can go unnoticed if calcium levels are not alarming.\n\nAcute pancreatitis in pregnancy is also rare with an incidence ranging between 0.02 and 0.1% (5).\n\nGallstone is the most common cause in pregnancy, due to weight and hormonal effects. A second scenario in pregnancy is hypertriglyceride-induced pancreatitis due to high fat levels, increased estrogen and familial tendency (14).\n\nAcute pancreatitis, as well as gallstone disease, occurs more frequently in the third trimester with advanced gestational age (15).\n\nIn addition, primary hyperparathyroidism is rarely a cause of acute or chronic pancreatitis with a prevalence of 3.6% (7).\n\nThe frequency of acute pancreatitis is much higher in pregnant women with hyperparathyroidism (7–13%) than in non-pregnant ones. It is assumed that it is more common in primiparas and mainly in the first and third trimester (2).\n\nIn small subset of patients, primary hyperparathyroidism can be attributed to radiation exposure or to rare genetic abnormalities, mainly MEN-1, MEN-2, familial parathyroid hyperplasia syndromes or jaw-tumor syndrome, especially in young population. Somatic loss of one MEN1 allele results in altered menin protein, which is a tumor suppressor, leading to the formation of adenoma involving one or more parathyroid glands. CDC73 mutations result in decreased parafibromin protein activity, which also acts as a tumor suppressor, leading to the development of adenoma or rarely carcinoma. Cyclin D1 overexpression is seen in adenoma and parathyroid hyperplasia. CaSR and other mutations have also been identified (16). Thus, genetic disease may have consequences on surgical therapy.\n\nManagement of PHPT in pregnancy is individualized according to symptoms, severity of hypercalcemia and gestational age (8). Early recognition and management reduce the complications, especially when diagnosis is established early in pregnancy. Mild hypercalcemia in pregnancy can be safely monitored, as compared to moderate and severe hypercalcemia (12).\n\nManagement is similar in pregnant and non-pregnant patients and consists on initial aggressive saline infusion. If needed, many medications can be used. Calcitonin, a category B drug, lowers calcium by inhibiting osteoclast formation. It is a relatively weak agent that rapidly lowers calcium concentration by a maximum of 1–2 mg/dL with an onset of action of 4–6 h. Its major adverse effect is tachyphylaxis. The efficacy of calcitonin is limited to the first 48 h of diagnosis even with repeated doses. Calcitonin does not cross the placenta and has been safely used in pregnancy. However animal studies showed that high doses of calcitonin may induce low birth weight in offsprings (2).\n\nFurosemide, category C medication, is mainly used to promote calciuresis.\n\nCinacalcet activates calcium-sensing receptors (CaSR) on parathyroid cells, C-cells of the thyroid, and renal distal tubular cells, thus reduces PTH, increases calcitonin release and decreases renal calcium reabsorption. However, its efficacy on the mother and fetus are still lacking. This drug is considered category C. CaSR are present in the placenta; therefore, cinacalcet inhibits active placental calcium transport. Multiple studies suggested adverse effects secondary to its use. Cinacalcet suppresses fetal PTH and can induce neonatal hypocalcemia (12).\n\nBisphosphonates, considered category C drugs, act by decreasing bone resorption. Their optimal benefit is reached 2–4 days after administration; therefore, they should be given in combination with calcitonin. They are the most potent drug category, but their use should be limited to emergent cases when their benefits outweigh their risks, to patients requiring short-term therapy and to those with severe hypercalcemia prior to surgery (17). Bisphosphonates are known to affect fetal bone development.\n\nOral phosphates, labeled as pregnancy category C medication, promote urinary calcium excretion but carry a risk of soft tissue calcifications and diarrhea.\n\nIn addition, management of severe hypercalcemia may require hemodialysis and in refractory cases, parathyroidectomy (8).\n\nIn pregnant patients, special attention is given to the potential complications of treatment and its adverse effects on women and fetuses. Thus, surgical approach remains the safest therapeutic option, preferably performed before pregnancy. During pregnancy, parathyroidectomy is recommended in the second trimester when anesthesia and surgical techniques are relatively safe and fetal organogenesis is complete (9). Anesthesia during parathyroidectomy in the first and third trimesters may lead to spontaneous abortion and premature delivery respectively (11).\n\nOur patient is a good example; she improved dramatically after parathyroidectomy with total amelioration of her abdominal pain, rash, pancreatitis and hypercalcemia.\n\nA major consideration after successful parathyroidectomy is hungry bone syndrome. The incidence of this syndrome during pregnancy is still unknown. Large size of parathyroid adenomas, high preoperative levels of blood urea nitrogen and alkaline phosphatase and old age are important risk factors for the development of hungry bone syndrome.\n\nConclusion\nPrimary hyperparathyroidism is a rare devastating event during pregnancy. Diagnosis can be challenging, and complications may be life threatening. A well-organized multidisciplinary approach is recommended to prevent adverse outcomes in woman and fetus.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nWritten informed consent has been obtained from the patient for publication of the submitted article and accompanying images.\n\nAuthor contribution statement\nDr Carine Ghassan Richa:wrote this article; Dr Mohamad Souheil EL Rawas : patient's physician,, revised critically this manuscript and gave final approval of the version;Dr Khadija Jamal Saad: participated in drafting this manuscript; Dr Ali Khaled Chaaban: contributed to diagnostic imaging.\n==== Refs\nReferences\n1 Hong MK Hsieh CT Chen BH Tu ST Chou PH \nPrimary hyperparathyroidism and acute pancreatitis during the third trimester of pregnancy . Journal of Maternal-fetal Medicine \n2001 \n10 \n214 –218 . (10.1080/jmf.10.3.214.218 )11444793 \n2 Krysiak R Wilk M Okopien B \nRecurrent pancreatitis induced by hyperparathyroidism in pregnancy . Archives of Gynecology and Obstetrics \n2011 \n284 \n531 –534 . (10.1007/s00404-010-1668-x )20848117 \n3 Lee CC Chao AS Chang YL Peng HH Wang TH Chao A \nAcute pancreatitis secondary to primary hyperparathyroidism in a postpartum patient: a case report and literature review. \nTaiwanese Journal of Obstetrics and Gynecology \n2014 \n53 \n252 –255 . (10.1016/j.tjog.2013.01.029 )25017280 \n4 Liu Y Wang J-N Huang Y Zhu Y-H Liu R-L Xu C-F Li X \nAcute pancreatitis and preeclampsia induced by parathyroid sdenoma in pregnancy: a case report and literature review . International Journal of Clinical and Experimental Medicine \n2016 \n9 \n22652 –22655 .\n5 Dale A Holbrook BD Sobel L Rappaport VJ \nHyperparathyroidism in pregnancy leading to pancreatitis and preeclampsia with severe features . Case Reports in Obstetrics and Gynecology \n2017 \n2017 \n1 –3 . (10.1155/2017/6061313 )\n6 Burks M Harary S Solorzano CC Bao S \nPrimary hyperparathyroidism in a first-trimester woman with hyperemesis gravidarum and pancreatitis . AACE Clinical Case Reports \n2017 \n3 \ne31 –e34 . (10.4158/EP151136.CR )\n7 Khoo T Vege SS Abu-Lebdeh HS Ryu E Nadeem S Wermers RA \nAcute pancreatitis in primary hyperparathyroidism: a population-based study . Journal of Clinical Endocrinology and Metabolism \n2009 \n94 \n2115 –2118 . (10.1210/jc.2008-1965 )19318456 \n8 Malekar-Raikar S Sinnott BP \nPrimary hyperparathyroidism in pregnancy – a rare cause of life-threatening hypercalcemia: case report and literature review . Case Reports in Endocrinology \n2011 \n2011 \n1 –6 . (10.1155/2011/520516 )\n9 Norman J Politz D Politz L \nHyperparathyroidism during pregnancy and the effect of rising calcium on pregnancy loss: a call for earlier intervention . Clinical Endocrinology \n2009 \n71 \n104 –109 . (10.1111/j.1365-2265.2008.03495.x )19138316 \n10 Hirsch D Kopel V Nadler V Levy S Toledano Y Tsvetov G \nPregnancy outcomes in women with primary hyperparathyroidism . Journal of Clinical Endocrinology and Metabolism \n2015 \n100 \n2115 –2122 . (10.1210/jc.2015-1110 )25751112 \n11 Rchachi M , et al\nPrimary hyperparathyroidism in pregnancy – a review . Annals of African Medicine \n2017 \n16 \n145 –147 . (10.4103/aam.aam_61_16 )28671157 \n12 Rubin M Silverberg SJ \nUse of cinacalcet and 99mTc-sestamibi imaging during pregnancy . Journal of the Endocrine Society \n2017 \n9 \n1156 –1159 . (10.1210/js.2017-00308 )\n13 Aboud A Vestergaard P \nPregnancy outcomes in women with primary hyperparathyroidism . European Journal of Endocrinology \n2014 \n171 \n69 –76 . (10.1530/EJE-13-0966 )24743398 \n14 Pitchumoni C Yegneswaran B \nAcute pancreatitis in pregnancy . World Journal of Gastroenterology \n2009 \n15 \n5641 –5646 . (10.3748/wjg.15.5641 )19960559 \n15 Abdullah B Kathiresan Pillai T Huay Cheen L Joshua Ryan R \nCase report severe acute pancreatitis in pregnancy . Case Reports in Obstetrics and Gynecology \n2015 \n2015 \n1 –4 . (10.1155/2015/239068 )\n16 Familial isolated hyperparathyroidism . Genetics Home Reference \n2018 \n1 –6 .\n17 Gokkaya N Gungor A Bilen A Bilen H Gviniashvili D Karadeniz Y \nPrimary hyperparathyroidism in pregnancy: a case series and literature review . Gynecological Endocrinology \n2016 \n32 \n783 –786 . (10.1080/09513590.2016.1188916 )27243597\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2052-0573", "issue": "2018()", "journal": "Endocrinology, diabetes & metabolism case reports", "keywords": "2018; 25-hydroxyvitamin-D3; Abdominal pain; Alanine aminotransferase; Amylase; Bilirubin; Bisphosphonates; Bone; Calcitonin; Calcitriol; Calcium; Calcium (serum); Calcium (urine); Calcium gluconate; Creatinine; Endoscopic ultrasound; Female; Fluid repletion; Furosemide; Histopathology; Hypercalcaemia; Hyperparathyroidism (primary); Kidney stones; Lebanon; Leukocytosis; Lipase (serum); MRI; Magnesium; March; Nausea; Obstetrics; PTH; Pancreatitis; Paraesthesia; Parathyroid; Parathyroid adenoma; Parathyroidectomy; Phosphate (serum); Pregnant adult; Pruritus; Saline; Ultrasound scan; Unique/unexpected symptoms or presentations of a disease; Urine 24-hour volume; Vomiting; White; Zoledronic acid", "medline_ta": "Endocrinol Diabetes Metab Case Rep", "mesh_terms": null, "nlm_unique_id": "101618943", "other_id": null, "pages": null, "pmc": null, "pmid": "29623207", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": "11444793;19138316;19318456;19960559;20848117;22937284;24743398;25017280;25628906;25751112;27243597;28487796;28671157;29264570", "title": "A rare case of hypercalcemia-induced pancreatitis in a first trimester pregnant woman.", "title_normalized": "a rare case of hypercalcemia induced pancreatitis in a first trimester pregnant woman" }	[ { "companynumb": "PHHY2019LB012741", "fulfillexpeditecriteria": "1", "occurcountry": "LB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CALCITONIN SALMON" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE: 4 IU/KG, BID AND THEN INCREASED 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{ "abstract": "Tacrolimus is a commonly used immunosuppressant medication after lung transplantation. In rare cases, tacrolimus causes a medication-induced optic neuropathy (TON) that can lead to significant vision loss.\nIn this series, we describe three cases of TON, 1-10 years after medication use. Two patients were young (22yr and 33yr) females with cystic fibrosis. The last case was a 65yr male with idiopathic pulmonary fibrosis. In 2/3 cases tacrolimus serum levels were normal. Visual acuity ranged from 20/20 to 20/300, and vision loss occurred acutely to sub-acutely, over a span of 2-3 months.\nAs presented here, TON can be highly variable. MRI findings are often non-specific, from normal brain findings to extensive white matter changes. There remains an unclear association with graft-versus-host disease and reduced kidney function. Visual findings are often subtle, including color vision aberration and peripheral visual field deficits, both of which usually require an ophthalmologic evaluation. When diagnosed in a timely fashion, TON is at least partially reversible in up to half of all cases. While rare, the cases described here support post-lung transplant ophthalmologic evaluation in those taking high-risk medications.", "affiliations": "Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY, United States.;Department of Neuro-Ophthalmology, University of California, San Francisco, CA, United States.;Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY, United States.", "authors": "Nanda\|Tavish\|T\|;Rasool\|Nailyn\|N\|;Bearelly\|Srilaxmi\|S\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.ajoc.2021.101056", "fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936\nElsevier\n\nS2451-9936(21)00047-5\n10.1016/j.ajoc.2021.101056\n101056\nCase Report\nTacrolimus induced optic neuropathy in post-lung transplant patients: A series of 3 patients\nNanda Tavish [email protected]\na∗\nRasool Nailyn b\nBearelly Srilaxmi a\na Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY, United States\nb Department of Neuro-Ophthalmology, University of California, San Francisco, CA, United States\n∗ Corresponding author. 635 W 165th St, New York, NY, 10032, United States. [email protected]\n11 3 2021\n6 2021\n11 3 2021\n22 10105617 7 2020\n21 2 2021\n© 2021 Published by Elsevier Inc.\n2021\n\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPurpose\n\nTacrolimus is a commonly used immunosuppressant medication after lung transplantation. In rare cases, tacrolimus causes a medication-induced optic neuropathy (TON) that can lead to significant vision loss.\n\nObservations\n\nIn this series, we describe three cases of TON, 1–10 years after medication use. Two patients were young (22yr and 33yr) females with cystic fibrosis. The last case was a 65yr male with idiopathic pulmonary fibrosis. In 2/3 cases tacrolimus serum levels were normal. Visual acuity ranged from 20/20 to 20/300, and vision loss occurred acutely to sub-acutely, over a span of 2–3 months.\n\nConclusions and importance\n\nAs presented here, TON can be highly variable. MRI findings are often non-specific, from normal brain findings to extensive white matter changes. There remains an unclear association with graft-versus-host disease and reduced kidney function. Visual findings are often subtle, including color vision aberration and peripheral visual field deficits, both of which usually require an ophthalmologic evaluation. When diagnosed in a timely fashion, TON is at least partially reversible in up to half of all cases. While rare, the cases described here support post-lung transplant ophthalmologic evaluation in those taking high-risk medications.\n\nKeywords\n\nTacrolimus\nOptic neuropathy\nLung transplant\nNeuro-ophthalmology\nToxicity\nOphthalmologic examination\nAbbreviations\n\nACR, acute cellular rejection\nAKI, acute kidney injury\nCNS, central nervous system\nCr, creatinine\nCT, computed tomography\nFLAIR, fluid attenuated inversion recovery\nGVHD, graft versus host disease\nJC, John Cunningham\nMRI, magnetic resonance imaging\nOCT, optical coherence topography\nPET, positron emission tomography\nPRES, posterior reversable encephalopathy syndrome\nTON, tacrolimus optic neuropathy\nVZV, varicella zoster virus\n==== Body\nIntroduction\n\nSince its approval in 1997 tacrolimus is now used in upwards of 93% of all post-lung transplant patients for maintenance immunosuppression.1 Tacrolimus induced optic neuropathy (TON) remains an extremely rare and elusive diagnosis, with only 13 cases published in the literature.2 Due to its infrequency, it remains a diagnosis of exclusion, after infectious, inflammatory, and neoplastic causes are evaluated. In many cases, the diagnosis remains presumptive. The exact mechanism remains unclear. Some authors support the possibility of an ischemic process, with two studies finding a delay or absence in vascular circulation on fluorescein angiography.3, 4, 5, 6, 7, 8 In contrast, biopsy of the optic nerve has demonstrated extensive demyelination without ischemic insult, and cortical cultures have shown direct oligodendritic toxicity and death.9,10 TON is likely distinct from cyclosporine-induced optic neuropathy, as patients who have been switched to cyclosporine due to suspected TON have demonstrated visual improvement.6\n\nClinically, TON usually presents as a slow reduction in visual acuity, progressive visual field deficits, and/or dyschromatopsia, though acute changes have also been described. MRI can show optic nerve and other white matter lesions, even in the context of normal tacrolimus levels.9,11 While tacrolimus can also affect the visual system from posterior involvement of the visual tracts or occipital lobes, due to tacrolimus-induced posterior reversible encephalopathy syndrome (PRES), TON is usually associated with optic nerve edema or pallor.2 Through an institutional review board-approved process (AAAS6456), we reviewed all post-lung transplant inpatient consults performed at our institution between 2014 and 2019. Of 65 consultations, 3 patients were found to have tacrolimus-induced optic neuropathy. This report does not contain any personal information that could lead to the identification of these 3 patients.\n\nFindings\n\nCase 1\n\nA 33-year-old female with a past medical history of diabetes and cystic fibrosis, status post double lung transplant 11 years prior, presented to the neurology service for non-specific headache, vision loss (blurriness, darkness, loss of peripheral vision), weakness, and lethargy. She had several prior admissions for headache, neck pain, and subjective fever. During these admissions, repeat lumbar punctures, along with extensive encephalitis panels, were unremarkable. A previous MRI, however, demonstrated new T2/FLAIR abnormalities along the optic chiasm and proximal optic tracts, hypothalamus, and cerebellum. Based on these findings her tacrolimus dose of 0.5mg/day was discontinued, even though she had remained within therapeutic range (5–20ng/ml). Her creatinine (Cr) function at that time was consistent with acute kidney injury (AKI) of 2.51.\n\n3 months later, on presentation to our institution, she reported continued worsening of her visual symptoms over the course of 2–3 months. On exam, her visual acuity was 20/300 in the right eye and 20/200 in the left eye. She had severe dyschromatopsia on Hardy-Rand-Rittler color plates (0/12 in both eyes). A 24–2 visual field (Fig. 1) demonstrated poor reliability, but suggested bitemporal field loss with significant field constriction. Dilated fundus examination was notable for optic nerve pallor and atrophy. This was confirmed on optical coherence tomography (OCT), which demonstrated diffuse ganglion cell layer loss.Fig. 1 Bitemporal hemianopsia on an automated 24–2 visual field in Case 1.\n\nLegend: Left = Right Eye, Right = Left Eye. Black and grey are regions of reduced sensitivity to visual stimuli when compared to normative data. Note the right worse than left visual field deficits. This visual field demonstrates an incongruent bitemporal hemianopsia with additional infero-nasal deficits in both eyes.\n\nFig. 1\n\nDuring this admission she was diagnosed and treated for a superficial cellulitis of the hand, which improved after intravenous vancomycin. A broader infectious examination - including coccidiomycosis, syphilis, tuberculosis, John Cunningham virus, cytomegalovirus, and bartonella - was negative. Inflammatory and neoplastic evaluation, including a PET scan, were unremarkable. Kidney function improved from her prior admissions (Cr of 1.50) and she underwent a repeat brain, orbit, and spinal MRI. Her MRI abnormalities remained unchanged, with persistent hyperintensity of the optic chiasm (Fig. 2). Her visual symptoms, which persisted after treatment of her cellulitis, along with her neuroradiologic findings, were deemed most consistent with a severe and atypical tacrolimus-induced toxicity.Fig. 2 FLAIR hyperintensity of the optic chiasm in Case 1.\n\nLegend: Left = an axial image with hyperintensity (arrow) over the optic chiasm consistent with TON. Right = a coronal image highlighting the same persistent hyperintensity (arrow).\n\nFig. 2\n\nCase 2\n\nA 65-year-old male with a history of idiopathic pulmonary fibrosis complicated by pulmonary hypertension, underwent a single left lung transplantation 2 years prior to admission. His immediate post-transplant course was complicated by cryptococcal meningitis, which resolved after treatment, with no residual deficits. His immunosuppressive regimen included tacrolimus at an alternating dose of 0.5mg and 0.25mg twice a day, prednisone 10mg daily, and cellcept 500mg three times a day. On admission, he presented with an acute change in mental status and slurring of speech and was found to have maculopapular lesions respecting the midline, consistent with varicella zoster virus (VZV) in the trigeminal V1 distribution.\n\nAt the time the patient also complained of blurry vision in his left eye, which warranted an ophthalmology consultation. On exam, vision was 20/50 in both eyes and was otherwise unremarkable, notable only for tilted optic discs, a benign finding. CT imaging was negative for stroke, but a lumbar puncture was VZV polymerase chain reaction positive, confirming CNS involvement. MRI brain revealed diffuse pachymeningeal enhancement. His titers resolved on intravenous anti-viral treatment with acyclovir, yet he remained lethargic and deconditioned. On treatment, he had a persistently mild AKI (Cr of 1.30–1.60). After several weeks, his condition improved and the patient returned to baseline.\n\nOne month later, however, he was reexamined for a subjective worsening of vision, now in the right eye. At this point, there was a decrease in right eye vision, from 20/50 to 20/70, a new right afferent pupillary defect, and a new temporal visual field deficit. Optic nerve exam demonstrated newfound pallor in both eyes, consistent with a sub-acute to chronic process. Color vision was reduced on Ishihara color plates, 1.5/14 right eye and 11.5/14 left eye. Optic nerve atrophy was confirmed on OCT, which demonstrated diffuse, asymmetric, nerve fiber layer loss (right > left) (Fig. 3). There was no evidence of vasculitis, or any MRI findings suggestive of leptomeningeal spread involving the optic nerves. Systemic infectious work-up remained negative and metabolic causes such as folate or vitamin B12 deficiency were excluded. Kidney function had normalized with fluid management, Cr 1.10–1.20, while being maintained on intravenous acyclovir 500mg twice a day. The interdisciplinary teams agreed that these findings were most consistent with TON, and his tacrolimus dosing was discontinued.Fig. 3 Macular thickness on optical coherence tomography in Case 2.\n\nLegend: Optical coherence tomography provides a detailed view of each layer of the retina. A thin retina is noted by the ‘red’ values in the two quantitative circles, when compared to normative data. While the right eye is off-center (see top box, left side), a qualitative assessment of the retinal layers in the images provided are consistent with retinal nerve fiber layer loss, which occurs in tacrolimus-induced nerve damage. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 3\n\nCase 3\n\nA 23-year-old female with cystic fibrosis, status post bilateral lung transplant one-year prior, was transferred to our medical intensive care unit due to acute on chronic respiratory failure. Prior to admission, her home dose of tacrolimus was 0.5mg daily and prednisone 10mg daily. On admission, she was intubated for acute respiratory distress syndrome. Infectious work up (including bronchoalveolar lavage cultures) remained negative, prompting a diagnosis of acute cellular rejection (ACR). Her tacrolimus level rose from 17 to 53 ng/ml acutely and was held. Of note, she'd had a prior admission one year ago for acute tacrolimus toxicity resulting in AKI, which had resolved. Creatinine on this admission was 2.37, consistent with AKI.\n\nShe was treated with pulse dose steroids, intravenous immunoglobulin and plasma exchange, and Thymoglobulin with eventual clinical improvement. She was extubated 5 days later. At one month, she reported a new right temporal visual field deficit. On exam, vision was 20/20 in both eyes. Visual field was full (Fig. 4A–B). Her dilated exam demonstrated temporal nerve pallor in the right eye and diffuse optic atrophy in the left eye. This was confirmed on optical coherence tomography, which demonstrated asymmetric nerve loss (left > right) and appeared consistent with TON (Fig. 4C–D).Fig. 4 24–2 visual fields and optical coherence tomography in Case 3.\n\nLegend: Panel A–B demonstrates a normal right and left visual field. This would not capture any far temporal peripheral field deficits, since a 24-2 measures only the central 24° of the visual field. In Panel C are quantitative measures of optic nerve health. The left eye (OS) is in red, indicating nerve fiber layer loss. While the left eye was convoluted by artifact (black components of the top right picture), thinning is further confirmed in Panel D which demonstrates a reduced average thickness of the macula. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 4\n\nShe was scheduled for a wider visual field test (Goldmann) to assess for far temporal visual field deficits but developed bifrontal seizures and altered mental status requiring admission to the neuro-intensive care unit. MRI brain demonstrated white matter changes consistent with PRES. Tacrolimus was discontinued with eventual improvement in both her symptoms and brain lesions. She remained hospitalized for another month due to the re-development of ACR requiring further medication management. She was subsequently discharged home on cyclosporine 375mg twice a day and oral prednisone 50mg daily, after a 3-month hospital stay.\n\nDiscussion\n\nThe diagnosis of tacrolimus induced optic neuropathy is clinically challenging. Previous cases report the development of TON anywhere from 2 months to 5 years after initiation.2 Toxicity usually occurs at a plasma level >20 ng/ml but can occur at normal or even sub-therapeutic levels (Table 1).12 Vision loss can be sudden, over a few days, or gradual (>1 year). Like the cases described herein, in which one patient maintained 20/20 vision while another declined to the 20/200–300 range, prior studies have reported 20/20 to light perception vision. Usually, TON is a bilateral process, but can affect one optic nerve prior to the other, as with case 2.2 Similar to case 1, visual deterioration can continue, even after tacrolimus discontinuation.5Table 1 Published Cases of Tacrolimus-Induced Optic Neuropathy (including the present study).\n\nTable 1Source\tAge/Sex\tDuration\tDose\tPlasma Level\tOnset\tVisual Acuity\tColor Vision\tVisual Field\tPupils\tEye\tTransplant\t\nBrazis et al., 2000\t58/M\t2mo\t4mg QD\tNR\t~3mo\tOD: 20/20\nOS: 20/100\tOD: 9.5/10\nOS: 3/10\tOD: Superior arcuate\nOS: Infero-altitudinal\tLeft APD\tOU\tLiver\t\nVenneti et al., 2010\t63/M\t5yr\tNR\t8.8 μg/L\t~2mo\tOD: 20/70\nOS: HM\tReduced\tOD: Inferonasal\nOS: Unable\tSluggish\tOU\tRenal\t\nLake et al., 2003\t38/M\tNR\t4mg QD\tNR\t~12mo\tOD: 3/60\nOD: 2/60\tNR\tOD: Normal\nOS: Normal\tNo APD\tOU\tPancreas\t\nAscaso et al., 2012\t56/F\t6mo\t1.5mg QD\t1.9 ng/ml\tSudden\tOD: 20/20\nOS: LP\tOS: None\tNR\tLeft APD\tOS\tLiver\t\nAkers et al., 2009\t47/F\tNR\tNR\t5.7ng/ml\t~4 days\tOD: 20/25\nOS: 20/40\tOD: 5/10\nOS: 1/10\tOD: Normal\nOS: Inferonasal\tNR\tOS\tRenal\t\nCanovai et al., 2019\t51/M\t3.5yr\t2mg BID\t4.4 μg/L\t~2wks\tOD: CF\nOS: CF\tNR\tOD: Central scotoma\nOS: Central scotoma\tNo APD\tOU\tMulti-visceral\t\nShao et al., 2012\t30/M\t3mo\tNR\t13.9ng/ml\t~5 days\tOD: HM\nOS: HM\tNR\tNR\tSluggish\nNo APD\tOU\tSmall Bowel\t\nYun et al., 2010\t54/M\t6mo\t2.5mg BID\t6.2mg/L\t~3mo\tOD: CF\nOS: CF\tNR\tOD: Cecocentral scotoma\nOS: Cecocentral scotoma\tLeft APD\tOS\tLiver\t\nKessler et al., 2006\t51/F\t5mo\t2mg QD\t12.9ng/ml\t“gradual”\tOD: 20/100\tNR\tNR\tNR\tOD\tPancreas\t\nGupta et al., 2012\t35/F\t2yr\t1mg BID\tNR\t~2wks\tOD: 6/6\nOS: 6/6\tNR\tOD: Normal\nOS: Inferonasal\tLeft APD\tOS\tNephrotic Syndrome\t\nRasool et al., 2018\t55/M\t4yr\t2mg BID\t8ng/ml\t~ few days\tOD: 20/200\nOS: 20/25\tOD: Normal\nOS: Reduced\tOD: Diffuse depression\nOS: Superior/Inferior nasal\tRight APD\tOU\tBMT\t\nRasool et al., 2018\t66/M\t5yr\t0.5mg BID\t10ng/ml\t~3mo\tOD: 20/25\nOS: 20/100\tOD: Reduced\nOS: Reduced\tOD: Temporal-inferior\nOS: Inferior arcuate\tNo APD\tOU\tPBSCT\t\nRasool et al., 2018\t63/M\t4mo\t0.5mg QD\t5ng/ml\t~3 days\tOD: 20/20\nOS: 20/50\tOD: NR\nOS: Reduced\tOD: Diffuse\nOS: Nasal loss\tLeft APD\tOU\tBMT\t\nCurrent Study\t33/F\t10yr\t0.5mg QD\t12.2ng/ml\t~2–3mo\tOD: 20/300\nOS: 20/200\tOD: 0/12\nOS: 0/12\tOD: Temporal field loss\nOS: Temporal field loss\tNo APD\tOU\tLung\t\nCurrent Study\t65/M\t2yr\t0.5mg/0.25mg BID\t8.3ng/ml\t~few days\tOD: 20/50\nOS: 20/50\tOD: 1.5/14\nOS: 11.5/14\tOD: Temporal defect\nOS: Normal\tRight APD\tOU\tLung\t\nCurrent Study\t23/F\t1yr\t0.5mg QD\t53ng/ml\tSudden\tOD: 20/20\nOS: 20/20\tOD: 6/6\nOS: 6/6\tOD: Normal\nOS: Normal\tNo APD\tOU\tLung\t\n\nMRI findings also vary considerably between patients, from extensive white matter changes to normal brain findings.2 Only 35.7% of patients with neurologic symptoms from tacrolimus have white matter abnormalities. Isolated cases of brain stem involvement have also been reported.13,14 In one study, 2/5 patients with tacrolimus toxicity had no reversal of white matter abnormalities upon discontinuation, even in the context of clinical improvement.15 This appears similar to case 1 in which white matter lesions persisted after medication discontinuation.\n\nTacrolimus, even after its metabolism by the liver, can maintain biologic activity. Combined with a wide range in half-life (3.5–40.5 hours), normal plasma levels may not accurately reflect a patient's tacrolimus burden.14,16 Studies have also found different genetic predispositions to drug pharmacokinetics that may increase susceptibility to CNS penetration, and presumably, optic nerve damage.17 One case series suggested that transient breakdown in the blood-brain barrier due to graft-versus-host disease (GVHD) may also allow for increased CNS penetration.2 This concept has been previously considered in other instances of rare medication toxicity, such as eye-drop induced visual hallucinations.18 GVHD is also known to reduce tacrolimus clearance by 20% due to hepatic dysfunction and by 40% from acute kidney injury in patients post hematopoietic transplantation.10 The second case in this series was diagnosed with VZV meningitis, which can also result in blood brain barrier disruption. This mechanism may be fundamentally similar to that of GVHD.19 Case 3 was particularly interestingly due to the subsequent development of PRES after a diagnosis of TON. Shao et al. describes a similar case, in which TON pre-dated the development of PRES.8 TON may be an early sign of vascular dysregulation and blood brain barrier dysfunction, and suggestive of impending posterior involvement.\n\nCase 3 was also convoluted by a history of significant nephrotoxicity and elevated serum tacrolimus level on presentation. The relationship between tacrolimus toxicity and renal function remains unclear, as tacrolimus is not cleared by the kidney. However, several studies have suggested an association between rising creatinine levels and the subsequent development of TON, even with AKI that occurs months prior to symptom development.2 While the other two cases did not present with elevated serum levels or significant nephrotoxicity, both had transient AKI, prior to or during the development of visual symptoms.\n\nConclusions\n\nTo our knowledge, this is the first series to report TON in lung transplant recipients (Table 1). These three cases occurred out of 65 consults, suggesting a higher incidence than expected. Our tertiary care center, however, may be biased towards a higher degree of comorbidity amongst the post-transplant population. Risk stratification is hampered by a wide range of reported doses, duration of use, and normalcy of plasma levels (Table 1). Unlike haemopoietic stem cell transplantation, there are no set guidelines for routine post-lung transplant ophthalmology follow-up.20 In the context of several other medical concerns, continued ophthalmologic follow-up after discharge is likely overlooked by the primary team. This series emphasizes the need for lung transplant services to consider establishing guidelines for outpatient post-transplant ophthalmic follow-up. Due to the presumptive nature of a TON diagnosis, there is likely a subset of patients who remain undiagnosed due to the subtle nature of some early cases, which require a more specialized ophthalmologic approach, including serial color vision and visual field testing. TON may be reversible in ~50% of cases with appropriate care, and immediate discontinuation is necessary to prevent continued visual decline, further highlighting the importance of early detection.2\n\nPatient consent\n\nAs per institutional review board approval, written consent to publish this case series was not required. This report does not contain any personal identifying information.\n\nFunding\n\nThe New York Community Trust--Frederick J and Theresa Dow Wallace Fund, Columbia University (S.B.).\n\nAuthorship\n\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nDeclaration of competing interest\n\nThe following authors have no financial disclosures: TN, NR, SB.\n\nAcknowledgements\n\nNone.\n==== Refs\nReferences\n\n1 Adult lung transplantation statistics Available from: http://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry 2016\n2 Rasool N. Boudreault K. Lessell S. 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Heterogeneity of radiological spectrum in tacrolimus-associated encephalopathy after lung transplantation Behav Neurol 2014 2014\n14 Saadi A. Schmahmann J.D. Pearls & Oy-sters: tacrolimus neurotoxicity presenting as an isolated brainstem lesion Neurology 86 11 2016 Mar 15 e109 e111 26976521\n15 Appignani B.A. Bhadelia R.A. Blacklow S.C. Neuroimaging findings in patients on immunosuppressive therapy: experience with tacrolimus toxicity AJR Am J Roentgenol 166 3 1996 Mar 683 688 8623651\n16 Jain A.B. Abu‐Elmagd K. Abdallah H. Pharmacokinetics of FK506 in liver transplant recipients after continuous intravenous infusion J Clin Pharmacol 33 7 1993 Jul 606 611 7690047\n17 Yamauchi A. Ieiri I. Kataoka Y. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene Transplantation 74 4 2002 Aug 27 571 572 12352921\n18 Nanda T. Rasool N. Callahan A.B. Ophthalmic timolol hallucinations: a case series and review of the literature J Glaucoma 26 9 2017 Sep 1 e214 e216 28671925\n19 Hoyer C. Eisele P. Ebert A.D. Blood-CSF-barrier dysfunction is a marker for encephalitic involvement in patients with aseptic meningitis/meningoencephalitis J Clin Virol 84 2016 Nov 1 82 86 27736668\n20 Majhail N.S. Rizzo J.D. Lee S.J. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation Hemtol Oncol Stem Cell Ther 5 1 2012 Jan 1 1 30\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2451-9936", "issue": "22()", "journal": "American journal of ophthalmology case reports", "keywords": "ACR, acute cellular rejection; AKI, acute kidney injury; CNS, central nervous system; CT, computed tomography; Cr, creatinine; FLAIR, fluid attenuated inversion recovery; GVHD, graft versus host disease; JC, John Cunningham; Lung transplant; MRI, magnetic resonance imaging; Neuro-ophthalmology; OCT, optical coherence topography; Ophthalmologic examination; Optic neuropathy; PET, positron emission tomography; PRES, posterior reversable encephalopathy syndrome; TON, tacrolimus optic neuropathy; Tacrolimus; Toxicity; VZV, varicella zoster virus", "medline_ta": "Am J Ophthalmol Case Rep", "mesh_terms": null, "nlm_unique_id": "101679941", "other_id": null, "pages": "101056", "pmc": null, "pmid": "33778180", "pubdate": "2021-06", "publication_types": "D002363:Case Reports", "references": "23128973;21112060;20559109;1514776;7690047;11781626;8957016;20151288;2977135;22446607;28671925;10764869;27736668;8623651;24970980;26976521;12352921;18987109;29420328", "title": "Tacrolimus induced optic neuropathy in post-lung transplant patients: A series of 3 patients.", "title_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients" }	[ { "companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP004228", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. 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TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. 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TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021?22:1?6. 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TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. 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TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:ARTICLE NUMBER 101056. 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"reactionoutcome": "6" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS.. 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TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021?22:101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210420", "receivedate": "20210420", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19157708, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "NVSC2021US076868", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "2", "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": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22(10105):1?6", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210407", "receivedate": "20210407", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19103856, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP004230", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S.. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM?J?OPHTHALMOL?CASE?REP. 2021?22101056.", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210915", "receivedate": "20210915", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19831539, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK053347", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, OD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, OD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Visual field defect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS.. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS.. 2021?22", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210413", "receivedate": "20210413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19125979, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-PBT-000579", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "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": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": "5", "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster meningitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021 MAR 11?22:101056. DOI: 10.1016/J.AJOC.2021.101056. PMID: 33778180? PMCID: PMC7985716.", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210417", "receivedate": "20210417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19149682, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "NVSC2021US076872", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "PREDNISONE." }, { "actiondrug": "1", "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": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22(101056):1?6", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210407", "receivedate": "20210407", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19103860, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-ACCORD-222003", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "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": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:ARTICLE NUMBER 101056. DOI: 10.1016/J.AJOC.2021.101056.", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210413", "receivedate": "20210413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19126095, "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" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0133999", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Visual field defect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:1?6. DOI:10.1016/J.AJOC.2021.101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210827", "receivedate": "20210412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19120235, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0133996", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ALTERNATING DOSE OF 0.5 MG AND 0.25 MG TWICE A DAY FROM 2 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, 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"24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021?22:1?6. DOI:10.1016/J.AJOC.2021.101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210827", "receivedate": "20210412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19122695, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-ASTELLAS-2021US010660", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "050708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "0.5 MG, ONCE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:NO INFORMATION", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210325", "receivedate": "20210325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19055041, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-292061", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant rejection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021?22:101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210420", "receivedate": "20210420", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19157871, "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" }, { "companynumb": "NVSC2021US076871", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE" }, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELLCEPT" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22(101056):1?6", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210407", "receivedate": "20210407", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19103861, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK053164", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Dyschromatopsia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS.. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:1?6", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210412", "receivedate": "20210405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19090641, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-PBT-000578", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021 MAR 11?22:101056. DOI: 10.1016/J.AJOC.2021.101056. PMID: 33778180? PMCID: PMC7985716.", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210417", "receivedate": "20210417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19149681, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0133994", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyschromatopsia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021?22:1?6. DOI:10.1016/J.AJOC.2021.101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210827", "receivedate": "20210412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19120101, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-PBT-000580", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "3", "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": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": "5", "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021 MAR 11?22:101056. DOI: 10.1016/J.AJOC.2021.101056. PMID: 33778180? 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"drugstructuredosagenumb": ".25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENVARSUS XR" } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Varicella zoster virus infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pupillary reflex impaired", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Visual field defect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S ET.AL. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS.. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210409", "receivedate": "20210409", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19109133, "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" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK053166", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, QD (DAILY)", "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": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD (DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S.. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS.. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS.. 2021?22:101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210409", "receivedate": "20210405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19091053, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-VELOXIS PHARMACEUTICALS-2021VELUS-000235", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "206406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "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": "ENVARSUS XR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "206406", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "0.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENVARSUS XR" } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Visual field defect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. ET.AL. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:ARTICLE NUMBER 101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210408", "receivedate": "20210401", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19081343, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-VELOXIS PHARMACEUTICALS-2021VELUS-000236", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "206406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "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": "ENVARSUS XR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "206406", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "0.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENVARSUS XR" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyschromatopsia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. ET.AL.. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:ARTICLE NUMBER 101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210409", "receivedate": "20210409", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19114463, "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": "OBJECTIVE\nDrug-induced thrombocytopenia (DITP) may be a fatal adverse reaction to many drugs. It is often misdiagnosed as primary immune thrombocytopenia (ITP), and thus diagnosis can be delayed and patients can be treated inappropriately. Amlodipine a calcium-channel blocker, and simvastatin, a statin, have very rarely been implicated in DITP. We report on an investigation of the causal relationship of amlodipine and simvastatin with thrombocytopenia occurring in the same patient, and review the literature.\n\n\nMETHODS\nWe present the case of a 78-year-old female hypertensive diabetic patient with three successive DITPs. The first attack of acute severe thrombocytopenia occurred after a 2-week course of amlodipine, and was initially misdiagnosed as ITP. Her platelet count normalized after the amlodipine was discontinued. The second attack followed her restarting simvastatin 3 weeks later. She had stopped it 2 months earlier having previously taken it for over 5 years. Again, she recovered once the simvastatin was discontinued. The third DITP attack occurred when she accidently took a single dose of amlodipine 9 months later.\n\n\nCONCLUSIONS\nWe provide clear evidence of a causal association of amlodipine with thrombocytopenia, and probable evidence of a causal association of simvastatin with thrombocytopenia. This is the first reported case of DITPs occurring with two of the most widely prescribed drugs in the same patient. Many hypertensive patients need to take multiple drugs in order to achieve their treatment goals and this increases their risk of drug-induced adverse reactions and makes identification of the causal drug (or drugs) extremely difficult.", "affiliations": "Department of Hematology, Clinical Hospital Center Zemun, Belgrade, Serbia. [email protected]", "authors": "Cvetković\|Zorica\|Z\|;Suvajdžić-Vuković\|Nada\|N\|;Todorović\|Zoran\|Z\|;Panić\|Miloš\|M\|;Nešković\|Aleksandar\|A\|", "chemical_list": "D000959:Antihypertensive Agents; D000960:Hypolipidemic Agents; D017311:Amlodipine; D019821:Simvastatin", "country": "England", "delete": false, "doi": "10.1111/jcpt.12051", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-4727", "issue": "38(3)", "journal": "Journal of clinical pharmacy and therapeutics", "keywords": null, "medline_ta": "J Clin Pharm Ther", "mesh_terms": "D000368:Aged; D017311:Amlodipine; D000959:Antihypertensive Agents; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents; D019821:Simvastatin; D013921:Thrombocytopenia", "nlm_unique_id": "8704308", "other_id": null, "pages": "246-8", "pmc": null, "pmid": "23442182", "pubdate": "2013-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Simvastatin and amlodipine induced thrombocytopenia in the same patient: double trouble and a literature review.", "title_normalized": "simvastatin and amlodipine induced thrombocytopenia in the same patient double trouble and a literature review" }	[ { "companynumb": "RS-LUPIN PHARMACEUTICALS INC.-2013-01605", "fulfillexpeditecriteria": "2", "occurcountry": "RS", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "GLICLAZIDE" }, "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": "GLICLAZIDE" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "IPRATROPIUM BROMIDE/FENOTEROL HYDROBROMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FOSINOPRIL" }, "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": "FOSINOPRIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "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": "FUROSEMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078103", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078043", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078043", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20110307", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20110307", "drugstartdateformat": "102", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078103", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DYSLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "69", "reaction": [ { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CVETKOVIC Z, SUVAJDZIC-VUKOVIC N, TODOROVIC Z, PARUC M, NESKOVIC A. SIMVASTATIN AND AMLODIPINE INDUCED THROMBOCYTOPENIA IN THE SAME PATIENT: DOUBLE TROUBLE AND A LITERATURE REVIEW. JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS. 2013 FEB 26;38:246-248.", "literaturereference_normalized": "simvastatin and amlodipine induced thrombocytopenia in the same patient double trouble and a literature review", "qualification": null, "reportercountry": "RS" }, "primarysourcecountry": "RS", "receiptdate": "20140707", "receivedate": "20140707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10279459, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150326" } ]
{ "abstract": "OBJECTIVE\nMitochondrial disorders (MIDs) may manifest phenotypically with a plethora of clinical features, but polyarthralgia and cutaneous lesions are still infrequently reported and recognized as phenotypic manifestations of a MID.\n\n\nMETHODS\nThe patient is a 27-year-old Caucasian female with a history of preterm birth, symptomatic myopathy, and polyarthralgia since infancy, followed by multiple endocrinopathies including pituitary insufficiency, cardiac conduction defects, nephrolithiasis, aseptic chronic pancreatitis and sialadenitis, anemia, hyperlipidemia, and dysmorphic features. The patient reported to have profited from hydrocortisone and long-term chloroquine, but hardly from long-term immunosuppression with various immunosuppressants. The diagnosis MID was established upon the multiorgan nature of the disease, presence of core clinical features of a MID, and a muscle biopsy indicative of a mitochondrial defect. The family history was positive for mitochondrial features in the mother and grandmother from the mother's side.\n\n\nCONCLUSIONS\nSeronegative and non-destructive polyarthralgia and unexplained cutaneous features mimicking cutaneous lupus should be considered as a phenotypic feature of a multisystem MID (mitochondrial multiorgan disorder syndrome, MIMODS). Mitochondrial metabolic defects may trigger secondary immune reactions. Core clinical features of a non-specific MID with infantile onset include symptomatic myopathy, endocrine abnormalities, cardiac conduction defects, dysmorphism, hyperlipidemia, anemia, and nephrolithiasis.", "affiliations": "Krankenanstalt Rudolfstiftung, Messerli Institute, Veterinary University of Vienna, Vienna, Austria. [email protected].;Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria.;Neurological Institute, Medical University of Vienna, Vienna, Austria.", "authors": "Finsterer\|Josef\|J\|;Melichart-Kotig\|Madleine\|M\|;Woehrer\|Adelheid\|A\|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1007/s00393-018-0551-1", "fulltext": null, "fulltext_license": null, "issn_linking": "0340-1855", "issue": "78(9)", "journal": "Zeitschrift fur Rheumatologie", "keywords": "Arthralgia; Mitochondrion; MtDNA; Myopathy; Neuromuscular; Pituitary insufficiency", "medline_ta": "Z Rheumatol", "mesh_terms": "D000328:Adult; D001172:Arthritis, Rheumatoid; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D028361:Mitochondrial Diseases", "nlm_unique_id": "0414162", "other_id": null, "pages": "875-880", "pmc": null, "pmid": "30291434", "pubdate": "2019-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25264167;26385056;25390621;20562457;25403780;28735506;28334504;29054425;27375219;11579427;22121133", "title": "Mitochondrial disorder mimicking rheumatoid disease.", "title_normalized": "mitochondrial disorder mimicking rheumatoid disease" }	[ { "companynumb": "AT-SAMSUNG BIOEPIS-SB-2020-18170", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IVABRADINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, 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"drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLECALCIFEROL" } ], "patientagegroup": "4", "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "75", "reaction": [ { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood creatine phosphokinase increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperlipidaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Temporomandibular joint syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nephrolithiasis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Brain natriuretic peptide increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Varicella zoster virus infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anosmia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sialoadenitis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood lactic acid increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ovarian cyst", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diastolic dysfunction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serum ferritin decreased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral haemangioma", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitamin D deficiency", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Secondary hypogonadism", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Migraine", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Menstrual disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bundle branch block right", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cutaneous lupus erythematosus", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pericardial effusion", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrioventricular block complete", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myoglobin blood increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Glomerular filtration rate decreased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Goitre", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Joint dislocation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood triglycerides increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FINSTERER, J.. MITOCHONDRIAL DISORDER MIMICKING RHEUMATOID DISEASE.. Z RHEUMATOL. 2019?78:10.1007/S00393-018-0551-1", "literaturereference_normalized": "mitochondrial disorder mimicking rheumatoid disease", "qualification": "1", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20200604", "receivedate": "20200604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17858919, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "AT-ALKEM LABORATORIES LIMITED-AT-ALKEM-2019-11190", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "JUVENILE IDIOPATHIC ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFASALAZINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "JUVENILE IDIOPATHIC ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFASALAZINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091249", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "27", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "75", "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FINSTERER J, MELICHART-KOTIG M, WOEHRER A. MITOCHONDRIAL DISORDER MIMICKING RHEUMATOID DISEASE. 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"activesubstance": { "activesubstancename": "TRAZODONE 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": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "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": "VITAMINE D" } ], "patientagegroup": "4", "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "75", "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pericardial effusion", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ovarian cyst", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Temporomandibular joint syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Joint dislocation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bundle branch block right", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cutaneous lupus erythematosus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sialoadenitis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood triglycerides increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Migraine", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood creatine phosphokinase increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperlipidaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrioventricular block complete", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nephrolithiasis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diastolic dysfunction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myoglobin blood increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anosmia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Goitre", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral haemangioma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Varicella zoster virus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Menstrual disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serum ferritin decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Glomerular filtration rate decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood lactic acid increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Brain natriuretic peptide increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitamin D deficiency", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Secondary hypogonadism", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FINSTERER J.? MELICHART-KOTIG M.? WOEHRER A.? ET.AL.. MITOCHONDRIAL DISORDER MIMICKING RHEUMATOID DISEASE. Z RHEUMATOL. 2019?78:875-880", "literaturereference_normalized": "mitochondrial disorder mimicking rheumatoid disease", "qualification": "3", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20200123", "receivedate": "20191231", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17220355, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" } ]
{ "abstract": "Primary synovial sarcoma is a very rare tumor of the mediastinum, which is unreported in the entire subcontinent of West Africa, and presents daunting challenges from diagnosis to management with lack of standard management strategies. We present a case of primary monophasic synovial sarcoma of the anterior mediastinum, in a 22-year-old Nigerian lady who presented with cough, chest pain, and pleural effusion. Chest X-ray (CXR) and computed tomography on admission showed a left-sided huge mass in the left anterior mediastinum with no metastasis to the contralateral pleural cavity. Complete resection of the mediastinal tumor was done and histologic and immunohistochemical analyses confirmed a diagnosis of monophasic synovial sarcoma. However, 10 months postoperation she represented with chest pain, productive cough and a repeat CXR showed multiple left pulmonary nodules. She received two cycles of docetaxel and gemcitabine chemotherapy, but declined further treatment until her demise 8 months later.", "affiliations": "Department of Morbid Anatomy, University of Nigeria, Enugu Campus, Enugu, Nigeria.", "authors": "Ukekwe\|F I\|FI\|;Ezemba\|N\|N\|;Olusina\|D B\|DB\|;Igbokwe\|U\|U\|;Ngene\|C\|C\|", "chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C056507:gemcitabine", "country": "India", "delete": false, "doi": "10.4103/1119-3077.175965", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "19(2)", "journal": "Nigerian journal of clinical practice", "keywords": null, "medline_ta": "Niger J Clin Pract", "mesh_terms": "D017024:Chemotherapy, Adjuvant; D002637:Chest Pain; D003371:Cough; D003841:Deoxycytidine; D000077143:Docetaxel; D017809:Fatal Outcome; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms; D008479:Mediastinal Neoplasms; D008482:Mediastinum; D010996:Pleural Effusion; D013902:Radiography, Thoracic; D013584:Sarcoma, Synovial; D043823:Taxoids; D014057:Tomography, X-Ray Computed; D055815:Young Adult", "nlm_unique_id": "101150032", "other_id": null, "pages": "293-7", "pmc": null, "pmid": "26856298", "pubdate": "2016", "publication_types": "D002363:Case Reports; D016422:Letter; D016454:Review", "references": null, "title": "Giant primary synovial sarcoma of the anterior mediastinum: A case report and review of literature.", "title_normalized": "giant primary synovial sarcoma of the anterior mediastinum a case report and review of literature" }	[ { "companynumb": "NG-CIPLA LTD.-2016NG02458", "fulfillexpeditecriteria": "1", "occurcountry": "NG", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYNOVIAL SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYNOVIAL SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "UKEKWE F, EZEMBA N, OLUSINA DB, IGBOKWE U, NGENE C. GIANT PRIMARY SYNOVIAL SARCOMA OF THE ANTERIOR MEDIASTINUM: A CASE REPORT AND REVIEW OF LITERATURE. NIGERIAN JOURNAL OF CLINICAL PRACTICE. 2016?19 (2):293 TO 297", "literaturereference_normalized": "giant primary synovial sarcoma of the anterior mediastinum a case report and review of literature", "qualification": "3", "reportercountry": "NG" }, "primarysourcecountry": "NG", "receiptdate": "20160318", "receivedate": "20160318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12190054, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" } ]
{ "abstract": "Toxic erythema of chemotherapy (TEC) is an infrequently reported cutaneous condition, with diagnosis predominately based on clinical presentation, histologic findings, and known reported associations. Therefore, it is important to both recognize common presentations of TEC and be mindful of chemotherapeutic agents associated with this cutaneous side effect to prevent misdiagnosis and prolonged time to treatment. Herein, we present a patient with TEC occurring in intertriginous skin (malignant intertrigo) with classic clinical and histologic findings. In our patient this was associated with a combination neoadjuvant gemcitabine and paclitaxel therapy, a relationship that, to our knowledge, has yet to be reported in the literature.", "affiliations": "Department of Dermatology, Lewis Katz School of Medicine, Philadelphia, PA.", "authors": "Jennings\|Erin\|E\|;Huang\|Simo\|S\|;Lee\|Jason B\|JB\|;Cha\|Jisun\|J\|;Hsu\|Sylvia\|S\|", "chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1087-2108", "issue": "26(9)", "journal": "Dermatology online journal", "keywords": null, "medline_ta": "Dermatol Online J", "mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D064146:Chemotherapy-Induced Febrile Neutropenia; D003841:Deoxycytidine; D004890:Erythema; D005260:Female; D006801:Humans; D007402:Intertrigo; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel; D010190:Pancreatic Neoplasms", "nlm_unique_id": "9610776", "other_id": null, "pages": null, "pmc": null, "pmid": "33054938", "pubdate": "2020-09-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel.", "title_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel" }	[ { "companynumb": "US-ACCORD-208034", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091594", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE/GEMCITABINE HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "205720", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL/PACLITAXEL LIPOSOME" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Intertrigo", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JENNINGS E, HUANG S, LEE JB, CHA J, HSU S. TOXIC ERYTHEMA OF CHEMOTHERAPY SECONDARY TO GEMCITABINE AND PACLITAXEL. DERMATOLOGY ONLINE JOURNAL. 2020?26(9).", "literaturereference_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201118", "receivedate": "20201118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18516154, "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" }, { "companynumb": "US-PFIZER INC-2020419383", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "076131", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "079183", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JENNINGS, E.. TOXIC ERYTHEMA OF CHEMOTHERAPY SECONDARY TO GEMCITABINE AND PACLITAXEL. DERMATOLOGY ONLINE JOURNAL. 2020?26 (9):10.5070/D3269050161", "literaturereference_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210721", "receivedate": "20201104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18462187, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-SAGENT PHARMACEUTICALS-2020SAG002356", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "209077", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JENNINGS E, HUANG S, LEE JB, CHA J, HSU S. TOXIC ERYTHEMA OF CHEMOTHERAPY SECONDARY TO GEMCITABINE AND PACLITAXEL. DERMATOLOGY ONLINE JOURNAL. 2020?26", "literaturereference_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201102", "receivedate": "20201102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18455448, "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" }, { "companynumb": "US-TEVA-2020-US-1851341", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75297", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "079160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JENNINGS E, HUANG S, LEE JB, CHA J, HSU S. TOXIC ERYTHEMA OF CHEMOTHERAPY SECONDARY TO GEMCITABINE AND PACLITAXEL. DERMATOL-ONLINE-J 2020?26:NO. 9.", "literaturereference_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201124", "receivedate": "20201124", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18542658, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2020-00692", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "EVERY CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": "811", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "207575", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "EVERY CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": "811", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE, UNKNOWN" } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intertrigo", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JENNINGS E, HUANG S, LEE J, HSU S. TOXIC ERYTHEMA OF CHEMOTHERAPY SECONDARY TO GEMCITABINE AND PACLITAXEL. DERMATOLOGY ONLINE JOURNAL. 2020 SEP?26(9):6:1-3.", "literaturereference_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201130", "receivedate": "20201130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18558698, "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" }, { "companynumb": "US-FRESENIUS KABI-FK202012037", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090242", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "077574", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JENNINGS E, HUANG S, LEE J, CHA J, HSU S. TOXIC ERYTHEMA OF CHEMOTHERAPY SECONDARY TO GEMCITABINE AND PACLITAXEL. DERMATOLOGY ONLINE JOURNAL. 2020 SEP?26 (9):.", "literaturereference_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201112", "receivedate": "20201112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18498731, "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" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0129285", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091365", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Intertrigo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JENNINGS E, HUANG S, LEE J, CHA J, HSU S. TOXIC ERYTHEMA OF CHEMOTHERAPY SECONDARY TO GEMCITABINE AND PACLITAXEL. DERMATOL ONLINE J. 2020?26(9):1?3. DOI:ORG/UC/ITEM/86M5F6HH", "literaturereference_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210715", "receivedate": "20201119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18522371, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Objective Invasive pulmonary aspergillosis (IPA) is a severe and often lethal infection. The possible risk factors, clinical presentation, and treatment of patients with simultaneous liver failure and IPA have received little attention in previous studies. The aim of this study was to investigate the epidemiology of IPA in patients with liver failure in an effort to reduce patient mortality. Methods The patients with liver failure (including acute liver failure , sub-acute liver failure , acute-on-chronic liver failure and chronic liver failure) were recruited from 2011 to 2016. The clinical data of these patients were retrieved for the study. Results In total, 1077 patients with liver failure were included in this study. Of the 1077 patients, 53 (4.9%) had IPA. Forty-four (83%) patients with IPA died. Independent risk factors for IPA were male sex (hazard ratio [HR] = 2.542), hepatorenal syndrome (HR = 2.463), antibiotic use (HR = 4.631), and steroid exposure (HR = 18.615). Conclusions IPA is a fatal complication in patients with liver failure. Male sex, hepatorenal syndrome, antibiotic use, and steroid exposure were independent risk factors for IPA. When patients with liver failure have these risk factors and symptoms of pneumonia such as cough or hemoptysis, clinicians should be cautious about the possibility of IPA.", "affiliations": "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.", "authors": "Zhang\|Xuan\|X\|;Yang\|Meifang\|M\|;Hu\|Jianhua\|J\|;Zhao\|Hong\|H\|;Li\|Lanjuan\|L\|", "chemical_list": "D000900:Anti-Bacterial Agents; D013256:Steroids", "country": "England", "delete": false, "doi": "10.1177/0300060517729907", "fulltext": "\n==== Front\nJ Int Med ResJ. Int. Med. ResIMRspimrThe Journal of International Medical Research0300-06051473-2300SAGE Publications Sage UK: London, England 2923926610.1177/030006051772990710.1177_0300060517729907Clinical ReportsEpidemiology of invasive pulmonary aspergillosis in patients with liver failure: Clinical presentation, risk factors, and outcomes Zhang Xuan Yang Meifang Hu Jianhua Zhao Hong Li Lanjuan State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaLanjuan Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. Email: [email protected] 9 2017 2 2018 46 2 819 827 7 6 2017 15 8 2017 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Objective\nInvasive pulmonary aspergillosis (IPA) is a severe and often lethal infection. The possible risk factors, clinical presentation, and treatment of patients with simultaneous liver failure and IPA have received little attention in previous studies. The aim of this study was to investigate the epidemiology of IPA in patients with liver failure in an effort to reduce patient mortality.\n\nMethods\nThe patients with liver failure (including acute liver failure , sub-acute liver failure , acute-on-chronic liver failure and chronic liver failure) were recruited from 2011 to 2016. The clinical data of these patients were retrieved for the study.\n\nResults\nIn total, 1077 patients with liver failure were included in this study. Of the 1077 patients, 53 (4.9%) had IPA. Forty-four (83%) patients with IPA died. Independent risk factors for IPA were male sex (hazard ratio [HR] = 2.542), hepatorenal syndrome (HR = 2.463), antibiotic use (HR = 4.631), and steroid exposure (HR = 18.615).\n\nConclusions\nIPA is a fatal complication in patients with liver failure. Male sex, hepatorenal syndrome, antibiotic use, and steroid exposure were independent risk factors for IPA. When patients with liver failure have these risk factors and symptoms of pneumonia such as cough or hemoptysis, clinicians should be cautious about the possibility of IPA.\n\nLiver failureinvasive pulmonary aspergillosisepidemiologyrisk factorsclinical presentationoutcomes\n==== Body\nIPA, invasive pulmonary aspergillosis; ACLF, acute-on-chronic liver failure; ALF, acute liver failure; SALF, subacute liver failure; CLF, chronic liver failure; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; INR, international normalized ratio; PTA, prothrombin activity; HIV, human immunodeficiency virus; HR, hazard ratio\n\nIntroduction\nInvasive pulmonary aspergillosis (IPA) is a severe and often lethal infection1 that mainly affects immunocompromised patients, such as those with hematologic malignancies and stem cell or solid organ transplants. Aspergillus spp. can cause invasive infection in patients with liver failure.2–5 Although patients with liver failure have a low incidence of invasive aspergillosis, recent data have indicated that this condition should be reconsidered as a devastating infectious disease in this population.3–5 Wu et al.5 showed that most patients with acute-on-chronic liver failure (ACLF) died within 7 days after the onset of IPA (25/29 patients).\n\nAchieving a clinical diagnosis of IPA is a huge challenge. Invasive diagnostic procedures such as fiberbronchoscopy are necessary to confirm a diagnosis of aspergillus infection, but such procedures are often not feasible in patients with severe respiratory insufficiency and critical illness who are not undergoing mechanical ventilation.6–9 Moreover, the European Organization for Research and Treatment of Cancer (EORTC) restricted the scope of the standard diagnostic definitions to receipt of a solid organ transplant, hereditary immunodeficiencies, connective tissue disorders, and receipt of immunosuppressive agents10; however, these criteria cannot necessarily be extrapolated to patients with liver failure.\n\nFew studies have been performed to evaluate patients with liver failure who develop IPA, and possible risk factors such as the ABO blood group and use of an artificial liver support system have received little attention. Little is known about the clinical presentation and treatment of IPA in patients with liver failure. Therefore, the aim of this study was to collect data about patients with liver failure to investigate the epidemiology and possible risk factors for IPA in an effort to reduce the mortality in this population.\n\nMethods\nStudy design\nThis retrospective study was conducted in the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, China. The study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University, and the need for consent was waived because the study was retrospective and the data were analyzed anonymously.\n\nStudy population\nPatients with liver failure [including acute liver failure (ALF), subacute liver failure (SALF), ACLF, and chronic liver failure (CLF)] were admitted into the infectious disease wards of the First Affiliated Hospital, College of Medicine, Zhejiang University, China from 2011 to 2016. The clinical data of these patients were retrieved for the study. The follow-up period for the patients with IPA was 3 months after discharge.\n\nDiagnostic criteria\nLiver failure was defined according to the following criteria specified by the 13th Asia-Pacific Congress of Clinical Microbiology and Infection Consensus Guidelines for the diagnosis and treatment of liver failure:11\n\nALF: Abrupt onset accompanied by grade II or higher hepatic encephalopathy (HE) (according to the I- to IV-grade classification) and appearance of the following symptoms within 2 weeks: a) fatigue with severe gastrointestinal tract symptoms such as anorexia, abdominal distension, nausea, and vomiting; b) progressive aggravation of jaundice; c) hemorrhagic tendency with an international normalized ratio (INR) of ≥1.5 or prothrombin activity (PTA) of ≤40% and exclusion of other causes; and d) progressive reduction in liver size.\n\nSALF: Slower onset than ALF and appearance of the following symptoms within 2 to 26 weeks: a) fatigue with gastrointestinal tract symptoms, b) rapidly deepening jaundice with a total bilirubin (TBil) level 10 times higher than the upper limit of normality or a daily increase of ≥17.1 µmol/L, c) occurrence of HE, and d) hemorrhagic tendency with an INR of ≥1.5 or PTA of ≤40% and exclusion of other causes.\n\nACLF: Acute or subacute deterioration of liver function in patients with chronic liver disease, usually accompanied by the following symptoms: a) fatigue with gastrointestinal tract symptoms, b) rapidly deepening jaundice with a TBil level 10 times higher than the upper limit of normality or a daily increase of ≥17.1 µmol/L, c) hemorrhagic tendency with an INR of ≥1.5 or PTA of ≤40% and exclusion of other causes, d) progressive reduction in liver size, and e) occurrence of HE.\n\nCLF: Progressive deterioration and decompensation of liver function in patients with liver cirrhosis, usually accompanied by the following symptoms: a) a significant increase in TBil, b) a significant decrease in albumin, c) a hemorrhagic tendency with an INR of ≥1.5 or PTA of ≤40% and exclusion of other causes, d) ascites or other symptoms of portal hypertension, and e) occurrence of HE.\n\nWe used the EORTC consensus definition of invasive Aspergillus infection,10 which was diagnosed if the following two criteria were fulfilled: one microbiologic criterion (positive sputum culture) and one clinical criterion. In the present study, a diagnosis of IPA was made based on the following: a) positive culture of Aspergillus spp. from sputum and b) the presence of one of the following three signs on computed tomography: dense, well-circumscribed lesions(s) with or without a halo sign, air-crescent sign, or cavity.\n\nRisk factors for IPA\nIn this study, the following variables were assessed as risk factors for the occurrence of IPA: sex, age, ABO blood group, type 2 diabetes mellitus, chronic bronchitis, malignancy, human immunodeficiency virus (HIV) infection, antibiotic use, steroid exposure, use of an artificial liver support system, neutropenia, gastrointestinal bleeding, HE, and hepatorenal syndrome (HRS). The definitions of some of these factors are summarized in Table 1.\nTable 1. Risk factors for invasive pulmonary aspergillosis in patients with liver failure.\n\nRisk factors\tRemarks (where applicable)\t\nChronic bronchitis\tDefined as the presence of a productive cough or expectoration for >90 days per year (but on separate days) and for >2 consecutive years, provided that a specific disorder responsible for these symptoms is not present.\t\nMalignancy\tSolid tumor and hematologic malignancy\t\nHIV infection\tDefined as HIV-positive status\t\nAntibiotic use\tAntimicrobial agent use for >5 days\t\nSteroid exposure\tSteroid treatment for >7 days\t\nNeutropenia\tTotal neutrophil count of ≤500/mm3\t\nHIV, human immunodeficiency virus.\n\n\n\nStatistical analysis\nThe statistical analysis was performed using SPSS version 18.0 (SPSS, Chicago, IL, USA). Student’s t-test was performed for descriptive analysis and comparison of continuous variables. Fisher’s exact probability test and the chi-square test were conducted to calculate and compare the percentages for categorical variables. Logistic regression analysis was used to examine the effects of independent variables on IPA. P value of <0.05 was considered statistically significant for all analyses.\n\nResults\nCharacteristics of the study cohort\nIn total, 1077 patients with liver failure were included in this study. Of these 1077 patients, 826 (76.7%) were male and the mean age was 49.22 ± 13.45 years. The characteristics of the patients are shown in Table 2 and Table 3. The most common reason for hospital admission was SCLF (543/50.4%), and the main cause of liver failure was hepatitis B (799/74.2%). A total of 511 (47.4%) patients received artificial liver support therapy, 710 (65.9%) received antibacterial treatment for >5 days, and 84 (7.8%) were exposed to corticosteroids for >7 days. The antibacterial treatments were administered for both prophylaxis and treatment (pneumonia, spontaneous bacterial peritonitis, and septicemia). Steroids were used to decrease persistent hyperbilirubinemia and treat autoimmune diseases. Eight (0.7%) patients developed neutropenia.\nTable 2. Characteristics of 1077 patients with liver failure.\n\nCharacteristic\tNumber of patients (%)\t\nDisease onset\t\t\n ALF\t71 (6.6)\t\n SALF\t51 (4.7)\t\n SCLF\t543 (50.4)\t\n CLF\t412 (38.3)\t\nEtiology of liver failure\t\t\n Hepatitis B\t799 (74.2)\t\n Hepatitis E\t5 (0.5)\t\n Alcohol\t32 (3.0)\t\n Drug\t59 (5.5)\t\n Autoimmunity\t23 (2.1)\t\n Hepatolenticular degeneration\t3 (0.3)\t\n Schistosome\t5 (0.5)\t\n Malignancy\t7 (0.6)\t\n Two or more factors\t69 (6.4)\t\n Unknown\t72 (6.7)\t\nACLF, acute-on-chronic liver failure; ALF, acute liver failure; SALF, subacute liver failure; CLF, chronic liver failure.\n\n\nTable 3. Demographic features of 1077 patients with liver failure and differences between those with and without IPA.\n\n\tAll patients with liver failure\tPatients with IPA\tPatients without IPA\tp value\t\nPatients\t1077\t53\t1024\t–\t\nMale\t826 (76.7)\t46 (86.8)\t780 (76.2)\t0.075\t\nAge (years)\t49.18 ± 13.48\t48.64 ± 12.07\t49.25 ± 13.52\t0.748\t\nABO blood group\t\t\t\t\t\n A\t343 (31.8)\t13 (24.5)\t331 (32.3)\t0.235\t\n B\t271 (25.2)\t9 (17.0)\t262 (25.6)\t0.159\t\n AB\t86 (8.0)\t6 (11.3)\t80 (7.8)\t0.358\t\n O\t377 (35.0)\t25 (47.2)\t351 (34.3)\t0.055\t\nMorbidities\t\t\t\t\t\n Type 2 diabetes mellitus\t102 (9.5)\t3 (5.7)\t99 (9.7)\t0.465\t\n Chronic bronchitis\t50 (4.6)\t2 (3.8)\t49 (4.8)\t0.995\t\n Malignancy\t88 (8.2)\t3 (5.7)\t85 (8.3)\t0.669\t\n HIV infection\t12 (1.1)\t0 (0.0)\t12 (1.2)\t0.903\t\nComplications\t\t\t\t\t\n Gastrointestinal bleeding\t116 (10.8)\t7 (13.2)\t109 (10.6)\t0.557\t\n HE\t484 (44.9)\t26 (49.1)\t458 (44.7)\t0.537\t\n HRS\t141 (13.1)\t14 (26.4)\t127 (12.4)\t0.003\t\nAntibiotic use\t710 (65.9)\t46 (88.5)\t663 (64.7)\t0.001\t\nSteroid exposure\t84 (7.8)\t26 (49.1)\t58 (5.7)\t<0.001\t\nArtificial liver support system\t511 (47.4)\t30 (56.6)\t481 (47.0)\t0.171\t\nNeutropenia\t8 (0.7)\t1 (1.9)\t7 (0.7)\t0.862\t\nData are presented as mean ± standard deviation or n (%). IPA, invasive pulmonary aspergillosis; HIV, human immunodeficiency virus; HE, hepatic encephalopathy; HRS, hepatorenal syndrome\n\n\n\nAmong all 1077 patients, 53 (4.9%) were diagnosed with IPA. The characteristics of the patients with IPA are shown in Table 3. Twenty-five (47.2%) of these patients had blood group O, 30 (56.6%) had received artificial liver support therapy, and 46 (86.8%) and 26 (49.1%) received antibacterial drugs and corticosteroids, respectively.\n\nRisk factors\nLogistic regression analysis showed that male sex [hazard ratio (HR) = 2.542, p = 0.035], HRS (HR = 2.463, p = 0.014), antibiotic use (HR = 4.631, p = 0.001), and steroid exposure (HR = 18.615, p < 0.001) were independent risk factors associated with the occurrence of IPA (Table 4).\nTable 4. Logistic regression analysis of risk factors associated with invasive pulmonary aspergillosis development in patients with liver failure.\n\nRisk factors\tHR\t95% CI for HR\tp value\t\nLower\tUpper\t\nHepatorenal syndrome\t2.463\t1.199\t5.061\t0.014\t\nMale sex\t2.542\t1.065\t6.063\t0.035\t\nAntibiotic use\t4.631\t1.866\t11.496\t0.001\t\nSteroid exposure\t18.615\t9.819\t35.048\t<0.001\t\nHR, hazard ratio; CI, confidence interval.\n\n\n\nClinical characteristics of patients with IPA\nThe symptoms and laboratory data of the 53 patients with IPA are shown in Table 5. Among all patients with IPA 44 (83%) died. After IPA diagnosis, three patients were admitted to the intensive care unit where mechanical ventilation and continuous renal replacement therapy were applied. Moreover, nine (17%) patients did not receive antifungal treatment. Twenty-four (45.3%) patients received voriconazole as antifungal treatment, 16 (30.2%) received caspofungin, and 4 (7.5%) received micafungin. There were no differences in the survival rate among patients treated with different antifungal agents (Table 6).\nTable 5. Characteristics of 53 patients with liver failure who developed invasive pulmonary aspergillosis (IPA).\n\nCharacteristics\tNumber of patients (%)\t\nSymptoms\t\t\n Fever\t53 (100.0)\t\n Cough\t50 (94.3)\t\n Hemoptysis\t23 (43.4)\t\n Dyspnea\t20 (37.7)\t\n Chest pain\t2 (3.8)\t\nLaboratory data\t\t\n Leukocyte count (×109/L)\t11.31 ± 5.71\t\n Neutrophil count (×109/L)\t9.29 ± 5.26\t\n Total bilirubin (µmol/L)\t489.12 ± 135.15\t\n INR\t3.08 ± 1.37\t\nImaging findings (X-ray or CT)\t\t\n Changes in bilateral lung fields\t43 (81.1)\t\n Right unilateral lung\t8 (15.1)\t\n Left unilateral lung\t2 (3.8)\t\n Cavity\t13 (24.5)\t\n Air-crescent sign\t10 (18.9)\t\n Pleural effusion\t19 (35.8)\t\nAntibiotic use (before IPA diagnosis)\t46 (86.8)\t\n One antibiotic\t44 (95.7)\t\n Two antibiotics\t2 (4.3)\t\n Carbapenems\t13 (28.3)\t\n Penicillins\t18 (39.1)\t\n Third-generation cephalosporins\t11 (23.9)\t\n Fourth-generation cephalosporins\t2 (4.3)\t\n Glycopeptides\t2 (4.3)\t\n Quinolones\t2 (4.3)\t\nIPA, invasive pulmonary aspergillosis; INR, international normalized ratio; CT, computed tomography\n\n\nTable 6. Effect of antifungal agents in the treatment of invasive pulmonary aspergillosis.\n\n\tDeath\tRecovery\tp value\t\nPatients\t44 (83%)\t9 (17%)\t–\t\nAntifungal agent\t\t\t\t\n Voriconazole\t19\t5\t0.755\t\n Caspofungin\t13\t3\t0.822\t\n Micafungin\t3\t1\t0.536\t\n Untreated\t9\t0\t0.329\t\n\n\nDiscussion\nInvasive aspergillosis has been traditionally regarded as an infection mainly occurring in immunocompromised or immunodeficient patients, such as those with neutropenia, hematologic malignancies, organ transplantation, or HIV.12 Although invasive aspergillosis has been reported in patients with liver cirrhosis and liver transplantation,13,14,15 IPA has rarely been observed in patients with liver failure.\n\nA previous study16 confirmed invasive aspergillosis as a frequent undiagnosed complication of patients with ALF or end-stage liver disease, with a mortality rate exceeding 70%. In the present study, the mortality rate among patients with liver failure who developed IPA was 83%. The reason for the high mortality was not only the difficulty in diagnosis and treatment of IPA but also a lack of enough recognition of IPA and the heavy economic burden, which led patients to give up treatments.\n\nDiagnosis of IPA in patients with liver failure is challenging. Patients with liver failure often have a high bleeding tendency, which is a contraindication for invasive examinations such as pulmonary puncture biopsy or bronchoscope. Thus, only one patient in our study had tissue evidence of Aspergillus fumigatus infection that was acquired after the recovery of liver failure. Moreover, liver failure is not a host factor of invasive fungal disease in the EORTC consensus; thus, the diagnosis of invasive Aspergillus infection in patients with liver failure is quite difficult according to the EORTC consensus definition. Because of delayed diagnosis and patients’ financial constraints, 17% of patients did not receive antifungal treatment. One study16 showed that a high percentage (52.8%) of patients with acute or advanced liver disease were diagnosed with invasive aspergillosis postmortem. Therefore, further research of the epidemiology, risk factors, and clinical manifestations of IPA in patients with liver failure may improve the diagnosis rate.\n\nIn the present study, the incidence of IPA in patients with liver failure was 4.9%. Bone marrow transplantation, prolonged neutropenia, and solid organ transplantation have been identified as high-risk factors for invasive aspergillosis.17–21 Invasive aspergillosis occurs in 1% to 9% of liver transplant recipients14; this is similar to the morbidity rate of the patients with liver failure in the present study. As a result of a depression of both humoral and cell-mediated immunity, liver disease alone predisposes to bacterial and fungal infections.22 Patients with liver failure patients are immunosuppressed and should be considered an at-risk population for IPA.\n\nAn expert consensus23 recommended that the main risk factors for IPA should include neutropenia, malignancy, and prolonged steroid treatment. In the present study, HRS (p = 0.014), steroid exposure (p < 0.001), and antibiotic use (p = 0.001) were independent risk factors associated with the occurrence of IPA in patients with liver failure. These findings are consistent with those of previous research.3,4,22\n\nIn this study, 26 (49.1%) patients had steroid exposure before IPA diagnosis. Surprisingly, patients with liver failure who took corticosteroids for >7 days had an 18-fold (HR = 18.615) higher risk of developing IPA than those who did not use corticosteroids or used them for <7 days. Corticosteroids predispose patients to opportunistic infections through functional impairment of macrophages and neutrophil function.24 Thus, corticosteroids should be used with caution in patients with liver failure.\n\nHRS may be precipitated by infection.25 Additionally, renal failure has been associated with defective cell-mediated immunity and impaired granulocyte–macrophage function, which are the predominant host defenses against fungal pathogens.26\n\nMoreover, male sex (p = 0.035) was also a risk factor for IPA; this has not been found in previous studies. A possible reason for this result is that immune system damage in male patients with liver failure is more severe than in female patients. However, this needs further research.\n\nIn patients with liver failure, both the clinical diagnosis and treatment of IPA are challenging. The guidelines of the Infectious Diseases Society of America27 recommended voriconazole as the primary therapy for IPA. However, this drug is metabolized in the liver and potentially hepatotoxic.27 Thus, it should be used with caution in patients with liver failure patients. In the present study, 24 (45.3%) patients received voriconazole as an antifungal agent, and the dose of voriconazole was not adjusted. No skin rashes or transient visual disturbances were observed. Moreover, it is difficult to estimate whether liver injury has been induced by voriconazole in patients with liver failure. Because such patients’ liver function is severely damaged, infection could lead to impaired liver function and ultimately higher mortality.28 However, liver function did not worsen after using voriconazole in our recovered patients.\n\nOur study has some limitations. First, the small numbers of patients with some host factors of invasive fungal disease development in the EORTC consensus, such as HIV or neutropenia, may have led to statistical error. Second, liver failure is not a host factor of invasive fungal disease development in the EORTC consensus; therefore, the patients in our study did not fulfill the definition of proven IPA according to the EORTC consensus. Moreover, invasive diagnostic procedures were not feasible in our patients with liver failure, which may have resulted in missing patients with suspected disease based on radiologic imaging. Third, we did not collect data on the daily corticosteroid dose and could not fully explore the impact of dose or duration on mortality. Finally, male sex as a risk factor for IPA was not thoroughly researched.\n\nIn conclusion, IPA is a potentially fatal complication in patients with liver failure, and delayed diagnosis and treatment may contribute to high mortality. Steroid exposure, antibiotic use, male sex, and HRS were independent risk factors associated with the occurrence of IPA. When patients with liver failure have these risk factors and symptoms of pneumonia such as cough or hemoptysis, clinicians should be aware of the possibility of IPA. Early and appropriate antifungal treatment may improve the survival rate in patients with liver failure.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThis study was supported by the Medical and Health Science and Technology Project of Zhejiang province (2015KYA102).\n==== Refs\nReferences\n1 Prodanovic H Cracco C Massard J et al. \nInvasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series . BMC Gastroenterol \n2007 ; 7 : 2 –2 .17266747 \n2 Li D Chen L Ding X et al. \nHospital-acquired invasive pulmonary aspergillosis in patients with hepatic failure . 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Diagn Microbiol Infect Dis \n2014 ; 80 : 72 –78 .24974271\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0300-0605", "issue": "46(2)", "journal": "The Journal of international medical research", "keywords": "Liver failure; clinical presentation; epidemiology; invasive pulmonary aspergillosis; outcomes; risk factors", "medline_ta": "J Int Med Res", "mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D002908:Chronic Disease; D003371:Cough; D005260:Female; D006469:Hemoptysis; D006530:Hepatorenal Syndrome; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D017093:Liver Failure; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D012737:Sex Factors; D013256:Steroids; D016019:Survival Analysis", "nlm_unique_id": "0346411", "other_id": null, "pages": "819-827", "pmc": null, "pmid": "29239266", "pubdate": "2018-02", "publication_types": "D016428:Journal Article", "references": "24151434;18462102;8198352;18177225;25828927;24647810;15872225;16387806;23817660;20450350;18667083;18195630;17266747;23924491;23206479;25348192;24514164;25928694;11303267;21108575;15882191;24579244;17413611;24726663;10896904;21866367;15987390;24974271", "title": "Epidemiology of invasive pulmonary aspergillosis in patients with liver failure: Clinical presentation, risk factors, and outcomes.", "title_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes" }	[ { "companynumb": "CN-PFIZER INC-2018108781", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. 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EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. 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EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. 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EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. 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EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. 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EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. 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EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649926, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108777", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649899, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108774", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649892, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108782", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649802, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108769", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649902, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108779", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649800, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108776", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649900, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108767", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649925, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108768", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649895, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108773", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649901, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108778", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649803, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108770", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649893, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108775", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES.. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649903, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" } ]
{ "abstract": "Purpose: A 28-year-old male reported to our hospital with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap syndrome that developed as an adverse drug reaction (ADR) to allopurinol. HLA-B58:01 allele is associated with an increased risk of developing allopurinol-induced SJS/TEN. Methods: Genomic DNA was extracted from peripheral blood leukocytes. DNA sequencing was done using SANGER sequencing method. Results: Pharmacogenetic testing results revealed positive for HLA-B58:01 allele. Symptoms of the patient receded after allopurinol withdrawal. Conclusion: The thrust of personalized therapy is from decoding the individual specific genetic variations astutely for better therapeutic outcomes such as reducing the ADRs. Pharmacogenetic testing is emerging as a safe, fast, and economic screening tool for personalized therapy by preventing ADRs. Pharmacogenetic HLA-B58:01 allele testing before allopurinol administration could significantly reduce the incidence of SJS/TEN and associated mortalities/morbidities and thereby represent a potential cost-effective intervention.", "affiliations": "Manipal Academy of Higher Education, Manipal, Karnataka, India.;Manipal Academy of Higher Education, Manipal, Karnataka, India.;Manipal Academy of Higher Education, Manipal, Karnataka, India.;Manipal Academy of Higher Education, Manipal, Karnataka, India.;Manipal Academy of Higher Education, Manipal, Karnataka, India.;Manipal Academy of Higher Education, Manipal, Karnataka, India.", "authors": "Lavu\|Alekhya\|A\|;Thiriveedi\|Sneha\|S\|;Thomas\|Levin\|L\|;Khera\|Kanav\|K\|;Saravu\|Kavitha\|K\|;Rao\|Mahadev\|M\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/0018578720934972", "fulltext": null, "fulltext_license": null, "issn_linking": "0018-5787", "issue": "56(6)", "journal": "Hospital pharmacy", "keywords": "Adverse drug reactions; Skin; analgesics; gene therapy; medication safety", "medline_ta": "Hosp Pharm", "mesh_terms": null, "nlm_unique_id": "0043175", "other_id": null, "pages": "660-663", "pmc": null, "pmid": "34732918", "pubdate": "2021-12", "publication_types": "D016428:Journal Article", "references": "26094938;30134124;25647431;21358399;21593754;21906289;21162721;2404462;23981744;15743917;28549177;28329382;17919772;7794310;8420497;28202399;23232549;24988075;28857441", "title": "Clinical Utility of HLA-B58:01 Genotyping to Prevent Allopurinol-Induced SJS/TEN.", "title_normalized": "clinical utility of hla b 58 01 genotyping to prevent allopurinol induced sjs ten" }	[ { "companynumb": "IN-ACCORD-191033", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "203154", "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": "ALLOPURINOL." } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "SJS-TEN overlap", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "LAVU A, THIRIVEEDI S, THOMAS L, KHERA K, SARAVU K, RAO M. CLINICAL UTILITY OF HLA?B58:01 GENOTYPING TO PREVENT ALLOPURINOL?INDUCED SJS/TEN. HOSPITAL PHARMACY. 2020. DOI:10.1177/0018578720934972.", "literaturereference_normalized": "clinical utility of hla b 58 01 genotyping to prevent allopurinol induced sjs ten", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20200719", "receivedate": "20200719", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18041206, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "IN-Indoco-000251", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "204467", "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": "ALLOPURINOL" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "SJS-TEN overlap", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "Lavu A, Thiriveedi S, Thomas L, Khera K, Saravu K, Rao M. Clinical Utility of HLA-B58:01 Genotyping to Prevent Allopurinol-Induced SJS/TEN. Hosp Pharm. 2021 Dec;56(6):660-663.", "literaturereference_normalized": "clinical utility of hla b 58 01 genotyping to prevent allopurinol induced sjs ten", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20211118", "receivedate": "20211118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20084675, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "A pharmacist-managed deep vein thrombosis (DVT) treatment program was put into operation at Jackson Memorial Hospital in Miami, Florida to provide appropriate transition of care to the outpatient setting for patients diagnosed with DVT. A postgraduate year 1 pharmacy practice resident partnered with a clinical pharmacist to establish and implement the DVT pilot program in the emergency department (ED). Once contacted, the pharmacy resident or the clinical pharmacist communicated with the ED physician and made recommendations regarding appropriate anticoagulation. The pharmacist met with the patient to obtain informed consent and provide counseling regarding the anticoagulants. A timely outpatient appointment at the pharmacy-managed warfarin clinic was arranged for the patient and contact information was exchanged between the patient and the pharmacist. On average, patients enrolled in the DVT program from the ED were released 18.29 hours (±7.06) following the time of arrival. Following release from the hospital, 91% of patients attended their outpatient follow-up appointment at the warfarin clinic. Since the initiation of the DVT program, 1 patient experienced a recurrent DVT and major bleed during their treatment course. Due to successful implementation of this pharmacist-managed DVT program in the ED, the services were subsequently extended to inpatients with DVT.", "affiliations": "Pharmacy Department, Jackson Memorial Hospital, Miami, FL, USA. [email protected]", "authors": "Davis\|Kyle A\|KA\|;Miyares\|Marta A\|MA\|;Price-Goodnow\|Venessa S\|VS\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/0897190012465953", "fulltext": null, "fulltext_license": null, "issn_linking": "0897-1900", "issue": "26(4)", "journal": "Journal of pharmacy practice", "keywords": "anticoagulation; deep vein thrombosis; transition of care; venous thromboembolism", "medline_ta": "J Pharm Pract", "mesh_terms": "D006801:Humans; D010595:Pharmacists; D010607:Pharmacy Service, Hospital; D020246:Venous Thrombosis", "nlm_unique_id": "8900945", "other_id": null, "pages": "438-41", "pmc": null, "pmid": "23172896", "pubdate": "2013-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Optimizing transition of care through the facilitation of a pharmacist-managed deep vein thrombosis treatment program.", "title_normalized": "optimizing transition of care through the facilitation of a pharmacist managed deep vein thrombosis treatment program" }	[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-006494", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "009218", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEEP VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DAVIS KA, MIYARES MA, PRICE-GOODNOW VS. OPTIMIZING TRANSITION OF CARE THROUGH THE FACILITATION OF A PHARMACIST-MANAGED DEEP VEIN THROMBOSIS TREATMENT PROGRAM. V.S. JOURNAL OF PHARMACY PRACTICE. 2013?26(4):438-41", "literaturereference_normalized": "optimizing transition of care through the facilitation of a pharmacist managed deep vein thrombosis treatment program", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200131", "receivedate": "20200131", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17353415, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]
{ "abstract": "OBJECTIVE\nSarcoidosis is a chronic granulomatous disease for which there are limited therapeutic options. This is the first randomized, placebo-controlled study to demonstrate that antimycobacterial therapy reduces lesion diameter and disease severity among patients with chronic cutaneous sarcoidosis.\n\n\nOBJECTIVE\nTo evaluate the safety and efficacy of once-daily antimycobacterial therapy on the resolution of chronic cutaneous sarcoidosis lesions.\n\n\nMETHODS\nA randomized, placebo-controlled, single-masked trial on 30 patients with symptomatic chronic cutaneous sarcoidosis lesions deemed to require therapeutic intervention.\n\n\nMETHODS\nA tertiary referral dermatology center in Nashville, Tennessee.\n\n\nMETHODS\nParticipants were randomized to receive either the oral concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) regimen or a comparative placebo regimen for 8 weeks with a 180-day follow-up.\n\n\nMETHODS\nParticipants were monitored for absolute change in lesion diameter and decrease in granuloma burden, if present, on completion of therapy.\n\n\nMETHODS\nIn the intention-to-treat analysis, the CLEAR-treated group had a mean (SD) decrease in lesion diameter of -8.4 (14.0) mm compared with an increase of 0.07 (3.2) mm in the placebo-treated group (P = .05). The CLEAR group had a significant reduction in granuloma burden and experienced a mean (SD) decline of -2.9 (2.5) mm in lesion severity compared with a decline of -0.6 (2.1) mm in the placebo group (P = .02).\n\n\nCONCLUSIONS\nAntimycobacterial therapy may result in significant reductions in chronic cutaneous sarcoidosis lesion diameter compared with placebo. These observed reductions, associated with a clinically significant improvement in symptoms, were present at the 180-day follow-up period. Transcriptome analysis of sarcoidosis CD4+ T cells revealed reversal of pathways associated with disease severity and enhanced T-cell function following T-cell receptor stimulation.\n\n\nBACKGROUND\nclinicaltrials.gov Identifier: NCT01074554.", "affiliations": "Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee2Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.", "authors": "Drake\|Wonder P\|WP\|;Oswald-Richter\|Kyra\|K\|;Richmond\|Bradley W\|BW\|;Isom\|Joan\|J\|;Burke\|Victoria E\|VE\|;Algood\|Holly\|H\|;Braun\|Nicole\|N\|;Taylor\|Thyneice\|T\|;Pandit\|Kusum V\|KV\|;Aboud\|Caroline\|C\|;Yu\|Chang\|C\|;Kaminski\|Naftali\|N\|;Boyd\|Alan S\|AS\|;King\|Lloyd E\|LE\|", "chemical_list": "D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D017963:Azithromycin; D004977:Ethambutol; D015242:Ofloxacin; D012293:Rifampin", "country": "United States", "delete": false, "doi": "10.1001/jamadermatol.2013.4646", "fulltext": null, "fulltext_license": null, "issn_linking": "2168-6068", "issue": "149(9)", "journal": "JAMA dermatology", "keywords": null, "medline_ta": "JAMA Dermatol", "mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D015496:CD4-Positive T-Lymphocytes; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D004977:Ethambutol; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D015242:Ofloxacin; D012293:Rifampin; D012507:Sarcoidosis; D012720:Severity of Illness Index; D016037:Single-Blind Method; D012871:Skin Diseases; D059467:Transcriptome; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "101589530", "other_id": null, "pages": "1040-9", "pmc": null, "pmid": "23863960", "pubdate": "2013-09", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "18578557;22291603;17190623;22395590;21146388;1656742;12615627;12781508;19218196;10573213;16954298;10472755;18429644;22552860;19622457;23021769;11176663;22596102;19910611;19192299;19131956;18328208;22825614;20397737;17277290;17676945;15332711;18439270;14977983;17357846;19464956;17088357;12453366;20665394;15753209;21553656;17560299", "title": "Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study.", "title_normalized": "oral antimycobacterial therapy in chronic cutaneous sarcoidosis a randomized single masked placebo controlled study" }	[ { "companynumb": "US-JNJFOC-20130916846", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CUTANEOUS SARCOIDOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "ONE DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "CUTANEOUS SARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020634", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CUTANEOUS SARCOIDOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVAQUIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "UPTO A MAXIMUM DOSAGE OF 1200 MG PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CUTANEOUS SARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "10MG/KG/DAY UPTOA MAXIMUM DOSAGE OF 300 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CUTANEOUS SARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "CUTANEOUS SARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVAQUIN" } ], "patientagegroup": null, 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ORAL ANTIMYCOBACTERIAL THERAPY IN CHRONIC CUTANEOUS SARCOIDOSIS: A RANDOMIZED, SINGLE-MASKED, PLACEBO-CONTROLLED STUDY. JAMA DERMATOLOGY 09-JAN-2013;149 (9):1040-1049.", "literaturereference_normalized": "oral antimycobacterial therapy in chronic cutaneous sarcoidosis a randomized single masked placebo controlled study", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150525", "receivedate": "20150412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11019488, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" }, { "companynumb": "US-JNJFOC-20130916847", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, 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ORAL ANTIMYCOBACTERIAL THERAPY IN CHRONIC CUTANEOUS SARCOIDOSIS: A RANDOMIZED, SINGLE-MASKED, PLACEBO-CONTROLLED STUDY. JAMA DERMATOLOGY 09-JAN-2013;149 (9):1040-1049.", "literaturereference_normalized": "oral antimycobacterial therapy in chronic cutaneous sarcoidosis a randomized single masked placebo controlled study", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150525", "receivedate": "20150412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11019460, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" }, { "companynumb": "US-JNJFOC-20130916425", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, 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"drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DRAKE WP, OSWALD-RICHTER K, RICHMOND BW, ISOM J, BURKE VE, ALGOOD H, ET AL. ORAL ANTIMYCOBACTERIAL THERAPY IN CHRONIC CUTANEOUS SARCOIDOSIS: A RANDOMIZED, SINGLE-MASKED, PLACEBO-CONTROLLED STUDY. JAMA DERMATOLOGY 01-SEP-2013;149 (9):1040-1049.", "literaturereference_normalized": "oral antimycobacterial therapy in chronic cutaneous sarcoidosis a randomized single masked placebo controlled study", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150525", "receivedate": "20150412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11019571, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]
{ "abstract": "Patients on chronic immunosuppressant therapy after renal transplantation have a high rate of in-hospital mortality and approximately 20% mortality rate per year after conventional valve surgery. While transcatheter aortic valve replacement (TAVR) is an appealing option to consider for such patients, there are not significant outcome data for the procedure in this patient population. We report two cases of aortic root rupture after TAVR in renal transplant patients on chronic immunosuppressant therapy.", "affiliations": "Medical City Hospital, Dallas, Texas; Cardiopulmonary Research Science and Technology Institute, Plano, Texas.", "authors": "Holper\|Elizabeth M\|EM\|;Kim\|Rebeca J\|RJ\|;Brooks\|Aaron\|A\|;Mack\|Michael\|M\|", "chemical_list": "D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": "10.1002/ccd.25513", "fulltext": null, "fulltext_license": null, "issn_linking": "1522-1946", "issue": "85(5)", "journal": "Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions", "keywords": "TAVR; aortic rupture; renal transplant", "medline_ta": "Catheter Cardiovasc Interv", "mesh_terms": "D000368:Aged; D001013:Aorta, Thoracic; D001019:Aortic Rupture; D001024:Aortic Valve Stenosis; D017548:Echocardiography, Transesophageal; D017809:Fatal Outcome; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008875:Middle Aged; D061330:Multidetector Computed Tomography; D065467:Transcatheter Aortic Valve Replacement", "nlm_unique_id": "100884139", "other_id": null, "pages": "909-15", "pmc": null, "pmid": "24740848", "pubdate": "2015-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Aortic root rupture after TAVR in two renal transplant patients on chronic immunosuppressant therapy.", "title_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy" }	[ { "companynumb": "US-ZYDUS-010399", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077621", "drugbatchnumb": "UNKNOWN", "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": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "PREDNISONE/PREDNISONE ACETATE" } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pericardial effusion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haematoma", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coronary artery occlusion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bundle branch block", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram ST segment elevation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER- CARDIOVASC-INTERV 2015?85(5):909-915.", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160310", "receivedate": "20160310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12166807, "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": "US-DRREDDYS-USA/USA/16/0077811", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "CYCLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "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": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic calcification", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Haematoma", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aortic valve replacement", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aortic stenosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER E, KIM R, BROOKS A, MACK M. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER CARDIOVASC INTERV. 2015?85(5):909-15.", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20160316", "receivedate": "20160316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12182386, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "US-TEVA-640364USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "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": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER-CARDIOVASC-INTERV 2015?85(5):909-915.", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160304", "receivedate": "20160304", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12147222, "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": "PHHY2016US023238", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "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": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "048", "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." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M.. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER-CARDIOVASC-INTERV. 2015?85(5):909-15", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160225", "receivedate": "20160225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12116580, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "US-MYLANLABS-2016M1008448", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "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": "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": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075568", "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": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER-CARDIOVASC-INTERV 2015?85(5):909-915.", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160229", "receivedate": "20160229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12128160, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "US-APOTEX-2016AP006852", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "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." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "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": "CYCLOSPORINE." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M.. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY.. CATHETER-CARDIOVASC-INTERV. 2015?85(5):909-915", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160303", "receivedate": "20160303", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12139565, "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": "US-STRIDES ARCOLAB LIMITED-2016SP001437", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematoma", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER-CARDIOVASC-INTERV. 2015?85(5):909-915", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160304", "receivedate": "20160304", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12144191, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "PHHY2016US022386", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "80336", "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": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "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": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M.. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER-CARDIOVASC-INTERV. 2015?85(5):909-15", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160225", "receivedate": "20160225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12116681, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-112197", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "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": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER CARDIOVASC INTERV. 2015;85(5):909-915", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170906", "receivedate": "20170906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13940161, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-MYLANLABS-2016M1008449", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090596", "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": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER-CARDIOVASC-INTERV 2015?85(5):909-915.", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160229", "receivedate": "20160229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12128123, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]
{ "abstract": "OBJECTIVE\nTo compare the occurrence of non-infectious uveitis based on the type of tumour necrosis factor (TNF) inhibitor used to manage spondyloarthritis in ankylosing spondylitis (AS) patients.\n\n\nMETHODS\nThe occurrence (new-onset and recurrence) of uveitis was reviewed retrospectively in AS patients receiving different TNF inhibitor therapies (adalimumab [ADA], infliximab [IFX], etanercept [ETN], and golimumab [GOL]) for the management of spondyloarthritis from 2005 to 2018. Kaplan-Meier analysis was performed to calculate the cumulative occurrence rates of uveitis during TNF inhibitor therapy, and a log-rank test was used to analyse differences between the survival curves. Multivariable Cox proportional-hazards models were used to compute hazard ratios (HRs) of different TNF agents for uveitis occurrence after adjusting for concurrent confounding factors.\n\n\nRESULTS\nThe three-year cumulative occurrence rates of uveitis were significantly different according to the type of anti-TNFs used (23.1% in IFX, 18.5% in ETN, and 11.9% in ADA+GOL group) (p=0.020). The risk of new-onset uveitis was similar for different drugs. However, the IFX group showed a 5.4 times higher risk of recurrence than the ADA+GOL group (p=0.022). After adjusting for other confounding factors, IFX use was independently associated with a more frequent occurrence of uveitis in AS patients (HR=2.01; p=0.011).\n\n\nCONCLUSIONS\nA significant number of AS patients who received anti-TNF therapy developed uveitis. Different types of anti-TNF drugs were associated with uveitis recurrence. Particularly, chimeric mouse-human monoclonal antibody (IFX) was found to increase the risk of uveitis occurrence compared to humanised monoclonal antibody (ADA or GOL).", "affiliations": "Department of Ophthalmology, The Institute of Vision Research, Severance Eye Hospital, Yonsei University College of Medicine, Seoul, Korea.;Department of Ophthalmology, The Institute of Vision Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Department of Ophthalmology, The Institute of Vision Research, Severance Eye Hospital, Yonsei University College of Medicine, Seoul, Korea. [email protected].", "authors": "Choi\|Eun Young\|EY\|;Lee\|Minwoo\|M\|;Lee\|Christopher Seungkyu\|CS\|", "chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept", "country": "Italy", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0392-856X", "issue": "38(6)", "journal": "Clinical and experimental rheumatology", "keywords": null, "medline_ta": "Clin Exp Rheumatol", "mesh_terms": "D000068879:Adalimumab; D015331:Cohort Studies; D000068800:Etanercept; D006801:Humans; D000069285:Infliximab; D012189:Retrospective Studies; D013167:Spondylitis, Ankylosing; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014605:Uveitis", "nlm_unique_id": "8308521", "other_id": null, "pages": "1132-1137", "pmc": null, "pmid": "32828140", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": null, "title": "Uveitis occurrence in patients with ankylosing spondylitis according to the type of tumour necrosis factor inhibitor: a cohort study of 175 patients.", "title_normalized": "uveitis occurrence in patients with ankylosing spondylitis according to the type of tumour necrosis factor inhibitor a cohort study of 175 patients" }	[ { "companynumb": "KR-JNJFOC-20200844680", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANKYLOSING SPONDYLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMICADE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Uveitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHOI E, LEE M, LEE C. UVEITIS OCCURRENCE IN PATIENTS WITH ANKYLOSING SPONDYLITIS ACCORDING TO THE TYPE OF TUMOUR NECROSIS FACTOR INHIBITOR:A COHORT STUDY OF 175 PATIENTS. CLINICAL AND EXPERIMENTAL RHEUMATOLOGY. 2020?.", "literaturereference_normalized": "uveitis occurrence in patients with ankylosing spondylitis according to the type of tumour necrosis factor inhibitor a cohort study of 175 patients", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20200908", "receivedate": "20200908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18243208, "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\nTransplantation and immunosuppressive drugs are major limitations to the success of pregnancy. In 1988, the first pregnancy after a heart transplant was reported, which has given female recipients the hope to give birth. During pregnancy, physiologic changes with increased blood volume and hemodilution may influence blood drug level.\n\n\nMETHODS\nWe reported our experience in monitoring on immunosuppressive drugs for 2 cases. Both of them underwent heart transplantation in 2006 and were 34 and 37 years old at time of pregnancy. For both cases, we frequently monitored the blood level and increased the dosage of immunosuppressive drugs accordingly. Both cases had uneventful pregnancy and delivery to healthy babies at the National Taiwan University Hospital in Taiwan. Their postpartum courses were uneventful as well.\n\n\nCONCLUSIONS\nWe advocate adjusting the immunosuppressive dosage according to the blood level before pregnancy.", "affiliations": "Department of Nursing, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Nursing, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan; Department of Surgery, Fu Jen Catholic University Hospital, and Fu Jen Catholic University College of Medicine, New Taipei City, Taiwan. Electronic address: [email protected].", "authors": "Tsao\|C-I\|CI\|;Chou\|N-K\|NK\|;Chi\|N-H\|NH\|;Huang\|S-C\|SC\|;Tsan\|C-Y\|CY\|;Wang\|C-H\|CH\|;Yu\|H-Y\|HY\|;Wu\|I-H\|IH\|;Chen\|Y-S\|YS\|;Shun\|C-T\|CT\|;Wang\|S-S\|SS\|", "chemical_list": "D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1345", "issue": "48(3)", "journal": "Transplantation proceedings", "keywords": null, "medline_ta": "Transplant Proc", "mesh_terms": "D000328:Adult; D005260:Female; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome", "nlm_unique_id": "0243532", "other_id": null, "pages": "978-81", "pmc": null, "pmid": "27234783", "pubdate": "2016-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Surveillance of Immunosuppression During Pregnancy After Heart Transplantation: Case Report.", "title_normalized": "surveillance of immunosuppression during pregnancy after heart transplantation case report" }	[ { "companynumb": "TW-ACCORD-044013", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED WITH 1.5 MG AND THEN INCREASED TO 2 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEART TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAO CI, CHOU NK, CHI NH, HUANG SC, TSAN CY, WANG CH ET AL. SURVEILLANCE OF IMMUNOSUPPRESSION DURING PREGNANCY AFTER HEART TRANSPLANTATION: CASE REPORT. TRANSPLANTATION PROCEEDINGS. 2016; 48(3): 978-981", "literaturereference_normalized": "surveillance of immunosuppression during pregnancy after heart transplantation case report", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20160921", "receivedate": "20160921", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12765118, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" }, { "companynumb": "PHHY2016TW076985", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "65017", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MOTHER DOSE: 75 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MOTHER DOSE: 1.25 MG, QD", "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": "EVEROLIMUS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MOTHER DOSE: 1 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "65017", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MOTHER DOSE: 125 MG, QD", "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": "CICLOSPORIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CANDESARTAN CILEXETIL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLOPRESS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tuberous sclerosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WANG S, TSAO C, CHOU N, CHI N, HUANG S, TSAN C ET AL.. SURVEILLANCE OF IMMUNOSUPPRESSION DURING PREGNANCY AFTER HEART TRANSPLANTATION: CASE REPORT. TRANSPLANTATION PROCEEDINGS. 2016;48:978-81", "literaturereference_normalized": "surveillance of immunosuppression during pregnancy after heart transplantation case report", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20160608", "receivedate": "20160607", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12442426, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" } ]
{ "abstract": "Here we describe a patient with a rare movement disorder, hemichorea-hemiballismus, which is described as a complication of non-ketotic hyperglycaemia. This complication may be seen in individuals with poorly controlled long-standing diabetes mellitus. Proper diagnosis is established with CT and MRI of the brain, which typically show classic findings in the basal ganglia. Treatment focuses on improvement of glycaemic control and usually results in rapid resolution of the movement disorder. Nevertheless, recurrent episodes of hemichorea-hemiballismus, and even more ominous complications such as ischaemic stroke may occur.", "affiliations": "Universidad de Cuenca, Cuenca, Azuay, Ecuador. [email protected]", "authors": "Carrion\|Diego M\|DM\|;Carrion\|Andres F\|AF\|", "chemical_list": null, "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": "D002819:Chorea; D003937:Diagnosis, Differential; D020820:Dyskinesias; D006801:Humans; D006943:Hyperglycemia; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020521:Stroke; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "23470671", "pubdate": "2013-03-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12127677;13798206;2757526;15205134;20039938;19305947;21995866;20566257;22095170", "title": "Non-ketotic hyperglycaemia hemichorea-hemiballismus and acute ischaemic stroke.", "title_normalized": "non ketotic hyperglycaemia hemichorea hemiballismus and acute ischaemic stroke" }	[ { "companynumb": "EC-APOTEX-2017AP017027", "fulfillexpeditecriteria": "1", "occurcountry": "EC", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN ASPART" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERGLYCAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN ASPART" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INSULIN GLARGINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERGLYCAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN GLARGINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075984", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERGLYCAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APO-METFORMINA" } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemic stroke", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperglycaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ballismus", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chorea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "CARRION DM, CARRION AF.. NON-KETOTIC HYPERGLYCAEMIA HEMICHOREA-HEMIBALLISMUS AND ACUTE ISCHAEMIC STROKE. BMJ CASE REP. 2013;1-3", "literaturereference_normalized": "non ketotic hyperglycaemia hemichorea hemiballismus and acute ischaemic stroke", "qualification": "3", "reportercountry": "EC" }, "primarysourcecountry": "EC", "receiptdate": "20170829", "receivedate": "20170829", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13916152, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]
{ "abstract": "Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.", "affiliations": "Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio.;National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland.;National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland.;Medical Genetics Institute, Cedars Sinai Medical Center, Division of Medical Genetics, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California.;Section of Medical Genetics, Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Section of Medical Genetics, Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.;Greenwood Genetic Center, Columbia, South Carolina.;Greenwood Genetic Center, Columbia, South Carolina.;Laboratory of Pathology, National Cancer Institute, National Institute of Health, Bethesda, Maryland.;Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia.;Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia.;Clinical Genetics Service, Nottingham University Hospitals Trust, Nottingham, United Kingdom.;Medical Genetics Institute, Cedars Sinai Medical Center, Division of Medical Genetics, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California.", "authors": "Russell\|Bianca\|B\|;Johnston\|Jennifer J\|JJ\|;Biesecker\|Leslie G\|LG\|;Kramer\|Nancy\|N\|;Pickart\|Angela\|A\|;Rhead\|William\|W\|;Tan\|Wen-Hann\|WH\|;Brownstein\|Catherine A\|CA\|;Kate Clarkson\|L\|L\|;Dobson\|Amy\|A\|;Rosenberg\|Avi Z\|AZ\|;Vergano\|Samantha A Schrier\|SA\|;Helm\|Benjamin M\|BM\|;Harrison\|Rachel E\|RE\|;Graham\|John M\|JM\|", "chemical_list": "C473949:ASXL1 protein, human; D012097:Repressor Proteins", "country": "United States", "delete": false, "doi": "10.1002/ajmg.a.37131", "fulltext": null, "fulltext_license": null, "issn_linking": "1552-4825", "issue": "167A(9)", "journal": "American journal of medical genetics. Part A", "keywords": "ASXL1; Bohring-Opitz syndrome; Wilms tumor; cyclic vomiting; failure to thrive; hypertrichosis; intellectual disability; myopia; nevus flammeus", "medline_ta": "Am J Med Genet A", "mesh_terms": "D000015:Abnormalities, Multiple; D019046:Bone Marrow Neoplasms; D002648:Child; D002675:Child, Preschool; D003398:Craniosynostoses; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008607:Intellectual Disability; D008297:Male; D009154:Mutation; D012097:Repressor Proteins; D009396:Wilms Tumor", "nlm_unique_id": "101235741", "other_id": null, "pages": "2122-31", "pmc": null, "pmid": "25921057", "pubdate": "2015-09", "publication_types": "D016428:Journal Article; D052060:Research Support, N.I.H., Intramural", "references": "11038445;23505322;9477319;21368916;17498985;12657473;19833123;24255920;10405439;23649928;21706002;7546453;22419483;10861669;20717007;10861670;22186017;7258228;19606480;22897849;23672984;16528754;16925531;23383720;25426837;16691589;12514360;1190170;10861668;17531565", "title": "Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.", "title_normalized": "clinical management of patients with asxl1 mutations and bohring opitz syndrome emphasizing the need for wilms tumor surveillance" }	[ { "companynumb": "US-JNJFOC-20150903756", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LORAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "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": null, "activesubstance": { "activesubstancename": "CYPROHEPTADINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYCLIC VOMITING SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYPROHEPTADINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "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": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." } ], "patientagegroup": "3", "patientonsetage": "36", "patientonsetageunit": "802", "patientsex": "2", "patientweight": "2.43", "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RUSSELL B, JOHNSTON JJ, BIESECKER LG, KRAMER N, PICKART A, RHEAD W, ET AL. CLINICAL MANAGEMENT OF PATIENTS WITH ASXL1 MUTATIONS AND BOHRING?OPITZ SYNDROME, EMPHASIZING THE NEED FOR WILMS TUMOR SURVEILLANCE. AMERICAN JOURNAL OF MEDICAL GENETICS 01-SEP-2015?2015: 167 (9):2122-2131.", "literaturereference_normalized": "clinical management of patients with asxl1 mutations and bohring opitz syndrome emphasizing the need for wilms tumor surveillance", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151013", "receivedate": "20151013", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11622818, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "US-JNJFOC-20150902239", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTINOMYCIN D" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROBLASTOMA", "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": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "050718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LIPOSOME INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HYDROCHLORIDE." } ], "patientagegroup": "3", "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RUSSELL B, JOHNSTON JJ, BIESECKER LG, KRAMER N, PICKART A, RHEAD W, ET AL. CLINICAL MANAGEMENT OF PATIENTS WITH ASXL1 MUTATIONS AND BOHRING-OPITZ SYNDROME, EMPHASIZING THE NEED FOR WILMS TUMOR SURVEILLANCE. AMERICAN JOURNAL OF MEDICAL GENETICS 01-SEP-2015?167 (9):2122-2131.", "literaturereference_normalized": "clinical management of patients with asxl1 mutations and bohring opitz syndrome emphasizing the need for wilms tumor surveillance", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151113", "receivedate": "20151113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11736230, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" } ]
{ "abstract": "For patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are not eligible for intensive chemotherapy because of comorbidities, advanced age, or relapse after heavy salvage regimens, treatment options are very limited and prognosis is poor. We retrospectively analyzed 29 patients with relapsed/refractory DLBCL treated with combination bendamustine plus rituximab (BR) between July 2010 and January 2014 to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and treatment safety. Twenty-eight patients were available for this analysis. ORR was 50% (14 patients), with 39.3% CR (11 patients), and 10.7% PR (3 patients). SD was reported in 2 patients (7.2%) and PD in 12 patients (42.8%). At the median follow up of 8 months (range 1-37.4 months), the median PFS was 8 months for all patients (95% CI 5.5-26.6). The median DOR was 24.7 months (95% CI 3.2-24.7). Grade 3/4 toxicity observed included hematologic events: lymphopenia (42.8%), neutropenia (32.1%), anemia (17.2%), and thrombocytopenia (14.2%). BR can be considered to have a role in the treatment of patients with relapsed/refractory DLBCL with limited therapeutic options, in that it can induce long-term remission in some patients with an acceptable toxicity profile.", "affiliations": "Hematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi, Italy. Electronic address: [email protected].;Hematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi, Italy.;Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari Medical School, Bari, Italy.;Hematology Unit, Department of Medical and Experimental Oncology, IRCCS National Cancer Research Centre \"Giovanni Paolo II\", Bari, Italy.;Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari Medical School, Bari, Italy.;Hematology Unit, Department of Medical and Experimental Oncology, IRCCS National Cancer Research Centre \"Giovanni Paolo II\", Bari, Italy.;Hematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi, Italy.;Hematology Unit, Foundation Hospital Cardinal \"G. Panico\", Tricase, Lecce, Italy.;Hematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi, Italy.", "authors": "Merchionne\|Francesca\|F\|;Quintana\|Giovanni\|G\|;Gaudio\|Francesco\|F\|;Minoia\|Carla\|C\|;Specchia\|Giorgina\|G\|;Guarini\|Attilio\|A\|;Quarta\|Giovanni\|G\|;Pavone\|Vincenzo\|V\|;Melpignano\|Angela\|A\|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D009588:Nitrogen Mustard Compounds; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0145-2126", "issue": "38(12)", "journal": "Leukemia research", "keywords": "Bendamustine; DLBCL; Rituximab; Salvage therapy", "medline_ta": "Leuk Res", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009588:Nitrogen Mustard Compounds; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D015996:Survival Rate", "nlm_unique_id": "7706787", "other_id": null, "pages": "1446-50", "pmc": null, "pmid": "25455656", "pubdate": "2014-12", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a retrospective analysis.", "title_normalized": "bendamustine plus rituximab for relapsed or refractory diffuse large b cell lymphoma a retrospective analysis" }	[ { "companynumb": "IT-ROCHE-1508165", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "375", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENDAMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT A DOSE BETWEEN 70 AND 120 MG/M2 (MEAN 90 MG/M2) ON DAYS 1 AND 2 OF EACH 28-DAY CYCLE FOR UP TO SI", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDAMUSTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": ", QUINTANA G, GAUDIO F, MINOIA C, SPECCHIA G, GUARINI A, QUARTA G, PAVONE V AND MELPIGNANO A. BENDAMUSTINE PLUS RITUXIMAB FOR RELAPSED OR REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA: A RETROSPECTIVE ANALYSIS. LEUKEMIA RESEARCH 2014 DEC 01;38(12):1446-1450.", "literaturereference_normalized": "bendamustine plus rituximab for relapsed or refractory diffuse large b cell lymphoma a retrospective analysis", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20141229", "receivedate": "20141229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10677816, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]
{ "abstract": "Although advancing age can greatly increase the complexities of treating metastatic breast cancer, chronological age alone is insufficient to determine the type or intensity of treatment. Older patients require an individualized approach that takes into account the patient's physical ability, social circumstances and mental capacity to tolerate treatment. This section features three older women treated with eribulin for metastatic breast cancer. In the first case, a 70-year-old woman maintained stable disease into her 34th month of treatment with third-line eribulin. In the remaining cases, two heavily pretreated women (80 and 90 years, respectively) with metastatic disease and liver involvement presented objective radiological benefit to later-line eribulin along with prolonged clinical improvement and good tolerability.", "affiliations": "Medical Oncology Department, Medical-Surgical Hospital of Jaén, Jaén, Spain.;Medical Oncology Department, Medical-Surgical Hospital of Jaén, Jaén, Spain.;Medical Oncology Department, Medical-Surgical Hospital of Jaén, Jaén, Spain.;Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.;Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.;Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.", "authors": "Garrido\|Maria Lomas\|ML\|;Morago\|Ana Jaén\|AJ\|;Rovira\|Pedro Sánchez\|PS\|;Olarte\|Paula Espinosa\|PE\|;Sánchez\|Cristina Pernaut\|CP\|;Sánchez\|Luis Manso\|LM\|", "chemical_list": "D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; C490954:eribulin", "country": "England", "delete": false, "doi": "10.2217/fon-2017-0357", "fulltext": null, "fulltext_license": null, "issn_linking": "1479-6694", "issue": "14(7s)", "journal": "Future oncology (London, England)", "keywords": "elderly; eribulin; metastatic breast cancer", "medline_ta": "Future Oncol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D005260:Female; D005663:Furans; D006801:Humans; D007659:Ketones; D016896:Treatment Outcome", "nlm_unique_id": "101256629", "other_id": null, "pages": "21-27", "pmc": null, "pmid": "29611758", "pubdate": "2018-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Experience with eribulin in the treatment of elderly women with metastatic breast cancer: case studies.", "title_normalized": "experience with eribulin in the treatment of elderly women with metastatic breast cancer case studies" }	[ { "companynumb": "ES-EISAI MEDICAL RESEARCH-EC-2018-037942", "fulfillexpeditecriteria": "2", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "062", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ERIBULIN MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "201532", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "UNKNOWN", "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": "HALAVEN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALPRAZOLAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ERIBULIN MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "201532", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201402", "drugstartdateformat": "610", "drugstructuredosagenumb": "1.23", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALAVEN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "062", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "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": "50", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ERIBULIN MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "201532", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "10% DOSE REDUCTION", "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": "HALAVEN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CELECOXIB" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELECOXIB." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disorientation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201610" } }, "primarysource": { "literaturereference": "LOMAS GARRIDO M, JAEN MORAGO A, SANCHEZ ROVIRA P, ESPINOSA OLARTE P, PERNAUT SANCHEZ C, MANSO SANCHEZ L. EXPERIENCE WITH ERIBULIN IN THE TREATMENT OF ELDERLY WOMEN WITH METASTATIC BREAST CANCER: CASE STUDIES. FUTURE ONCOLOGY. 2018?14(7S):21-27.", "literaturereference_normalized": "experience with eribulin in the treatment of elderly women with metastatic breast cancer case studies", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20180413", "receivedate": "20180413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14757994, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "ES-ACCORD-066944", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040743", "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": "201310", "drugstartdateformat": "610", "drugstructuredosagenumb": "500", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "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": "201310", "drugstartdateformat": "610", "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DYSAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "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": "201310", "drugstartdateformat": "610", "drugstructuredosagenumb": "250", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "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": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201310", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMITRIPTYLINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DYSAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMITRIPTYLINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, 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{ "abstract": "Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab. In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14-24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1-90%). Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%. Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.", "affiliations": "Department of Hematology and Oncology, KIM IV, Faculty of Medicine, University Halle-Wittenberg, Halle, Germany.;Division of Endocrinology and Diabetology, Department of Medicine II, University of Freiburg, Freiburg, Germany.;Institute of Pathology, University of Freiburg, Germany.;Department of Nuclear Medicine, University of Freiburg, Germany.;Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.;Institute of Pathology, University of Freiburg, Germany.;Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.;German Cancer Research Center (DKFZ), Heidelberg, Germany.;Outcomes Research Unit, Department of Endocrine Surgery, Endocrine Center Stuttgart, Diakonie Klinikum Stuttgart, Stuttgart, Germany.;Klinikum Villingen-Schwenningen, Hämatologie/Onkologie, Villingen-Schwenningen, Germany.;Department of Nuclear Medicine, University of Freiburg, Germany.;Division of Endocrinology/Diabetology, Department of Internal Medicine, University Hospital Würzburg, Würzburg, Germany.;Zentrum für Strahlentherapie, Freiburg, Germany.;Praxis für Nuklearmedizin, Freiburg, Germany.;Institute of Medical Bioinformatics and Systems Medicine and Institute of Molecular Medicine and Cell Research; Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Eisai GmbH, Frankfurt/Main, Germany.;Outcomes Research Unit, Department of Endocrine Surgery, Endocrine Center Stuttgart, Diakonie Klinikum Stuttgart, Stuttgart, Germany.;Division of Endocrinology and Diabetology, Department of Medicine II, University of Freiburg, Freiburg, Germany.;Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.;Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.;Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.;Department of General and Visceral Surgery, University Hospital Freiburg, Freiburg, Germany.", "authors": "Dierks\|Christine\|C\|;Seufert\|Jochen\|J\|;Aumann\|Konrad\|K\|;Ruf\|Juri\|J\|;Klein\|Claudius\|C\|;Kiefer\|Selina\|S\|;Rassner\|Michael\|M\|;Boerries\|Melanie\|M\|;Zielke\|Andreas\|A\|;la Rosee\|Paul\|P\|;Meyer\|Philipp Tobias\|PT\|;Kroiss\|Matthias\|M\|;Weißenberger\|Christian\|C\|;Schumacher\|Tilmann\|T\|;Metzger\|Patrick\|P\|;Weiss\|Harald\|H\|;Smaxwil\|Constantin\|C\|;Laubner\|Katharina\|K\|;Duyster\|Justus\|J\|;von Bubnoff\|Nikolas\|N\|;Miething\|Cornelius\|C\|;Thomusch\|Oliver\|O\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1089/thy.2020.0322", "fulltext": "\n==== Front\nThyroid\nThyroid\nthy\nThyroid\n1050-7256\n1557-9077\nMary Ann Liebert, Inc., publishers 140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA\n\n33509020\n10.1089/thy.2020.0322\n10.1089/thy.2020.0322\nThyroid Cancer and Nodules\nCombination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma\nDierks et al.\nLenvatinib/Pembrolizumab in ATC/PDTC\nDierks Christine 12\nSeufert Jochen 3\nAumann Konrad 4\nRuf Juri 5\nKlein Claudius 245\nKiefer Selina 4\nRassner Michael 2\nBoerries Melanie 678\nZielke Andreas 9\nla Rosee Paul 10\nMeyer Philipp Tobias 511\nKroiss Matthias 1213\nWeißenberger Christian 14\nSchumacher Tilmann 15\nMetzger Patrick 816\nWeiss Harald 17\nSmaxwil Constantin 9\nLaubner Katharina 3\nDuyster Justus 2\nvon Bubnoff Nikolas 218\nMiething Cornelius 2611\nThomusch Oliver 19\n1 Department of Hematology and Oncology, KIM IV, Faculty of Medicine, University Halle-Wittenberg, Halle, Germany.\n2 Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.\n3 Division of Endocrinology and Diabetology, Department of Medicine II, University of Freiburg, Freiburg, Germany.\n4 Institute of Pathology, University of Freiburg, Germany.\n5 Department of Nuclear Medicine, University of Freiburg, Germany.\n6 German Cancer Research Center (DKFZ), Heidelberg, Germany.\n7 Comprehensive Cancer Center Freiburg (CCCF), University Medical Center, University of Freiburg, Freiburg, Germany.\n8 Institute of Medical Bioinformatics and Systems Medicine and Institute of Molecular Medicine and Cell Research; Faculty of Medicine, University of Freiburg, Freiburg, Germany.\n9 Outcomes Research Unit, Department of Endocrine Surgery, Endocrine Center Stuttgart, Diakonie Klinikum Stuttgart, Stuttgart, Germany.\n10 Klinikum Villingen-Schwenningen, Hämatologie/Onkologie, Villingen-Schwenningen, Germany.\n11 German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.\n12 Division of Endocrinology/Diabetology, Department of Internal Medicine, University Hospital Würzburg, Würzburg, Germany.\n13 Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.\n14 Zentrum für Strahlentherapie, Freiburg, Germany.\n15 Praxis für Nuklearmedizin, Freiburg, Germany.\n16 Faculty of Biology, University of Freiburg, Freiburg, Germany.\n17 Eisai GmbH, Frankfurt/Main, Germany.\n18 Department of Hematology/Oncology, University of Luebeck, Luebeck, Germany.\n19 Department of General and Visceral Surgery, University Hospital Freiburg, Freiburg, Germany.\n These authors contributed equally to this work.\n\nAddress correspondence to: Christine Dierks, MD, Department of Hematology and Oncology, KIM IV, Faculty of Medicine, University Halle-Wittenberg, Ernst-Grube-Str. 40, Freiburg D-06120, Germany [email protected]\n01 7 2021 July 2021\n08 7 2021\n08 7 2021\n31 7 10761085\n© Christine Dierks et al., 2021; Published by Mary Ann Liebert, Inc.\n2021\nChristine Dierks et al.\nhttps://creativecommons.org/licenses/by/4.0/ This Open Access article is distributed under the terms of the Creative Commons License [CC-BY] (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBackground: Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab.\n\nPatients and Methods: In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14–24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1–90%).\n\nResults: Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%.\n\nConclusions: Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.\n\nanaplastic thyroid cancer\nATC\nlenvatinib\nPDTC\npembrolizumab\npoorly differentiated thyroid cancer\n==== Body\nIntroduction\n\nAnaplastic thyroid carcinoma (ATC) is a rare disease with an extremely high mortality rate and a 10-year survival below 5% (1). ATCs grow very fast, infiltrate into cervical structures, such as the esophagus, trachea, or blood vessels, and metastasize to the lung, brain, and bone. Even with extensive multimodal therapy (surgery, external beam radiotherapy, and chemotherapy), the median overall survival (OS) is only 3–5 months (1–3). ATC frequently arises from differentiated thyroid carcinoma (DTC) but can also emerge de novo. Typical molecular features of ATC are mutations in TP53 (54–64%), TERT (61%), KRAS/NRAS (28–43%), BRAF (18–28%), NF1, NF2, PI3K, PTEN, and genes in the WNT signaling pathway (4–9). BRAF/MEK inhibitor combinations (dabrafenib/trametinib) are approved for BRAFV600E-mutated ATCs and have significantly enhanced survival and has high treatment response (overall response rate [ORR] 69%) (10,11). All other locally advanced or metastatic ATCs (about 75%) are individually treated with carboplatin, paclitaxel, or doxorubicin containing chemotherapeutic regimens with very modest ORR (10–20%) lasting only for a few months (progression-free survival [PFS] 3–4 months) (12–15). Poorly differentiated thyroid carcinoma (PDTC) has a more favorable prognosis, with some patients being partially responsive to radioiodine therapy (RIT), but 10-year survival is also below 10%.\n\nCompared with DTC, ATC/PDTC are characterized by an elevated tumor mutation burden, higher programmed death ligand 1 (PD-L1) levels, and increased neoangiogenesis (VEGFR/FGFR signaling) (7,16–22), suggesting that they may be sensitivity to immune checkpoint and neoangiogenesis inhibitors.\n\nLenvatinib is an antiangiogenic (VEGFR 1–3/FGFR 1–4) and antiproliferative (RET/PDGFR) tyrosine kinase inhibitor (TKI), which is approved for DTC refractory to radioiodine treatment (23). PFS in DTC is 19.4 months (23–26), but it is reduced to 14.8 months in PDTC, and all patients ultimately develop treatment resistance or treatment intolerance (26). In ATC, the PFS is even shorter (5.6–7.4 months) with variable ORR between 17.4% and 43%, depending on the initial tumor stage (27–29).\n\nPembrolizumab is an immune checkpoint inhibitor targeting PD-1 on immune cells. Response to pembrolizumab treatment is associated with elevated expression of PD-L1 or high tumor mutational burden (TMB) (30–34). DTC have low TMB and low PD-L1 expression (CPS/TPS) and hence have low response rates to immune checkpoint inhibitor treatments (ORR 9%) (35). In ATC with higher PD-L1/TMB, the effect of immune checkpoint inhibitors is still low (ORR <10%) (36,37), as the slow response to treatment (>8 weeks) cannot keep pace with the aggressive tumor growth.\n\nIn vitro studies and mouse experiments indicate synergism between lenvatinib and pembrolizumab (38). Lenvatinib not only blocks tumor neoangiogenesis and proliferation but also enhances immune cell invasion into the tumor and therefore fosters immune responses induced by immune checkpoint inhibitors (38). Furthermore, phase II trials with the lenvatinib/pembrolizumab combination in patients with extensively pretreated metastatic solid tumors (renal, ovarian, and endometrial carcinoma) not only showed acceptable toxicity but also very promising response rates (84% partial response [PR], 16% stable disease [SD]). Phase II/III trials for endometrial, head and neck, and hepatocellular carcinoma validated the high efficacy and safety for this combination (39–42). In ATC, pembrolizumab treatment was used as a salvage strategy after patients had failed lenvatinib or dabrafenib monotherapy or a dabrafenib/trametinib combination therapy. Pembrolizumab was added to the respective TKI and induced PR rates of 43%, but with a very short PFS of only 2.96 months (43).\n\nIn contrast to this study, we directly combined lenvatinib and pembrolizumab as front-line therapy after chemotherapy failure in eight patients with metastatic ATC (n = 6) or PDTC (n = 2) and examined treatment outcome and biomarkers for this approach.\n\nMaterials and Methods\n\nStudy population and patient characteristics\n\nThis is a retrospective, single-center (University Medical Center Freiburg) cohort study of eight patients with metastatic ATC (n = 6) or PDTC (n = 2) treated with a combination of the multikinase inhibitor lenvatinib and the immune checkpoint inhibitor pembrolizumab (L/P). Patient data were collected from March 2016 to December 2019 (Table 1). ATC/PDTC diagnosis was histopathologically confirmed by the Institute for Pathology, Freiburg, in all patients. Patients had no BRAFV600E mutation, but numerous other mutations were present (Supplementary Table S1). All patients were pretreated with irradiation, chemotherapy, or RIT (Table 1 and Supplementary Table S2). Adverse events (AEs) were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 5)–GBG (Table 2). The retrospective study was approved by the Institutional Review Board (IRB) of the University Freiburg.\n\nTable 1. Baseline Characteristics\n\nMedian age at treatment start (range), years\t63.5 (49–88)\t\nSex, n (%)\t\n Men\t4 (50)\t\n Women\t4 (50)\t\nPerformance status, n (%)\t\n ECOG 0\t3 (37.5)\t\n ECOG 1\t3 (37.5)\t\n ECOG 2\t2 (25)\t\nPathological diagnosis, n (%)\t\n ATC\t6 (75)\t\n PDTC\t2 (25)\t\nLocation of metastases, n (%)\t\n Lung\t8 (100)\t\n Bone\t2 (25)\t\n Kidney\t1 (12.5)\t\n Brain\t1 (12.5)\t\n Liver\t1 (12.5)\t\n Skin\t1 (12.5)\t\nCervical relapse, n (%)\t6 (75)\t\nPrevious therapy, n (%)\t\n Surgery\t8 (100)\t\n Radiation ± chemosensitizing\t7 (87.5)\t\n Chemotherapy\t6 (75)\t\n RIT\t2 (25)\t\nATC, anaplastic thyroid carcinoma; ECOG, Eastern Cooperative Oncology Group; PDTC, poorly differentiated thyroid carcinoma; RIT, radioiodine therapy.\n\nTable 2. Adverse Events According to the Common Terminology Criteria for Adverse Events Version 5.0\n\nEvent\tGrade I/II (%)\tGrade III/IV (%)\t\nTotal\t8/8 (100)\t3/8 (36)\t\nHypertension\t5/8 (63)\t \t\nFatigue\t2/8 (25)\t1/8 (13)\t\nAnorexia\t2/8 (25)\t2/8 (25)\t\nOral mucositis\t2/8 (25)\t \t\nJoint/muscle pain\t1/8 (13)\t \t\nHand–foot syndrome\t1/8 (13)\t \t\nDiarrhea\t1/8 (13)\t \t\nProteinuria\t1/8 (13)\t \t\nAbdominal pain\t \t1/8 (13)\t\nCervical bleeding\t \t1/8 (13)\t\nData are given as totals and %. Events reported are listed in descending frequency of columns for grade I/II and grade III/IV. A patients with several multiple occurrences of an adverse event is counted only once with the highest grade. A patient with multiple adverse events is counted only once in the total row.\n\nTreatment strategy\n\nPatients started with lenvatinib 24 mg oral daily if the body weight (BW) was more than 80 kg, or 20 mg for BW less than 80 kg. Pembrolizumab infusions were started in between 1 and 4 weeks after initiation of lenvatinib at a fixed dose of 200 mg total every 3 weeks. Dose for lenvatinib was stepwise reduced upon occurrence of side effects according to clinical judgment. Lenvatinib was given at least for 1 year and was then stopped in patients with confirmed complete response (CR). Pembrolizumab was given for up to 40 months. It will be continued in all patients reaching a CR for two more years.\n\nResponse assessment\n\nRadiology assessment including cervical, chest, and abdominal computed tomography (CT) scans was performed before treatment and then every 3–4 months. Response to therapy was determined centrally using the RECIST 1.1 criteria (Fig. 1A and Supplementary Table S3). Positron emission tomography (PET)–CT using [18F] fluorodeoxyglucose (FDG) (PET/CT) was performed before treatment, and after 12–16 months of treatment to confirm CRs (the European Organisation for Research and Treatment of Cancer [EORTC] response criteria for PET). In case of persistent lesions without tracer uptake on PET/CT (PR according to the RECIST 1.1 [CT scan], but CR according to the EORTC criteria for PET), lesions were surgically removed (1/8) to confirm the absence of viable tumor tissue (pathological CR criteria, Supplementary Table S4).\n\nFIG. 1. (A) ORR after 3–4 months of treatment, 6/8 PR, 1/8 SD, 1/8 PD. (B) BOR within 16 months of treatment. (C) Lenvatinib dosage and changes over time. (D) Treatment duration and ongoing treatment. Patients in CR. BOR, best overall response; CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.\n\nThe efficacy of the combination treatment was assessed by ORR 3–4 months after starting treatment, best overall response (BOR) (Fig. 1B), PFS, and OS. PFS was defined as the time elapsed between starting treatment and progression or death, whichever occurred first. OS was defined as the time between starting treatment and death.\n\nMolecular testing and immunohistochemistry\n\nMolecular testing by whole-exome sequencing (WES) was performed from formalin-fixed and paraffin-embedded tissue specimens at the Deutsches Krebsforschungszentrum Heidelberg (DKFZ) as described previously (44,45). PD-L1 status was determined by immunohistochemistry (antibody clone SP263; Ventana) in tumor tissue specimens obtained at initial diagnosis before treatment. The tumor proportion score (TPS) was determined as proportion of PD-L1-positive tumor cells of 100 tumor cells. The combined proportion score (CPS), as amount of PD-L1-positive tumor and immune cells within 100 tumor cells, was also determined centrally at the Department of Pathology of the University Medical Center Freiburg.\n\nStatistical analysis\n\nKaplan–Meier curves were used for OS and PFS. Descriptive statistics were used to summarize patients' characteristics and AEs. Statistical analysis was performed using IBM SPSS Statistics version 25.\n\nResults\n\nEight patients with metastatic ATC (n = 6) or PDTC (n = 2) were treated with a combination of lenvatinib and pembrolizumab after failing chemotherapy, irradiation, or RIT (Table 1 and Supplementary Table S2). All the 8 patients had been extensively pretreated with surgery (8/8), local cervical external beam radiation therapy (6/8), RIT (2/2), local cerebral irradiation therapy (1/8), or systemic chemotherapy alone (6/8) (carboplatin/paclitaxel [4/8], cisplatin/paclitaxel [1/8], cisplatin/doxorubicin [1/8], and paclitaxel only [1/8]) (Table 1 and Supplementary Table S2). The median patient age was 66.4 years. At the beginning of treatment with lenvatinib/pembrolizumab, all patients had stage IVC. All patients had lung metastasis (8/8), and 2 of 8 skeletal metastasis, 1 of 8 liver metastasis, 1 of 8 kidney metastasis, 1 of 8 skin metastasis, and 1 of 8 brain metastasis. Six of eight patients also had progression of their local tumor. Eastern Cooperative Oncology Group (ECOG) performance status ranged from 0 to 2, with 3 ECOG 0 (38%), 3 ECOG 1 (38%), and 2 ECOG 2 (25%). Molecular diagnostics showed that none of the patients had a BRAFV600E mutation, but numerous other mutations typical for ATC/PDTC were detected and are listed in Supplementary Table S1.\n\nTreatment regimen and AEs\n\nLenvatinib was started at a daily dose of 24 mg in 5 of 8 patients (BW more than 80 kg) and 20 mg in 2 patients with bodyweight less than 80 kg. An 88-year-old woman started on 14 mg/day (Fig. 1C and Table 3). Pembrolizumab treatment was initiated after a median of 2.7 weeks (ranging from 1 to 4 weeks after starting lenvatinib) and was given i.v. at a fixed dose of 200 mg every 3 weeks. In general, the therapy was well tolerated with the predominant grade II to IV AEs (AEs according to the CTCAE) being hypertension (5/8), fatigue (4/8), weight loss/anorexia (3/8), oral mucositis (2/8), diarrhea (2/8), joint/muscle pain (1/8), and hand–foot syndrome (1/8) (Table 2). The lenvatinib dose was reduced stepwise upon occurrence of intolerable side effects from 24 to 20, 14, 12, and 10 mg/day (Fig. 1C). Most side effects resolved after reducing the dose of lenvatinib, but in two patients, lenvatinib-induced AEs required treatment discontinuation (patients 3 and 6, Table 3). One grade IV serious adverse event (SAE) with a lethal cervical bleeding occurred after removal of the tracheostomy in patient 5 despite being in complete remission (Tables 2 and 3).\n\nTable 3. Patient History\n\nPatient\tEntity\tAge, years\tPrior treatment\tORR in 3/4 months\tBOR CT+PET\tPFS, months\tOS, months\tAdverse events (CTCAE in grade °)\tMedian dose lenvatinib, mg/day\tCurrent therapy/ outcome\t\n1\tPDTC\t63\tS Rx C/T\tPR\tPR\t25\t27\tHypertension °II\nFatigue °II\nAnorexia °I\nOral mucositis °I\t24\tPD/death after stopping lenvatinib due to a knee surgery\t\n2\tATC\t76\tS Rx C/T\tPR\tCR\t40\t40\tHypertension °II\nAnorexia °II\t24\tAlive, CR after 12 months lenvatinib/pembrolizumab, now without treatment\t\n3\tPDTC\t49\tS RIT C/T\tPR\tPR\t15\t23\tAnorexia °III\nAbdominal pain °III\t14\tPD/death, lenvatinib on/off due to weight loss/abdominal pain\t\n4\tATC\t68\tS Rx C/T\tPR\tCR\t26\t26\tAnorexia °I\nLoss of appetite °II\nProteinuria °I\nHypertension °II\t20\tAlive, CR after 10 months of treatment, now pembrolizumab mono\t\n5\tATC\t63\tS Rx C/T\tPR\tCR\t11\t11\tDiarrhea °II\nHypertension °II\nCervical bleeding °IV\t20\tCR after 7 months of treatment. Death due to cervical bleeding\t\n6\tATC\t88\tS Rx C/T\tSD\tSD\t4\t7\tDiarrhea °II\nAnorexia °III\nProteinuria °II\nFatigue °III\nOral mucositis °II\t14\tPD/death after stopping medication due to side effects\t\n7\tATC\t64\tS RIT Rx\tPR\tCR\t19\t19\tHypertension °II\nFatigue °II\nJoint pain °II\nHand–foot syndrome °I\t24\tAlive, CR, lenvatinib/pembrolizumab for 12 months, now pembrolizumab mono\t\n8\tATC\t60\tS R C/T\tPD\tPD\t1\t1\tHypertension °II\t24\tPD/death due to cervical tumor progression\t\nPatient characteristics including diagnosis, previous therapy (S, RIT, Rx, C/T), patient age, PFS, ORR, BOR, OS, response after 3 months, maximum response, main side effects, median dose lenvatinib in mg/day, dose pembrolizumab, current treatment/outcome. CTCAE grades in roman numbers. Responses were assessed via the RECIST v1.1 radiology assessment and FDG uptake according to the EORTC criteria for PET.\n\nBOR, best overall response; C/T, chemotherapy; CT, computed tomography; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; FDG, [18F] fluorodeoxyglucose; ORR, overall response rate; OS, overall survival; PD, progressive disease; PET, positron emission tomography; PFS, progression free survival; PR, partial response; Rx, radiation therapy; S, surgery; SD, stable disease.\n\nAfter four months of treatment, lenvatinib/pembrolizumab was discontinued due to severe weight loss/anorexia (grade III) in the 88-year-old patient (patient 6), and she died due to disease progression three months later. One patient was intolerant to lenvatinib treatment due to grade III abdominal pain and weight loss/anorexia (patient 3). Lenvatinib was reduced from 24 to 20 to 14 and 12 mg/day in a stepwise manner, and after 14 months, lenvatinib/pembrolizumab treatment was discontinued. Two patients received the full dose of lenvatinib 24 mg for 24 months (Fig. 1C). Pembrolizumab was given for up to 40 months and will be continued in all patients reaching a CR for two more years (Fig. 1D).\n\nTreatment efficacy\n\nTreatment response was first assessed 3–4 months after lenvatinib/pembrolizumab treatment. Six of eight patients had a PR according to the RECIST v1.1 criteria (Fig. 1A). ORR for ATCs was 66% (4/6 PR). The 88-year-old patient (ATC) at 14 mg lenvatinib had SD (patient 6). One ATC patient (patient 8) did not respond to lenvatinib/pembrolizumab treatment combination and died within the first month of treatment due to cervical tumor progression (1/8 progressive disease) (Fig. 1A and Supplementary Data).\n\nBOR changed in four ATC patients from PR to CR within 16 months of treatment (total CR rate 50%, CR rate for ATC 66%) (Fig. 1B). Individual patient history is summarized in the Supplementary Data. ATC patient 2 had a confirmed CR for all target- and nontarget lesions 16 months after lenvatinib/pembrolizumab treatment, and stopped taking lenvatinib after 2 years (24 mg daily for 24 months), but continued pembrolizumab for 16 more months (40 months total). He stopped treatment for 6 months and is still in CR. ATC patient 4 with lung and brain metastases had a PR 12 months after starting treatment, but all lesions in the lung were without FDG uptake (CR according to the EORTC criteria for PET). All lung lesions were surgically removed and showed a pathological CR (no viable tumor cells). Therefore, the patient was judged as having a CR and has discontinued lenvatinib after 1 year of treatment, and continues with pembrolizumab only (26 months total). Patient 7 with a massive neck tumor and lung metastasis had a PET/CT confirmed CR 12 months after starting treatment. He stopped lenvatinib after 15 months and now continues with pembrolizumab only (19 months total). ATC patient 5 had confirmed CR 10 months after treatment start, but unfortunately died due to bleeding complications after removal of the tracheostomy tube (Table 3 and Supplementary Table S2).\n\nTreatment durations ranged from 1 to 40 months (ATC: 40, 26, 19, 18, 4, and 1 month; PDTC: 25 and 15 months, respectively), with three patients being treated for more than 2 years (Fig. 1D). At the time of data cutoff, 3 of 8 patients (patients 2, 4, and 7, all ATCs) were still alive and on therapy (40, 26, and 19 months). We stopped the treatment of patient 2 after 40 months of treatment, and he is now regularly monitored by CT scans every 3 months. The other patients died due to disease progression (2/6 ATC, 2/2 PDTC) or hemorrhage (grade IV SAE, patient 5, Table 3). ATC patient 8 was resistant to the treatment. ATC patients 1 and 6 died shortly after discontinuation of the lenvatinib treatment caused by lenvatinib intolerance in patient 6 (grade III anorexia), and because lenvatinib had to be discontinued due to an infectious complication after a knee surgery in patient 1 (Table 3). The median PFS for the total cohort was 17.6 months, and the median OS was 19 months (Fig. 2). Data analysis for ATC only showed a median PFS of 16.8 months and a median OS of 17.3 months (Fig. 2).\n\nFIG. 2. Kaplan–Meier curves for ATCs only and total patients. (A) PFS in all patients and ATC only. (B) OS in all patients and ATC only. ATC, anaplastic thyroid carcinoma; OS, overall survival; PFS, progression-free survival.\n\nBiomarkers\n\nTo assess potential predictors of treatment response, we investigated the PD-L1 expression of the tumor cells and macrophages/immune cells. Furthermore, WES was performed in 7 of 8 patients, and sequences were compared to germ line sequences to assess somatic mutations and the TMB. In 1 patient (1/8), targeted sequencing for 11 frequently mutated genes (Supplementary Table S1) was performed due to low material. All tumors were positive for PD-L1 expression with a TPS ranging from 1% to 90%, and 5 of 8 patients with TPS >50% (Table 4). The CPS ranged from 5 to 100 (Table 4). Interestingly, the ATC patient with the lowest TPS (1%) and CPS 5 did not respond to the treatment (patient 8). In contrast, the patients with responses lasting more than two years and those achieving a CR all had PD-L1 TPS >50% (5/8), a CPS >75 (3/8), or a high mutation frequency above 5 mutations per megabase (3/8). The patient (patient 2) with the highest number of mutations (>1400 somatic mutations) has the longest CR duration (30 months).\n\nTable 4. Biomarker Analysis\n\nPatient\tORR after 3/4 months (RECIST 1.1)\tBOR (CT/MRI/PET-CT)\tResponse according to PET-CT\tTPS, %\tCPS\tSomatic mutations\tTMB (mutations/Mb)\t\n1\tPR\tPR\tPR\t50\t40\t106\t13.79\t\n2\tPR\tCR\tCR\t60\t75\t1447\t81.87\t\n3\tPR\tPR\tPR\t10\t10\t79\t4.08\t\n4\tPR\tCR\tCR\t90\t100\t19\t3\t\n5\tPR\tCR\tn.a.\t80\t100\t29\t3.3\t\n6\tSD\tSD\tn.a.\t60\t65\t24\t3.58\t\n7\tPR\tCR\tCR\t5\t7\t138\t5.59\t\n8\tPD\tPD\tn.a.\t1\t5\tn.a.\tn.a.\t\nCPS, combined proportion score; MRI, magnet resonance tomography; n.a., not applicable; TMB, tumor mutation burden; TPS, tumor proportion score.\n\nDiscussion\n\nCurrent treatment options for ATC are limited, and response rates are low and short-lived, with marginal to absent CR (13,14). Only the small proportion of BRAFV600E-mutated ATC (about 20%) can be effectively treated with a BRAF/MEK inhibitor combination of dabrafenib and trametinib (10,11), but for the other 70–80% of ATCs, no treatment options are approved after chemotherapy failure in most countries.\n\nATC and PDTC are characterized by a very high proliferation rate and tumor invasiveness, driven by concurrent mutations in several pro-proliferative pathways (RAS, WNT, loss of TP53), and strongly activated VEGF/FGF signaling. PD-L1 and TMB are upregulated, but the response to single immune checkpoint inhibition often comes too late and is overrun by the aggressiveness of the disease (36).\n\nWhile many kinase inhibitors (sorafenib/pazopanib) failed to show treatment efficacy in ATC (30–32), lenvatinib trials demonstrated some promising effects, with 17.4–43% PRs and up to 50% SD (27–29). CRs were absent and PFS lasted only between 77 days and 7.4 months (27–29). Besides its fast, but short-lived antiproliferative effects, lenvatinib was shown to improve immune responses to immune checkpoint inhibitors in mice. Therefore, by combining both agents, we aimed to use lenvatinib as a fast and effective bridging treatment and immuno-sensitizer for the immune checkpoint inhibitor pembrolizumab in ATC/PDTC patients.\n\nIn contrast to single-agent therapy, the combination of lenvatinib and pembrolizumab was highly effective in our treatment cohort. Eight ATC/PDTC patients who had previously been treated with several lines of therapy including chemotherapy, chemoirradiation, and even single immune checkpoint inhibition (1/8) received a combination of lenvatinib and pembrolizumab for a maximum of 40 months. The combination treatment was well tolerated and could be sustained over one year in half of the patients, and even over two years in 37% (3/8) of the patients. Half of the ATC patients (3/6) were still on therapy at data cutoff with no sustained grade III/IV toxicities despite having initially metastatic disease; three patients had confirmed CR by PET/CT and/or histopathologic examination of former metastatic sites. Seventy-five percent of all patients and 66% of the ATC patients reached a PR/CR within 16 months of treatment. The remission rates observed with lenvatinib/pembrolizumab combination in ATC/PDTC are similar to previously published data for other heavily pretreated solid tumors, such as patients with head and neck tumors, endometrial, renal cell, or hepatocellular carcinoma (39–42). As CRs and long-lasting remissions were rarely observed in ATC patients treated with lenvatinib only (27–29), the addition of pembrolizumab is most likely inducing this effect.\n\nIn patients who are already resistant to TKI treatment, the addition of pembrolizumab is only partially functional with a PFS of only 2.96 months (43), which indicates that the up-front combination of lenvatinib and pembrolizumab might be much more effective than using these drugs sequentially.\n\nTMB and PD-L1 expression levels (TPS/CPS) are independent biomarkers for response to immune checkpoint inhibitors in solid tumors (30,46,47). In our analysis, patients reaching a CR or those who had long-term remission over two years all had a TPS above 50%, a CPS higher than 75, and/or a TMB >5/MB, indicating that those may be biomarkers for response to lenvatinib/pembrolizumab treatment in ATC/PDTC.\n\nIn general, the combination of lenvatinib and pembrolizumab was well tolerated even in the elderly patients with a higher ECOG performance status. Results are encouraging with an ORR of 75%, including a CR rate of 50% (66% in ATCs) and responses over 2 years. Therefore, the treatment results and biomarkers will be further evaluated in a phase II clinical trial with lenvatinib and pembrolizumab in ATC/PDTC patients (ATLEP trial, Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab, EudraCT No. 2017-004570-34).\n\nSupplementary Material\n\nSupplemental data\n\nSupplemental data\n\nSupplemental data\n\nSupplemental data\n\nSupplemental data\n\nAcknowledgments\n\nThanks to our patients and relatives for their support for this study. Thanks to Prof. Roland Mertelsmann for his continuous support and wisdom. Thanks to the molecular tumor board and the CCCF for their support.\n\nAuthors' Contributions\n\nC.D., J.S., C.M., O.T., H.W., and N.B. wrote the article. J.R., C.K., and P.T.M. performed and evaluated PET/CTs. K.A., and S.K. performed PD-L1 staining and evaluation. M.R. designed figures. M.B. and P.M. analyzed WES data. A.Z., P.R., M.K., C.W., T.S., C.S., C.M., C.K., N.B., and K.L. treated patients and revised the article.\n\nAuthor Disclosure Statement\n\nC.D. received honoraria and travel costs for consultancy role at Eisai, AbbVie, and Gilead. M.K. received honoraria and travel costs for consultancy role at Eisai GmbH. A.Z. received honoraria and travel costs for consultancy role at Eisai, J&J, and Merck and participates in the Keynote 158 trial.\n\nFunding Information\n\nResarch funding grant for IIT trials from the University of Freiburg.\n\nSupplementary Material\n\nSupplementary Data\n\nSupplementary Table S1\n\nSupplementary Table S2\n\nSupplementary Table S3\n\nSupplementary Table S4\n==== Refs\nReferences\n\n1. Wendler J, Kroiss M, Gast K, Kreissl MC, Allelein S, Lichtenauer U, Blaser R, Spitzweg C, Fassnacht M, Schott M, Fuhrer D, Tiedje V 2016 Clinical presentation, treatment and outcome of anaplastic thyroid carcinoma: results of a multicenter study in Germany. 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Nature 515 :563–567 25428504\n\n", "fulltext_license": "CC BY", "issn_linking": "1050-7256", "issue": "31(7)", "journal": "Thyroid : official journal of the American Thyroid Association", "keywords": "ATC; PDTC; anaplastic thyroid cancer; lenvatinib; pembrolizumab; poorly differentiated thyroid cancer", "medline_ta": "Thyroid", "mesh_terms": null, "nlm_unique_id": "9104317", "other_id": null, "pages": "1076-1085", "pmc": null, "pmid": "33509020", "pubdate": "2021-07", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "27288464;30913016;27696251;30515783;28383817;29029287;28351340;27718847;25891174;3902203;30638399;27045886;28778959;26629286;23721245;31929884;30762153;27398740;31319771;20200039;26878173;25913680;32913998;30105871;25576899;27926471;10958311;27090296;30895946;28324060;25428504;30832606;31235699;26412456;29372535;25671254;28299283;30922731;29072975;20418080;29996921;23945592", "title": "Combination of Lenvatinib and 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Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma. THYROID. 2021;31(7):1076-85", "literaturereference_normalized": "combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220307", "receivedate": "20220307", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20559976, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "DE-NOVARTISPH-NVSC2022DE048446", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "76959", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK CARBOPLATIN AUC5, 5 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anaplastic thyroid cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG/M2, CYCLIC (5 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anaplastic thyroid cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL" } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to lung", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to lymph nodes", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaplastic thyroid cancer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thyroid cancer recurrent", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Dierks C, Seufert J, Aumann K, Ruf J, Klein C, Kiefer S et al.. Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma. THYROID. 2021;31(7):1076-85", "literaturereference_normalized": "combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220302", "receivedate": "20220302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20543320, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "DE-NOVARTISPH-NVSC2022DE048445", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "76959", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (5 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anaplastic thyroid cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "2", "drugtreatmentdurationunit": "802", "medicinalproduct": "CARBOPLATIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (5 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anaplastic thyroid cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "2", "drugtreatmentdurationunit": "802", "medicinalproduct": "PACLITAXEL" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to lung", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to skin", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to bone", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaplastic thyroid cancer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thyroid cancer recurrent", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20180701" } }, "primarysource": { "literaturereference": "Dierks C, Seufert J, Aumann K, Ruf J, Klein C, Kiefer S et al.. Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma. THYROID. 2021;31(7):1076-85", "literaturereference_normalized": "combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220307", "receivedate": "20220307", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20559963, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]
{ "abstract": "Ceftriaxone is a widely used third-generation cephalosporin showing advantageous pharmacokinetic properties and a broad antimicrobial spectrum. We herein report a case of ceftriaxone-induced neurotoxicity in a 56-year-old man on hemodialysis. Seven days after initiating high-dose ceftriaxone, the patient developed impaired consciousness along with facial myoclonus and sporadic phonation. The symptoms clearly disappeared shortly after withdrawal of the drug. Ceftriaxone is considered a safe antibiotic for patients with renal insufficiency, since it is excreted via both haptic and renal pathways. Physicians should note that antibiotic-associated encephalopathy may develop in patients administered ceftriaxone, especially in those complicated with renal dysfunction.", "affiliations": "Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan.;Department of Pharmacy, Osaka University Hospital, Japan.;Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan.;Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan.;Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Japan.;Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Japan.;Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Japan.;Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan.;Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan.", "authors": "Hagiya\|Hideharu\|H\|;Miyawaki\|Koji\|K\|;Yamamoto\|Norihisa\|N\|;Yoshida\|Hisao\|H\|;Kitagawa\|Akihiro\|A\|;Asaoka\|Tadafumi\|T\|;Eguchi\|Hidetoshi\|H\|;Akeda\|Yukihiro\|Y\|;Tomono\|Kazunori\|K\|", "chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.8774-16", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2894356210.2169/internalmedicine.8774-16Case ReportCeftriaxone-induced Neurotoxicity in a Patient after Pancreas-Kidney Transplantation Hagiya Hideharu 1Miyawaki Koji 2Yamamoto Norihisa 1Yoshida Hisao 1Kitagawa Akihiro 3Asaoka Tadafumi 3Eguchi Hidetoshi 3Akeda Yukihiro 1Tomono Kazunori 1\n1 Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan\n2 Department of Pharmacy, Osaka University Hospital, Japan\n3 Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, JapanCorrespondence to Dr.　Hideharu Hagiya, [email protected]\n\n25 9 2017 15 11 2017 56 22 3103 3107 27 12 2016 27 3 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Ceftriaxone is a widely used third-generation cephalosporin showing advantageous pharmacokinetic properties and a broad antimicrobial spectrum. We herein report a case of ceftriaxone-induced neurotoxicity in a 56-year-old man on hemodialysis. Seven days after initiating high-dose ceftriaxone, the patient developed impaired consciousness along with facial myoclonus and sporadic phonation. The symptoms clearly disappeared shortly after withdrawal of the drug. Ceftriaxone is considered a safe antibiotic for patients with renal insufficiency, since it is excreted via both haptic and renal pathways. Physicians should note that antibiotic-associated encephalopathy may develop in patients administered ceftriaxone, especially in those complicated with renal dysfunction. \n\nantibiotic-associated encephalopathyceftriaxonechronic kidney diseasehemodialysisnonconvulsive status epilepticustransplantation\n==== Body\nIntroduction\nCeftriaxone (CTRX) is a common antibiotic frequently used in both in- and outpatients. The pharmacological advantages of CTRX include a broad microbial spectrum, long half-life, and good penetration into systemic tissues, including the central nervous system. In contrast to other beta-lactams, CTRX is metabolized at the liver, and a renal dose adjustment is usually not necessary. In addition, side effects and drug interactions are uncommon. Therefore, it is generally assumed that CTRX can be safely administered to elderly patients, including those with chronic kidney disease (1).\n\nFollowing antimicrobial treatments, some patients may develop antibiotic-associated encephalopathy (AAE). Among beta-lactams, cefepime, a fourth-generation cephalosporin, is known to cause encephalopathy, particularly in elderly patients with renal insufficiency (2,3). According to a previous review, CTRX is listed as a low-to-medium-risk agent based on its structural characteristics (4,5); however, CTRX-associated encephalopathy has rarely been reported. To our knowledge, only 10 such cases have been documented in the literature to date (6-11). In this report, we describe another case of CTRX-induced neurotoxicity complicated by involuntary facial movements.\n\nCase Report\nThe patient was a 56-year-old man (dry body weight: 50.5 kg). He had undergone simultaneous pancreas-kidney transplantation five years earlier, but he was on hemodialysis due to graft failure. One day, he was found to have a low blood pressure and decreased oxygen saturation at a hemodialysis clinic and was immediately transferred to our hospital as an emergency case. On admission, he was alert but in a state of shock. He reported pain in his left chest, which was intensified by deep breaths and dry cough. The patient was prescribed prednisolone (2.5 mg per day), cyclosporine (120 mg per day), mycophenolate mofetil (500 mg per day), and everolimus (1 mg per day). He had no history of neurological disorders or brain surgery. Laboratory results showed elevated serum C-reactive protein levels (CRP, 21.14 mg/dL). A chest radiograph demonstrated permeability decay in his left lower lung, and computed tomography (CT) of his chest revealed diffuse consolidation in the left lower lobe. The patient was diagnosed with septic shock secondary to pneumonia and pleurisy and was hospitalized at an emergency center. Treatment was started empirically with renal doses of meropenem and levofloxacin.\n\nThree days after hospitalization, the patient was moved to a general ward. Although a bacterial culture of his sputum was unremarkable, antibiotic therapy was switched to CTRX (2 g q12h) and minocycline (100 mg q12h) on day 6. Despite antibiotic treatment, the pleural effusion increased, and he underwent paracentesis of the pleural cavity on day 8. The pleural fluid was clear, and a bacterial culture was negative. Nevertheless, the levels of serum inflammatory markers and his body temperature remained high.\n\nOn admission day 13, the patient started to become disoriented and agitated. At that time, he was afebrile, and laboratory data showed the serum CRP level to be 11.1 mg/dL; otherwise, there were no markedly abnormal values. On the same day, continuous air leakage emerged. Chest CT revealed a newly formed pulmonary cavity in the left lower lobe, indicating pulmonary suppuration and a subsequent thoracic empyema. No explanation was found for the patient's altered consciousness, but the patient was subjected to emergency thoracoscopic surgery. Although there was no apparent purulent effusion, pus was found inside the cavity. Postoperatively, the patient was extubated and admitted to an intensive-care unit. The administration of CTRX was continued in combination with levofloxacin (250 mg q48h) and clindamycin (600 mg q6h). Before the operation, he had undergone intermittent hemodialysis three times per week, which was changed to continuous hemodiafiltration postoperatively.\n\nEven after the discontinuation of sedative drugs, his consciousness remained impaired. The patient's conscious state was mostly at E2V2M5 on the Glasgow Coma Scale, but occasionally, he was unresponsive to stimuli or seemed to be confused or agitated. In addition, involuntary facial movements, including rhythmic contractions of the orbicularis oculi muscles and tongue were observed (Supplementary material). Sporadic phonation seemed to be triggered by dispersive contractions of laryngeal muscles. We did not observe convulsion or athetosis. CT and magnetic resonance imaging (MRI) of his head did not reveal any abnormalities; however, an electroencephalogram (EEG) showed bursts of generalized, high-voltage slow-wave activity throughout the measurement period (Fig. 1A). The differential diagnosis included encephalopathy caused by metabolic, renal, and drug-related etiologies, delirium, and a psychogenic reaction. The levels of serum electrolytes, liver function, thyroid function, thiamine, and ammonia were all within normal ranges, while the serum levels of total protein and albumin declined to 5.0 and 2.4 g/dL, respectively. A cerebrospinal fluid examination showed normal findings: initial pressure, 16 cmH2O, cells 1 /μL, protein 36 mg/dL, and glucose 67 mg/dL. Therefore, an adverse drug effect remained a potential cause of the impaired consciousness. Throughout the clinical course, the serum level of cyclosporine was closely monitored and maintained in an appropriate range.\n\nFigure 1. Electroencephalogram (EEG). (A) EEG on day 18. The patient manifested impaired consciousness. Generalized moderate-to-high-amplitude epileptiform bursts continued throughout the test. (B) EEG on day 28. Three days after the patient recovered from unconsciousness. The abnormal spikes completely disappeared, and alpha waves emerged mainly at the occipital lobes.\n\nOn reviewing the patient's course, a high dose of CTRX was continuously administered for 7 days before the patient fell unconscious (usual dose: 1 to 2 g per 24 h). At this point, CTRX-induced neurotoxicity was suspected. The dosage of CTRX was reduced to 2 g per day on day 18, but the patient's condition did not improve. Subsequently, CTRX was discontinued and switched for piperacillin/tazobactam (2.25 g q8h) on day 20. Five days after the cessation of treatment with CTRX, the patient recovered completely. He was still slightly febrile (37.6℃), but his general condition and vital signs were stable, and his serum CRP level decreased to 3.5 mg/dL. A follow-up EEG showed no abnormal patterns (Fig. 1B), and no neurological symptoms recurred until his discharge from the hospital. The patient's clinical course is illustrated in Fig. 2.\n\nFigure 2. Clinical course of the presented patient. Seven days after initiating CTRX, the patient developed impaired consciousness (day 13). He remained unconscious postoperatively but regained consciousness to a full level (GCS, E4V5M6) 5 days after the cessation of CTRX treatment. Aside from antibiotics, the patient did not receive any drugs continuously after hospitalization. CLDM: clindamycin, CTRX: ceftriaxone, GCS: Glasgow Coma Scale, LVFX: levofloxacin, MEPM: meropenem, MINO: minocycline, PIPC/TAZ: piperacillin/tazobactam\n\nDiscussion\nWe encountered a case of CTRX-associated neurotoxicity occurring in a patient after pancreas-kidney transplantation. The onset and resolution of the neurological symptoms appeared to be closely related to the initiation and discontinuation of CTRX administration, and the EEG findings were similar to previous cases (6,9). Although one or more of the other drugs concurrently administered with CTRX (cyclosporine, meropenem, levofloxacin, and minocycline) might have potentially caused the encephalopathy, the influence of any of these drugs seemed unlikely, given the clinical course.\n\nNeurological complications are relatively common after solid organ transplantations, appearing in approximately one-third of such patients (12). Frequent etiologies include immunosuppressive agents (e.g. calcineurin inhibitors), central nervous system infections, and encephalopathy. In particular, the differential diagnosis of neural involvement in the late phase (>6 months) includes viral (Herpes simplex virus, Cytomegalovirus, Epstein-Barr virus, Varicella-zoster virus, and progressive multifocal leukoencephalopathy by JC polyomavirus), fungal (Cryptococcus neoformans, Aspergillus spp., and Mucor), and parasitic (Toxoplasma gondii, Amebiasis, Strongyloides stercoralis) infections (13). In addition, neoplastic etiologies such as post-transplantation lymphoproliferative disorder should also be considered.\n\nTable summarizes the present and previous cases of CTRX-induced neurotoxicity (6-11). Notably, elderly patients with chronic kidney disease are at particularly high risk for drug-associated encephalopathy. Of the 11 cases, 8 (72.7%) were over 60 years of age. In addition, four had chronic kidney disease, and half of the patients were on either hemodialysis or peritoneal dialysis. Renal insufficiency is in general a common factor for AAE; 25% of all cases of AAE and over 70% of cephalosporin-associated cases have been associated with renal insufficiency (14). A possible reason for the association between renal insufficiency and AAE is impaired biliary excretion in patients with renal dysfunction (5). Impaired biliary excretion may be responsible for the delayed elimination of CTRX, and a subsequently higher serum concentration of the drug can trigger the neurotoxicity.\n\nTable. Summary of Reported Cases of Ceftriaxone (CTRX)-induced Neurotoxicity.\n\nCase\tAge\tSex\tRenal function\tDose of CTRX (g/day)\tNeurological manifestation\tDays to onset\tDays to remission\tTreatment\tReference\t\n1\t83\tF\tCKD\t2\tAltered mental status, myoclonus\t4\t5\tDiscontinue, AED\t6\t\n2\t78\tF\tCKD\t2\tAltered mental status, myoclonus\t6\t5\tDiscontinue, AED\t6\t\n3\t60\tF\tCKD\t2\tAltered mental status\t4\t3\tDiscontinue\t7\t\n4\t80\tF\tHemodialysis\t4\tChoreoathetosis\t5\t12\tDiscontinue\t8\t\n5\t72\tF\tHemodialysis\t1\tChoreoathetosis\t2\t1\tDiscontinue\t8\t\n6\t76\tM\tHemodialysis\t2\tChoreoathetosis\t6\tnd\tDiscontinue\t8\t\n7\t76\tM\tHemodialysis\t2\tChoreoathetosis\t5\t2\tDiscontinue\t8\t\n8\t65\tF\tCKD\t2\tGeneralized myoclonic jerks\t5\t2\tDiscontinue\t9\t\n9\t8\tM\tNormal\t1\tAltered mental status\t3\t3\tDiscontinue\t10\t\n10\t37\tF\tPeritoneal dialysis\t2\tAgitation, paranoia, visual hallucination\t3\t1.5\tDiscontinue\t11\t\n11\t56\tM\tHemodialysis\t4\tAltered mental status, Facial myoclonus, sporadic phonation\t7\t5\tDiscontinue\tPresent case\t\nNeurological prognosis of the patients were all favorable.\n\nAED: anti-epileptic drug, CKD: chronic kidney disease, nd: not described\n\nAn excessive dosage can be another predisposing factor for cephalosporin-associated neurotoxicity (15-17). However, the dosages of CTRX administered in the reported cases were mostly normal (≤2 g per day in 8 of 10 adult cases in Table). Thus, the relationship between overdose of the drug and neurotoxicity is uncertain. As few or no reports on the previous CTRX-associated encephalopathy measured the serum concentration of the drug, the association between the serum concentration and neurotoxicity is inconclusive.\n\nAlthough the pathophysiological mechanisms of cephalosporin-associated neurotoxicity have yet to be fully elucidated, beta-lactam associated encephalopathy is believed to be related to the competitive inhibition of γ-aminobutyric acid in brain tissues (15). CTRX penetrates efficiently into the central nervous system and can trigger increased neural excitability even at normal dosages.\n\nOnce recognized, AAE is easily treatable by discontinuing the offending drugs. However, the early diagnosis of CTRX-induced neurotoxicity is challenging for three reasons. First, many clinicians are unaware of this rare adverse effect related to CTRX. Second, the clinical presentations may vary among patients; reported symptoms include altered mental status (6 cases), choreoathetosis (4 cases), and myoclonus (4 cases) (Table). Interestingly, our patient manifested facial myoclonus along with sporadic phonation. Third, radiographic and cerebrospinal fluid examinations do not provide any useful information for the diagnosis. Findings based on EEGs, although not specific, may aid in the diagnosis.\n\nPatients' clinical courses provide the strongest basis for the diagnosis of AAE. The time spans to both the onset and amelioration of AAE have been reported to be 5 days in the median for most offending antibiotics (14). In previous cases of CTRX-induced neurotoxicity, the administration periods before the onset of neurological symptoms were 2 to 6 days, and clinical improvement was seen 1 to 12 days after cessation of the drug (9). In our case, the patient developed neurologic symptoms 7 days after initiation and recovered 5 days after the discontinuation of the drug. Rigorous documentation and observation of the patient's course can therefore lead to a definitive diagnosis of CTRX-induced neurotoxicity.\n\nSpecific treatment for CTRX-induced neurotoxicity may not be available. Hemodialysis is ineffective, as CTRX binds well to serum albumin and therefore cannot be removed from the blood (1). As such, discontinuation of the offending drug following an early diagnosis is crucial (14).\n\nIn conclusion, this report illustrated a case of CTRX-induced transient encephalopathy that involved a patient on hemodialysis. Although CTRX is a widely available and potent antibiotic in various clinical settings, clinicians need to be aware that patients with an impaired renal function may develop neurotoxicity. The clinical manifestations may be subtle or nonspecific, and therefore, the diagnosis of the adverse event is challenging; however, the early recognition followed by the discontinuation of the causal drug can lead to a rapid recovery. Close observation of a patient's clinical course can provide essential cues regarding the diagnosis.\n\n\nInformed consent was obtained from the patient for the publication of this case.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nSupplementary Materials\nVideo file for the involuntary facial movements Rhythmic contractions of orbicularis oculi muscles and tongue were observed.\n\nClick here for additional data file.\n==== Refs\n1. \nPatel I , Sugihara J , Weinfeld R , Wong E , Siemsen A , Berman S \nCeftriaxone pharmacokinetics in patients with various degrees of renal impairment . 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Am J Med \n111 : 115 -119 , 2001 .11498064 \n7. \nRoncon-Albuquerque Jr R , 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 \n8. \nSato Y , Morita H , Wakasugi H , et al \nReversible chreoathetosis after the administration of ceftriaxone sodium in patients with end-stage renal disease . Am J Med Sci \n340 : 382 -384 , 2010 .20724905 \n9. \nKim KB , Kim SM , Park W , Kim JS , Kwon SK , Kim H-Y \nCeftiaxone-induced neurotoxicity: case report, pharmacokinetic considerations, and literature review . J Korean Med Sci \n27 : 1120 -1123 , 2012 .22969263 \n10. \nSharma N , Batish S , Gupta A \nCeftriaxone-induced acute reversible encephalopathy in a patient with enteric fever . Indian J Pharmacol \n44 : 124 , 2012 .22345886 \n11. \nSafadi S , Mao M , Dillon JJ \nCeftriaxone-induced acute encephalopathy in a peritoneal dialysis patient . Case Rep Nephrol \n2014 : 108185 , 2014 .25544915 \n12. \nMarco S , Cecilia F , Patrizia B \nNeurologic complications after solid organ transplantation . Transpl Int \n22 : 269 -278 , 2009 .19076332 \n13. \nPruitt AA , Graus F , Rosenfeld MR \nNeurological complications of solid organ transplantation . Neurohospitalist \n3 : 152 -166 , 2013 .24167649 \n14. \nBhattacharyya S , Darby RR , Raibagkar P , Castro LNG , Berkowitz AL \nAntibiotic-associated encephalopathy . Neurology \n86 : 963 -971 , 2016 .26888997 \n15. \nWallace KL \nAntibiotic-induced convulsions . Crit Care Clin \n13 : 741 -762 , 1997 .9330839 \n16. \nSchliamser SE , Cars O , Norrby SR \nNeurotoxicity of Β-lactam antibiotics: predisposing factors and pathogenesis . J Antimicrob Chemother \n27 : 405 -425 , 1991 .1856121 \n17. \nCalandra G , Lydick E , Carrigan J , Weiss L , Guess H \nFactors predisposing to seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/cilastatin . Am J Med \n84 : 911 -918 , 1988 .3284342\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "56(22)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "antibiotic-associated encephalopathy; ceftriaxone; chronic kidney disease; hemodialysis; nonconvulsive status epilepticus; transplantation", "medline_ta": "Intern Med", "mesh_terms": "D000900:Anti-Bacterial Agents; D001927:Brain Diseases; D002443:Ceftriaxone; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D006435:Renal Dialysis", "nlm_unique_id": "9204241", "other_id": null, "pages": "3103-3107", "pmc": null, "pmid": "28943562", "pubdate": "2017-11-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19033476;19299850;22969263;16863493;3284342;11498064;6329080;1856121;22506251;22345886;24167649;9330839;16261307;26888997;19076332;25544915;20724905", "title": "Ceftriaxone-induced Neurotoxicity in 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"patientweight": "50.5", "reaction": [ { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HAGIYA, H.. 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CEFTRIAXONE-INDUCED NEUROTOXICITY IN A PATIENT AFTER PANCREAS-KIDNEY TRANSPLANTATION. INTERNAL MEDICINE. 2017;56(22); 3103-3107. DOI: 10.2169/INTERNALMEDICINE.8774-16. ?", "literaturereference_normalized": "ceftriaxone induced neurotoxicity in a patient after pancreas kidney transplantation", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20171214", "receivedate": "20171214", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14283600, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]
{ "abstract": "Capecitabine, an oral prodrug of 5-fluorouracil (5FU), has been integrated into the management of multiple cancer types because of convenience of administration and efficacy comparable with 5fu. Cardiotoxicity induced by 5FU-in particular angina-has been well described in the literature, but reports of adverse cardiac events with capecitabine are also emerging. The mechanism underlying 5FU cardiotoxicity has long been thought to result from coronary vasospasm, but animal-model studies and patient echocardiographic findings both suggest a cardiomyopathic picture. Although 5FU cardiotoxicity is often reversible and can be managed supportively, presentations that are more severe-including arrhythmias, acute ischemic events, and cardiogenic shock-have been documented. In this report, we describe the case of a patient who ultimately required a pacemaker after developing symptomatic bradycardia and sinus arrest while receiving capecitabine for colon cancer.", "affiliations": "Department of Oncology, McGill University Health Centre, Montreal, QC.", "authors": "Ang\|C\|C\|;Kornbluth\|M\|M\|;Thirlwell\|M P\|MP\|;Rajan\|R D\|RD\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3747/co.v17i1.437", "fulltext": "\n==== Front\nCurr OncolCOCurrent Oncology1198-00521718-7729Multimed Inc. 66 Martin St. Milton, ON, Canada L9T 2R2 20179805conc17-1-59Case ReportCapecitabine-induced cardiotoxicity: case report and review of the literature Ang C. MDKornbluth M. MD†Thirlwell M.P. MDRajan R.D. MD** Department of Oncology, McGill University Health Centre, Montreal, QC† Department of Cardiology, McGill University Health Centre, Montreal, QCCorresponding author: Raghu Rajan, Department of Oncology, McGill University, Montreal General Hospital, Room A7-130, Medical Oncology, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4., E-mail: \[email protected] 2010 17 1 59 63 2010 Multimed Inc.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.Capecitabine, an oral prodrug of 5-fluorouracil (5fu), has been integrated into the management of multiple cancer types because of convenience of administration and efficacy comparable with 5fu. Cardiotoxicity induced by 5fu—in particular angina—has been well described in the literature, but reports of adverse cardiac events with capecitabine are also emerging. The mechanism underlying 5fu cardiotoxicity has long been thought to result from coronary vasospasm, but animal-model studies and patient echocardiographic findings both suggest a cardiomyopathic picture. Although 5fu cardiotoxicity is often reversible and can be managed supportively, presentations that are more severe—including arrhythmias, acute ischemic events, and cardiogenic shock—have been documented. In this report, we describe the case of a patient who ultimately required a pacemaker after developing symptomatic bradycardia and sinus arrest while receiving capecitabine for colon cancer.\n\n5-Fluorouracilcapecitabinecardiotoxicitychemotherapy\n==== Body\n1. CASE DESCRIPTION\nA 75-year-old man with known hypertension, diabetes, and dyslipidemia was diagnosed with a stage iiib rectosigmoid adenocarcinoma in July 2007. He underwent a lower anterior resection, and 12 cycles of modified folfox-6 [oxaliplatin 85 mg/m2, 5-fluorouracil (5fu) 400 mg/m2 bolus, and leucovorin (lv) 400 mg/m2, followed by 5fu 2.4 g/m2 by continuous infusion over 46 hours] adjuvant chemotherapy were planned.\n\nFollowing chemotherapy cycle 7 in late January 2008, the patient developed atrial fibrillation, and he was admitted to the coronary care unit (ccu) at the Montreal General Hospital. At that time, echocardiography revealed an ejection fraction of 55%–60%, mild left ventricular diastolic dysfunction, and mild mitral regurgitation, with otherwise normal readings. He was converted to sinus rhythm on oral sotalol (80 mg twice daily), with the plan to initiate anticoagulation upon completion of chemotherapy. One week post discharge, he developed an upper extremity deep venous thrombosis on the side of his implanted catheter, and he was started on dalteparin. Two weeks later, his chemotherapy was changed to capecitabine monotherapy at 1500 mg/m2 twice daily.\n\nAbout 6 days after starting capecitabine, the patient had a syncopal episode lasting approximately 2 minutes. He recovered spontaneously and, after some transient disorientation, returned to his baseline mental status. A few hours later, he experienced two presyncopal episodes accompanied by flushing and dizziness. He went to the emergency department, where he was found to have bradycardia at 54 bpm, although he was hemodynamically stable with a blood pressure of 140/79 mmHg. Initial blood work did not reveal any electrolyte abnormalities or tropinemia. An electrocardiogram demonstrated sinus bradycardia (Figure 1).\n\nWhile on telemetry, the patient had a witnessed episode of presyncope associated with a pulse of 30–40 bpm and systolic pressure between 160– 170 mmHg. With the exception of sotalol, he received the evening doses of all of his other medications (capecitabine, metformin, venlafaxine, and valsartan) and was kept in the emergency department overnight for monitoring. Approximately 6 hours later, he had a sinus arrest of 15 s, from which he spontaneously recovered (Figure 2). Transcutaneous pacemaker pads were placed, and he was transferred to the ccu with atropine at the bedside. All medications were subsequently held.\n\nThe rest of the night was uneventful, but the following morning he had recurrent episodes of symptomatic bradycardia followed by another sinus arrest lasting 10 s. A transvenous pacemaker was inserted followed by a permanent pacemaker a few days later. Sotalol was resumed, and he was discharged without any further complications. He remains in clinical remission from his malignancy, and no further chemotherapy is planned.\n\n2. DISCUSSION\nCoronary vasospasm resulting in angina and even myocardial infarction is a well-known adverse effect of 5fu. Although cardiotoxicity is often reversible with discontinuation of 5fu and application of supportive care 1, the condition has the potential to be fatal. Reported overall mortality rates range from 2.2% to as high as 13.3% 2. The incidence of 5fu-induced cardiotoxicity in the literature ranges from 1.2% to 18%, although its true incidence may actually be higher, given that silent, reversible ST segment deviations on electrocardiography are known to occur 3,4. Other manifestations of 5fu-induced cardiotoxicity include heart failure, hyper- or hypotension, cardiomyopathy, arrhythmias, conduction disturbances, and cardiac arrest 5. However, these latter cardiac adverse events have been reported much less frequently.\n\nCapecitabine is an oral prodrug that is converted to 5fu in a sequential 3-step enzymatic reaction that occurs primarily in the liver and in tumour cells. It has gained popularity because of its efficacy, ease of administration, and milder toxicity profile as compared with 5fu 6. However, as the use of capecitabine becomes more widespread, the rare but significant cardiotoxic potential of the drug is beginning to surface. In a retrospective analysis performed on studies of patients undergoing chemotherapy for metastatic breast and colon cancer, the incidence of cardiotoxicity with capecitabine was found to be comparable to that of 5fu–lv 7. Wijesinghe et al. 8 reported an acute coronary syndrome in a patient with no history of cardiovascular disease who had been on capecitabine for only 2 days. Kosmas et al. 5 documented myocardial infarction, electrocardiographic abnormalities, and ventricular extrasystoles in patients on capecitabine. Furthermore, Goldsmith et al. 9 recently reported exercise-induced global myocardial ischemia with an ejection fraction of 36% in a patient with normal coronary arteries and resting left ventricular function who was on capecitabine for recurrent breast cancer.\n\nWe present the first reported case of a patient who ultimately required a permanent pacemaker after developing symptomatic bradycardia followed by sinus arrest while on capecitabine. Although the patient was taking sotalol, which can itself cause bradycardia and asystole, the sotalol had been started a month before the relevant episode, during which time the patient did not experience any of the noted complications. Given that capecitabine was started less than a week before presentation, it would appear to be the most likely culprit in the absence of other medication changes at the time.\n\nThe clinical manifestations of 5fu cardiotoxicity are frequently attributed to coronary vasospasm. However, anti-vasospastic agents including nitroglycerin and calcium channel blockers have not been consistently effective at relieving symptoms of angina in affected patients 1,5,10. In a study by Freeman et al. 11, ergonovine challenge followed by 5fu infusion did not produce coronary vasospasm in a patient who had developed severe chest pain and ischemic electrocardiographic changes. In vivo studies in animal models have also provided evidence suggesting that mechanisms aside from coronary vasospasm may be responsible. Tsibiribi et al. 12 subjected rabbits to either bolus or infusional 5fu. Rabbits that received the bolus suffered massive hemorrhagic myocardial infarcts with evidence of proximal coronary vasospasm. In contrast, animals in the infusion group demonstrated histologic changes consistent with toxic myocarditis. In addition, echocardiographic studies in patients with 5fu cardiotoxicity have revealed decreased ejection fraction and significant global or regional left ventricular dysfunction consistent with a cardiomyopathic picture 13,14.\n\nThe metabolites of 5fu have been implicated in mediating cardiac damage, in particular fluoroacetate (fac), which is known to be directly myocardiotoxic 15. Fluoroacetate is converted into an inhibitor of citrate metabolism 16 and interestingly, intramyocardial citrate accumulation has been found in guinea pig recipients of 5fu 17. A report by de Forni et al. 18 also noted a trend toward increased urinary excretion of fac during 5fu administration in 14 patients, including 6 who developed cardiotoxicity, although there was no strict temporal relationship with symptom onset. Other hypothesized mechanisms that are undergoing further investigation include the possibility of an autoimmune reaction, endothelial damage, and a procoagulable effect of 5fu 19,20.\n\nThe route of administration, the dose intensity, and the schedule of 5fu also appear to influence the development of cardiotoxicity. In studies by Jensen et al. 2 and Kosmas et al. 5, a higher frequency of symptoms was recorded with continuous 5fu infusions (24 hours) than with shorter (<3 hours) infusions. Given that the pharmacokinetics of capecitabine mimic a continuous 5fu infusion, it is not surprising that the frequency of cardiac symptoms noted with capecitabine is similar to that with the 24-hour infusion 5. Higher doses of 5fu were associated with earlier symptom onset, and a weak trend toward longer symptom duration with capecitabine than with intravenous 5fu was also observed 2.\n\nDrug pharmacokinetics and pharmacodynamics should also be considered to be additional factors that may predispose patients to developing cardiotoxicity with capecitabine. Lethal gastrointestinal toxicities have been reported with capecitabine, which have been attributed to a deficiency of dihydropyridine dehydrogenase (dpd), the first enzymatic step in 5fu catabolism 21. Cytidine deaminase (cda) is a critical enzyme for the activation of capecitabine in hepatocytes and tumour cells. Excessive levels of cda resulting in overmetabolism of capecitabine into 5fu could explain the development of severe toxicities even in patients who are not dpd-deficient 22. Interestingly, geographic differences in tolerance to capecitabine have been documented, with the highest rates of toxicity occurring in American patients and the lowest in East Asian patients 23. Although cultural and dietary differences, in addition to regional variations in the reporting of toxicities, may have contributed to these observations, polymorphisms in the genes responsible for 5fu and capecitabine metabolism may have been a factor as well 23.\n\nThe patient presented here received capecitabine after experiencing a cardiac event (atrial fibrillation) while on 5fu. It is unclear whether his atrial fibrillation was a result of exposure to 5fu. Although the patient had risk factors for coronary artery disease, he never exhibited clinical, electrocardiographic, or laboratory abnormalities to suggest that ischemia contributed to his conduction abnormalities. Nevertheless, this case raises several important issues, the first of which is how one might identify patients who may be at risk of developing cardiotoxicity on 5fu. In some studies, a history of heart disease was a risk factor for experiencing a higher incidence and grade of cardiotoxicity 2,24,25. Conversely, Tsibiribi et al. reported symptoms of cardiotoxicity in 16 patients with no prior cardiac history 26. Other risk factors include advanced age, renal insufficiency 2, and mediastinal irradiation (which induces coronary artery intraluminal hyperplasia and collagen deposition 27). In view of what is being learned about the pharmacokinetics of capecitabine and 5fu, the measurement of key enzymes such as dpd and cda might eventually become important in helping to predict—and hopefully spare patients from—severe toxicities resulting from these drugs.\n\nAnother issue relates to monitoring while on therapy, with the goal of detecting preclinical markers of toxicity. Holubec et al. 28 recently evaluated the utility of measuring brain natriuretic peptide (bnp) and troponin I (tni) in patients receiving 5fu-based chemotherapy for colorectal cancer. In that study, 57% of patients were found to have laboratory evidence of ischemia and heart failure. Upon questioning, patients recalled transient symptoms of angina, dyspnea, and edema, although the timing of biomarker elevation and symptom onset was not precisely defined. Given the high incidence of cardiotoxicity that was observed, the authors proposed that all patients for whom 5fu chemotherapy is planned should undergo baseline electrocardiographic screening or, in those with prior cardiac history, echocardiography. They also suggested that tni and bnp be monitored throughout the course of chemotherapy as surrogate markers of cardiotoxicity.\n\nFinally, there is the question of rechallenging and giving prophylaxis to patients who have experienced cardiotoxicity but who nevertheless stand to benefit from 5fu. Cianci et al. 29 successfully re-administered 5fu to 3 patients who developed symptoms of angina during the initial infusion— albeit using reduced doses administered together with prophylactic trans-epidermal nitroglycerin. In another case series of 6 patients who developed transient asymptomatic bradycardia on infusional 5fu, 4 patients were able to continue treatment, but 2 had to change their regimen because of persistent and recurring bradycardia with subsequent cycles 30. Patients in series reporting more severe cardiotoxicity, such as myocardial infarction, were not rechallenged 7,31. In such patients, for whom a rechallenge of 5fu or capecitabine seems too risky, raltitrexed appears to be a viable substitute 25.\n\n3. CONCLUSIONS\nIn summary, cardiotoxicity induced by 5fu or capecitabine has multiple manifestations and may occur more frequently than previously reported. Although this cardiotoxicity is transient and often reversible, it has the potential to cause serious morbidity and even mortality. There are currently no published guidelines for screening, monitoring, and prophylaxis. Decisions with respect to managing and rechallenging patients who have developed cardiotoxicity on 5fu must be made on an individual basis. Oncologists and cardiologists alike must maintain a heightened awareness of the possibility of this phenomenon and collaborate closely to ensure patient safety.\n\n4. CONFLICT OF INTEREST\nThe authors declare no conflicts of interest.\n\nFIGURE 1 Electrocardiogram taken upon initial presentation of the patient to the emergency department.\n\nFIGURE 2 Electrocardiogram showing development of sinus bradycardia followed by sinus arrest 6 hours after the patient took capecitabine.\n==== Refs\n5. REFERENCES\n1 Robben NC Pippas AW Moore JO The syndrome of 5-fluorouracil cardiotoxicity: an elusive cardiopathy Cancer 1993 71 493 509 8422644 \n2 Jensen SA Sorensen JB Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine Cancer Chemother Pharmacol 2006 58 487 93 16418875 \n3 Akhtar SS Salim KP Bano ZA Symptomatic cardiotoxicity with high-dose 5-fluorouracil infusion: a prospective study Oncology 1993 50 441 4 8233284 \n4 Wacker A Lersch C Scherpinski U Reindl L Seyfarth M High incidence of angina pectoris in patients treated with 5-flurouracil. A planned surveillance study with 102 patients Oncology 2003 65 108 12 12931015 \n5 Kosmas C Kallistratos MS Kopterides P Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study J Cancer Res Clin Oncol 2008 134 75 82 17636329 \n6 Walko CM Lindley C Capecitabine: a review Clin Ther 2005 27 23 44 15763604 \n7 Van Cutsem E Hoff PM Blum JL Abt M Osterwalder B Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil Ann Oncol 2002 13 484 5 11996484 \n8 Wijesinghe N Thompson PI McAlister H Acute coronary syndrome induced by capecitabine therapy Heart Lung Circ 2006 15 337 9 16697705 \n9 Goldsmith YB Roitacher N Baum MS Capecitabine-induced coronary vasospasm J Clin Oncol 2008 17 3802 4 18669470 \n10 Eskilsson J Albertsson M Failure of preventing 5-fluorouracil cardiotoxicity by prophylactic treatment with verapamil Acta Oncol 1990 29 1001 3 2278719 \n11 Freeman NJ Constanza ME 5-Fluorouracil cardiotoxicity Cancer 1998 61 36 45 3275485 \n12 Tsibiribi P Bui–Xuan C Bui–Xuan B Cardiac lesions induced by 5-fluorouracil in the rabbit Hum Exp Toxicol 2006 25 305 9 16866187 \n13 Jakubowski AA Kemeny N Hypotension as a manifestation of cardiotoxicity in three patients receiving cisplatin and 5-fluorouracil Cancer 1988 62 266 9 3383127 \n14 Patel B Kloner RA Ensley J Al-Sarraf M Kish J Wynne J 5-Fluorouracil cardiotoxicity: left ventricular dysfunction and effect of coronary vasodilators Am J Med Sci 1987 294 238 43 3661619 \n15 Lemaire L Malet–Martino MC de Forni M Martino R Lasserre B Cardiotoxicity of 5-fluorouracil vials stems from alkaline hydrolysis of this drug Br J Cancer 1992 66 119 27 1637660 \n16 Mukherjee KL Heidelberger C Studies on fluorinated pyrimidines ix—the degradation of 5-fluorouracil J Biol Chem 1960 235 433 7 14425080 \n17 Matsubara I Kamiya J Imai S Cardiotoxic effects of 5-fluorouracil in the guinea pig Jap J Pharmacol 1980 30 871 9 7241861 \n18 de Forni M Malet–Martino MC Jaillais P Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study J Clin Oncol 1992 10 1795 801 1403060 \n19 Kuzel T Esparaz B Green D Kies M Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin Cancer 1990 65 885 9 2297659 \n20 Alter P Herzum M Soufi M Schaefer JR Maisch B Cardiotoxicity of 5-fluorouracil Cardiovasc Hematol Agents Med Chem 2006 4 1 5 16529545 \n21 Ciccolini J Mercier C Dahan L Toxic death-case after capecitabine–oxaliplatin (xelox) administration: probable implication of dihydropyridine dehydrogenase deficiency Cancer Chemother Pharmacol 2006 58 272 5 16292536 \n22 Mercier C Dupuis C Blesius A Early severe toxicities after capecitabine intake: possible implication of a cytidine deaminase extensive metabolizer profile Cancer Chemother Pharmacol 2009 63 1177 80 19107485 \n23 Haller DG Cassidy J Clark SJ Potential regional differences for the tolerability profiles of fluoropyrimidines J Clin Oncol 2008 26 2118 23 18445840 \n24 Labianca R Beretta G Clerici M Fraschini P Luporini G Cardiac toxicity of 5-fluorouracil: a study of 1083 patients Tumori 1982 68 505 10 7168016 \n25 Ng M Cunninham D Norman AR The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (crc) Eur J Cancer 2005 41 1542 6 15978800 \n26 Tsibiribi P Descotes J Lombard–Bohas C Cardiotoxicity of 5-fluorouracil in 1350 patients with no prior history of heart disease Bull Cancer 2006 93 E27 30 16567310 \n27 Galderisi M Marra F Esposito R Lomoriello VS Pardo M de Divitiis O Cancer therapy and cardiotoxicity: the need of serial Doppler echocardiography Cardiovasc Ultrasound 2007 5 4 17254324 \n28 Holubec L JrTopolcan O Finek J Dynamic monitoring of cardio-specific markers and markers of thyroid gland function in cancer patients—a pilot study Anticancer Res 2007 27 1883 6 17649788 \n29 Cianci G Morelli MF Cannita K Prophylactic options in patients with 5-fluorouracil–associated cardiotoxicity Br J Cancer 2003 88 1507 9 12771913 \n30 Talapatra K Rajesh I Rajesh B Selvamani B Subhashini J Transient asymptomatic bradycardia in patients on infusional 5-fluorouracil J Cancer Res Ther 2007 3 169 71 18079582 \n31 Shoemaker LK Arora U Rocha Lima CM 5fu-induced coronary vasospasm Cancer Control 2004 11 46 9 14749623\n\n", "fulltext_license": "CC BY", "issn_linking": "1198-0052", "issue": "17(1)", "journal": "Current oncology (Toronto, Ont.)", "keywords": "5-Fluorouracil; capecitabine; cardiotoxicity; chemotherapy", "medline_ta": "Curr Oncol", "mesh_terms": null, "nlm_unique_id": "9502503", "other_id": null, "pages": "59-63", "pmc": null, "pmid": "20179805", "pubdate": "2010-02", "publication_types": "D016428:Journal Article", "references": "14749623;12771913;8422644;8233284;15978800;18445840;2297659;17636329;16292536;12931015;7241861;16866187;3275485;17254324;15763604;3383127;19107485;3661619;1403060;16529545;7168016;16418875;2278719;16567310;1637660;18079582;11996484;18669470;14425080;16697705;17649788", "title": "Capecitabine-induced cardiotoxicity: case report and review of the literature.", "title_normalized": "capecitabine induced cardiotoxicity case report and review of the literature" }	[ { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-319401", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "204668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MILLIGRAM/SQ. METER, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Adenocarcinoma of colon", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN 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": "METFORMIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VENLAFAXINE 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": "VENLAFAXINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALSARTAN" }, "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": "VALSARTAN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiotoxicity", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Ang C, Kornbluth M, Thirlwell MP, Rajan RD.. Capecitabine-induced cardiotoxicity: case report and review of the literature. Curr Oncol. 2010;17(1):59-63", "literaturereference_normalized": "capecitabine induced cardiotoxicity case report and review of the literature", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220118", "receivedate": "20211203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20143471, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]
{ "abstract": "Distal intramural spread refers to microscopic tumor implantation in the intestinal wall, distal to the inferior edge of a macroscopic tumor but rarely beyond 2 cm. We report a case of rectal cancer with preoperatively diagnosed distant intramural spread to approximately 6.5 cm. A 75-year-old woman diagnosed with upper rectal cancer was scheduled to undergo low anterior resection 5 weeks after initial presentation. However, preoperative digital rectal examination and anoscopy under general anesthesia revealed a rectal tumor 4 cm proximal to the anal verge; adenocarcinoma was diagnosed based on frozen section analysis of the rectal tumor. Therefore, abdominoperineal resection was performed, and histopathological examination confirmed a moderately differentiated adenocarcinoma with distal intramural spread of 6.5 cm. The patient died 18 months postoperatively owing to lung metastasis. Although distal intramural spread is rare and can be difficult to detect prior to surgery, repeated rectal examination, with prompt histological examination of suspicious lesions, can ensure earlier diagnosis to achieve better local control by radical surgery including sufficient distal margin.", "affiliations": "1Department of Surgery, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192 Aichi Japan.;1Department of Surgery, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192 Aichi Japan.;2Department of Pathology, School of Medicine, Fujita Health University, Toyoake, Japan.;2Department of Pathology, School of Medicine, Fujita Health University, Toyoake, Japan.;Department of Surgery, Rokuwa Hospital, Inazawa, Japan.;1Department of Surgery, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192 Aichi Japan.;1Department of Surgery, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192 Aichi Japan.", "authors": "Sato\|Harunobu\|H\|0000-0003-4637-8853;Shiota\|Miho\|M\|;Okabe\|Asako\|A\|;Tsukamoto\|Tetsuya\|T\|;Honda\|Katsuyuki\|K\|;Morise\|Zenichi\|Z\|;Uyama\|Ichiro\|I\|", "chemical_list": null, "country": "Singapore", "delete": false, "doi": "10.1007/s13691-019-00385-3", "fulltext": null, "fulltext_license": null, "issn_linking": "2192-3183", "issue": "9(1)", "journal": "International cancer conference journal", "keywords": "Distal intramural spread; Rectal cancer; Sphincter-preserving operation", "medline_ta": "Int Cancer Conf J", "mesh_terms": null, "nlm_unique_id": "101734231", "other_id": null, "pages": "9-13", "pmc": null, "pmid": "31950010", "pubdate": "2020-01", "publication_types": "D002363:Case Reports", "references": "7648142;7551328;8625118;12620912;23050553;15637735;22067179;8918426;9102256;30022919;15273550;9711965;6831156;26753380;26671688;14685098", "title": "Rectal cancer with extensive distal intramural spread treated by abdominoperineal resection.", "title_normalized": "rectal cancer with extensive distal intramural spread treated by abdominoperineal resection" }	[ { "companynumb": "JP-ACCORD-170899", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "207474", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "85 MG/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LYMPH NODES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "85", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "040743", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG/M^2 BOLUS ON DAY 1 THEN 2,400 MG/M^2 5-FU AS INTRAVENOUS INFUSION OVER 46 H, EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG/ M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLINIC ACID" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG/ M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLINIC ACID" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "207474", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "85 MG/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "85", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "040743", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG/M^2 BOLUS ON DAY 1 THEN 2400 MG/M^2 5-FU AS INTRAVENOUS INFUSION OVER 46 H, EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Deep vein thrombosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SATO H, SHIOTA M, OKABE A, TSUKAMOTO T, HONDA K, MORISE Z ET AL. RECTAL CANCER WITH EXTENSIVE DISTAL INTRAMURAL SPREAD TREATED BY ABDOMINOPERINEAL RESECTION. INTERNATIONAL CANCER CONFERENCE JOURNAL. 2020?9(1):9-13.", "literaturereference_normalized": "rectal cancer with extensive distal intramural spread treated by abdominoperineal resection", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200129", "receivedate": "20200129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17338091, "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": "Cystic hygroma is a congenital malformation of the lymphatic system that mostly presents at birth. Though the classic treatment of this condition is surgical excision, recent alternative treatment modalities such as injection of sclerotherapeutic agents (e.g., bleomycin and OK-432) into the lesion has gained popularity due to its safe and effective response profile with minimal side effects. We report a rare complication of repeated bleomycin sclerotherapy in a follow-up patient of cystic hygroma, where the lesion underwent fibrolipomatous conversion with insinuation into multiple fascial planes, causing mass effect by encasement and compression of major vascular and airway structures. This is the first time such a complication of bleomycin sclerotherapy has been reported in literature. Such an unusual presentation reminds us that, in any patient presenting with recurrent gradually increasing swelling with worsening of symptoms following bleomycin sclerotherapy, a possibility of fibrolipomatous conversion of cystic hygroma should be borne in mind.", "affiliations": "Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.;Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.;Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.", "authors": "Reghunath\|Anjuna\|A\|;Ghasi\|Rohini G\|RG\|;Kushvaha\|Suchana\|S\|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/JCAS.JCAS_152_19", "fulltext": "\n==== Front\nJ Cutan Aesthet Surg\nJ Cutan Aesthet Surg\nJCAS\nJournal of Cutaneous and Aesthetic Surgery\n0974-2077 0974-5157 Wolters Kluwer - Medknow India \n\nJCAS-13-229\n10.4103/JCAS.JCAS_152_19\nCase Report\nThe Curious Case of Fibrofatty Conversion of Cystic Hygroma Treated with Bleomycin Sclerotherapy\nReghunath Anjuna Ghasi Rohini G. Kushvaha Suchana Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India\nAddress for correspondence: Dr. Rohini Gupta Ghasi, Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi 110029, India. E-mail: [email protected]\nJul-Sep 2020 \n13 3 229 232\nCopyright: © 2020 Journal of Cutaneous and Aesthetic Surgery2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Abstract\nCystic hygroma is a congenital malformation of the lymphatic system that mostly presents at birth. Though the classic treatment of this condition is surgical excision, recent alternative treatment modalities such as injection of sclerotherapeutic agents (e.g., bleomycin and OK-432) into the lesion has gained popularity due to its safe and effective response profile with minimal side effects. We report a rare complication of repeated bleomycin sclerotherapy in a follow-up patient of cystic hygroma, where the lesion underwent fibrolipomatous conversion with insinuation into multiple fascial planes, causing mass effect by encasement and compression of major vascular and airway structures. This is the first time such a complication of bleomycin sclerotherapy has been reported in literature. Such an unusual presentation reminds us that, in any patient presenting with recurrent gradually increasing swelling with worsening of symptoms following bleomycin sclerotherapy, a possibility of fibrolipomatous conversion of cystic hygroma should be borne in mind.\n\nKeywords:\nBleomycincystic hygromasclerotherapy\n==== Body\nINTRODUCTION\nLymphangiomas are benign hamartomatous lymphatic tumors, which may occur anywhere in the body, though most frequently seen in neck (75%), axilla (20%), and inguinal areas (2%).[1] Cystic hygroma is the most common form of lymphangioma occurring in head and neck region.[2] Sclerotherapy with bleomycin is a favored treatment regime for cystic hygromas, with minimal side effects and good response rate.[2] Fibrolipomatous conversion of cystic hygroma after recurrent bleomycin sclerotherapy has hitherto been unreported in literature. We report an index case of such a complication, which led to worsening of symptoms in the patient.\n\nCASE REPORT\nA 26-year-old male patient presented with a large swelling on the left side of neck along with the complaints of difficulty in breathing and swallowing. The patient was a previously diagnosed case of congenital cystic hygroma [Figure 1], who had undergone surgical excision twice at the age of 6 months and 8 years, only to gradually develop recurrent swellings at the same site. These swellings were treated with bleomycin sclerotherapy every 3 years. However, patient had an apparent “non-response” to sclerotherapeutic agent such as bleomycin since past 4 years, and hence was referred to us for a contrast-enhanced computed tomography (CECT) to ascertain the cause of increasing size of swelling and worsening of symptoms. The clinical provisional diagnosis was a recurrence of cystic hygroma in the patient.\n\nFigure 1 Frontal radiograph of neck and chest of the patient as an infant shows soft tissue swelling along neck, shoulder, axilla, and chest wall on left side, diagnosed as congenital cystic hygroma\n\nCECT of neck and thorax revealed a large non-encapsulated mass located in the left lateral aspect of neck and chest wall and left axilla [Figure 2]. The mass was a predominantly fat attenuation and contained few areas of coarsely calcified tubular soft tissue structures in the posterior aspect of neck and chest wall [Figure 3]. Few linear enhancing soft tissue components were also seen within the lesion.\n\nFigure 2 Three-dimensional volume-rendered CT image of the patient shows a large swelling on the left side of neck and chest wall\n\nFigure 3 CECT reveals a fatty mass in neck, chest wall, and axilla on left extending into superior mediastinum, with linear enhancing soft tissue components (asterisk) (A) and calcified tubular soft tissue structures (red arrow) (B) within. Lesion is also encasing left subclavian and axillary vessels (yellow arrow) (C) with fatty replacement of left sternocleidomastoid, trapezium, and scalene muscles\n\nThe lesion was diffusely infiltrative, and was seen extending from subcutaneous planes into inter- and intramuscular plane without respecting soft tissue planes, with subsequent fatty replacement of left sternocleidomastoid, trapezius, posterior paravertebral, and scalene muscles [Figure 3]. The lesion extended from scalp in left occipital region to D7 vertebral level along the posterior thoracic wall. No bony erosion was observed. Anteriorly, it reached up to the subcutaneous plane in neck and left anterior chest wall, abutting and narrowing left external jugular vein. Left axillary vessels were narrowed. Superomedially, lesion infiltrated into the floor of mouth, left supraglottis, and glottis, causing deviation of airway toward right side along with significant narrowing of airway and obliteration of left pyriform sinus [Figure 4]. Mass effect was present in the form of right-sided deviation of trachea, esophagus, and thyroid gland [Figure 4]. There was insinuation into superior mediastinum with encasement and narrowing of left internal jugular vein, left common carotid artery, and left subclavian artery. Considering the treatment history and imaging findings, a diagnosis of post-sclerotherapy fibrolipomatous conversion of cystic hygroma was made. The patient was planned for lipectomy in view of symptomatic airway compression.\n\nFigure 4 Axial CECT sections depicting lesion infiltration into the floor of mouth, supraglottis (A, B), and glottis (C) on left, causing narrowing and right-sided deviation of airway (yellow arrow) with complete obliteration of left pyriform sinus. Right pyriform sinus is small but visualized (red arrow). There is right-sided deviation of trachea, esophagus, and thyroid gland by lesion with encasement of left common carotid artery and internal jugular vein (IJV), causing progressive narrowing and elongation of vein (green arrow) in contrast to normal right-sided IJV\n\nDISCUSSION\nLymphangiomas are endothelium-lined spaces containing lymph, which can occur anywhere in the body, with the most common sites being head and neck.[3] Landing and Farber classified them into: (1) lymphangioma simplex, consisting of capillary-sized channels; (2) cavernous lymphangioma, comprising dilated lymphatic channels; and (3) cystic hygroma, consisting of multiple cysts with straw-colored fluid within.[3] Cystic hygroma usually presents as a painless congenital mass, which may be complicated with feeding and respiratory difficulty, fever, or sudden increase in size of lesion due to hemorrhage or infection.[2] Ultrasound is the primary imaging modality, which clearly demonstrates the cystic nature. They are mostly multilocular, containing septations of variable thickness.[2] Infected or hemorrhagic lesions may show fluid-fluid level. Both computed tomography (CT) and magnetic resonance imaging ascertain the extent of lesion and relations of the cyst with neurovascular bundle, especially before surgery.\n\nManagement of choice is surgical excision, however, the feasibility of complete excision of lesion is often questionable due to its infiltrative nature.[3] Chances of vital organ injuries, bleeding, infection, and scar formation are highly associated with surgery.[4] A recurrence rate of 15% is reported whenever residual tissue is left behind.[4] Safe and alternative treatment modalities such as sclerotherapy are now preferred, which can be performed in surgically inaccessible lesions also.[1] OK-432 and bleomycin are currently the most favored sclerotherapy agents for treating cystic hygroma.[5] In addition, cauterization, simple drainage or aspiration, radiofrequency ablation, and laser excision are being tried as an alternative to surgery or to reduce the pressure effect on respiratory and feeding passages.[2] Bleomycin is a deoxyribonucleic acid (DNA) synthesis inhibitor with sclerosing effect on endothelial cells due to inflammatory reaction.[6] According to a study by Kumar et al.,[1] response to bleomycin injection on clinical and Doppler assessment was found as excellent, good, or poor based on 100%, >50%, or <50% regression of lesion, respectively.\n\nIn a large systematic review of literature comparing sclerotherapy agents used in vascular malformation of head and neck by Horbach et al.,[7] the most common side effect following sclerotherapy injection was cellulitis and skin ulceration. Facial nerve palsy and skin necrosis were associated with ethanol and OK-432 sclerotherapy. Mean complication rate of bleomycin therapy was 6% in their study, with skin infection, pain, and swelling being common adverse reactions. In another retrospective review by Alomari et al.,[8] no serious side effect was encountered in patients on bleomycin sclerotherapy. Chen et al.[9] observed that high doses of bleomycin injection could lead to pulmonary fibrosis, especially when total cumulative dose exceeds 400 mg. However, to the best of our knowledge, fibrofatty conversion of cystic hygroma, after bleomycin injection, has never been reported in literature before.\n\nAnother condition that simulates the CECT picture as seen in our case is Madelung’s disease, an idiopathic disease where non-encapsulated fat masses are deposited in the face and cervical region.[10] Surgical treatment of Madelung’s disease includes lipectomy and liposuction, especially to remove the mass effect on vital organs.[10] Use of steroids and antiretroviral drugs, which may cause fat deposition, was excluded in our patient.[8] Hence, in any case of suspected non-response to bleomycin sclerotherapy in cystic hygroma or paradoxical increase in size of lesion or symptoms, the possibility of bleomycin-induced fibrofatty conversion of cystic hygroma should be kept in mind and the patient should undergo imaging for evaluation of the same.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Kumar V Kumar P Pandey A Gupta DK Shukla RC Sharma SP Intralesional bleomycin in lymphangioma: an effective and safe non-operative modality of treatment J Cutan Aesthet Surg 2012 5 133 6 23060708 \n2 Mirza B Ijaz L Saleem M Sharif M Sheikh A Cystic hygroma: an overview J Cutan Aesthet Surg 2010 3 139 44 21430825 \n3 Niramis R Watanatittan S Rattanasuwan T Treatment of cystic hygroma by intralesional bleomycin injection: experience in 70 patients Eur J Pediatr Surg 2010 20 178 82 20178075 \n4 Bill AH Jr Sumner DS A unified concept of lymphangioma and cystic hygroma Surg Gynecol Obstet 1965 120 79 86 14259790 \n5 Muir T Kirsten M Fourie P Dippenaar N Ionescu GO Intralesional bleomycin injection (IBI) treatment for haemangiomas and congenital vascular malformations Pediatr Surg Int 2004 19 766 73 14740248 \n6 Okada A Kubota A Fukuzawa M Imura K Kamata S Injection of bleomycin as a primary therapy of cystic lymphangioma J Pediatr Surg 1992 27 440 3 1381746 \n7 Horbach SE Lokhorst MM Saeed P de Goüyon Matignon de Pontouraude CM Rothová A van der Horst CM Sclerotherapy for low-flow vascular malformations of the head and neck: a systematic review of sclerosing agents J Plast Reconstr Aesthet Surg 2016 69 295 304 26723834 \n8 Alomari AI Karian VE Lord DJ Padua HM Burrows PE Percutaneous sclerotherapy for lymphatic malformations: a retrospective analysis of patient-evaluated improvement J Vasc Interv Radiol 2006 17 1639 48 17057006 \n9 Chen WL Huang ZQ Chai Q Zhang DM Wang YY Wang HJ Percutaneous sclerotherapy of massive macrocystic lymphatic malformations of the face and neck using fibrin glue with Ok-432 and bleomycin Int J Oral Maxillofac Surg 2011 40 572 6 21367582 \n10 Mohanty P Vivekanandh K Dash G Mohapatra L Madelung’s disease: a benign symmetric lipomatosis Indian J Dermatol Venereol Leprol 2018 84 190 1 29405131\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0974-2077", "issue": "13(3)", "journal": "Journal of cutaneous and aesthetic surgery", "keywords": "Bleomycin; cystic hygroma; sclerotherapy", "medline_ta": "J Cutan Aesthet Surg", "mesh_terms": null, "nlm_unique_id": "101525405", "other_id": null, "pages": "229-232", "pmc": null, "pmid": "33209001", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "21430825;20178075;14259790;1381746;14740248;17057006;26723834;23060708;29405131;21367582", "title": "The Curious Case of Fibrofatty Conversion of Cystic Hygroma Treated with Bleomycin Sclerotherapy.", "title_normalized": "the curious case of fibrofatty conversion of cystic hygroma treated with bleomycin sclerotherapy" }	[ { "companynumb": "IN-MEITHEAL PHARMACEUTICALS-2020MHL00075", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "205030", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYSTIC LYMPHANGIOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lipofibroma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "REGHUNATH A, GHASI RG, KUSHVAHA S. THE CURIOUS CASE OF FIBROFATTY CONVERSION OF CYSTIC HYGROMA TREATED WITH BLEOMYCIN SCLEROTHERAPY. J CUTAN AESTHET SURG. 2020?13(3):229-232", "literaturereference_normalized": "the curious case of fibrofatty conversion of cystic hygroma treated with bleomycin sclerotherapy", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20201113", "receivedate": "20201113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18501635, "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 Calcineurin inhibitor-induced posterior reversible encephalopathy syndrome (PRES) is well described in liver and kidney transplant patients, but there is a paucity of data in heart transplant patients. PRES syndrome in the setting of heart transplantation can occur as early as 5 days following transplantation. CASE REPORT A 32-year-old woman who had recently undergone orthotopic heart transplantation developed headaches, visual disturbances, and generalized tonic clonic seizures 5 days after initiating anti-rejection therapy (tacrolimus, mycophenolate, and prednisone). No focal neurological deficits were noted on physical exam. Multifocal subcortical fluid attenuation inversion recovery (FLAIR) hyperintensity signals and areas of diffusion restriction with postcontrast enhancement, diagnostic of PRES, were found on MRI brain. Her symptoms resolved 2 days after tacrolimus was switched to cyclosporine. A follow-up MRI after 6 weeks demonstrated complete resolution of areas of flair hyperintensity signal. She was sent home on a short course of seizure prophylaxis, which was discontinued after the resolution of radiological findings. She had no further episodes of seizures for 6 months following discontinuation of her anti-epileptic regimen. CONCLUSIONS Tacrolimus-induced PRES can occur as early as 5 days after orthotopic heart transplantation. Early recognition of symptoms and management can prevent permanent neurological sequelae.", "affiliations": "Department of Cardiology, Saint Luke's Mid-America Heart Institute, Kansas City, MO, USA.;Department of Cardiovascular Imaging, Saint Luke's Mid-America Heart Institute, Kansas City, MO, USA.;Department of Cardiology, University of Missouri - Kansas City School of Medicine, Saint Luke's Mid America Heart Institute, Kansas City, MO, USA.", "authors": "Ramirez\|Rigoberto\|R\|;Muskula\|Preetham Reddy\|PR\|;Everley\|Mark P\|MP\|", "chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus", "country": "United States", "delete": false, "doi": "10.12659/ajcr.903403", "fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2846549910.12659/AJCR.903403903403ArticlesPosterior Reversible Encephalopathy Syndrome After Orthotopic Heart Transplantation: A Case Report Ramirez Rigoberto E1Muskula Preetham Reddy EF2Everley Mark P. BE31 Department of Cardiology, Saint Luke’s Mid-America Heart Institute, Kansas City,MO, U.S.A.2 Department of Cardiovascular Imaging, Saint Luke’s Mid-America Heart Institute, Kansas City, MO, U.S.A.3 Department of Cardiology, University of Missouri – Kansas City School of Medicine, Saint Luke’s Mid America Heart Institute, Kansas City, MO, U.S.A.Authors’ 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\nCorresponding Author: Preetham R. Muskula, e-mail: [email protected] 03 5 2017 18 487 490 17 1 2017 14 2 2017 © Am J Case Rep, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 32\n\nFinal Diagnosis: Posterior reversible encephalopathy syndrome\n\nSymptoms: Seizures\n\nMedication: Tacrolimus\n\nClinical Procedure: —\n\nSpecialty: Cardiology\n\nObjective:\nRare disease\n\nBackground:\nCalcineurin inhibitor-induced posterior reversible encephalopathy syndrome (PRES) is well described in liver and kidney transplant patients, but there is a paucity of data in heart transplant patients. PRES syndrome in the setting of heart transplantation can occur as early as 5 days following transplantation.\n\nCase Report:\nA 32-year-old woman who had recently undergone orthotopic heart transplantation developed headaches, visual disturbances, and generalized tonic clonic seizures 5 days after initiating anti-rejection therapy (tacrolimus, mycophenolate, and prednisone). No focal neurological deficits were noted on physical exam. Multifocal subcortical fluid attenuation inversion recovery (FLAIR) hyperintensity signals and areas of diffusion restriction with postcontrast enhancement, diagnostic of PRES, were found on MRI brain. Her symptoms resolved 2 days after tacrolimus was switched to cyclosporine. A follow-up MRI after 6 weeks demonstrated complete resolution of areas of flair hyperintensity signal. She was sent home on a short course of seizure prophylaxis, which was discontinued after the resolution of radiological findings. She had no further episodes of seizures for 6 months following discontinuation of her anti-epileptic regimen.\n\nConclusions:\nTacrolimus-induced PRES can occur as early as 5 days after orthotopic heart transplantation. Early recognition of symptoms and management can prevent permanent neurological sequelae.\n\nMeSH Keywords:\nHeart TransplantationImmunosuppressionSeizuresTacrolimus\n==== Body\nBackground\nCalcineurin inhibitors revolutionized management of patients who underwent solid organ transplantation by effectively reducing acute rejection episodes and improving survival [1]. Neurotoxicity with these medications ranges from a mild tremor, acute confusional state, to status epilepticus or even major speech and motor abnormalities. Posterior reversible encephalopathy is one such neuroradiological phenomenon diagnosed by an MRI. Without prompt recognition and management, it can lead to progression of vasogenic edema to cytotoxic edema, resulting in permanent neurological deficits. This phenomenon is well studied in liver, kidney, and hematopoietic stem cell transplant patients, but very little data exist in the current literature about its incidence in post-heart transplant patients [1–3]. Here, we discuss the clinical course of one such case that was successfully identified and managed appropriately.\n\nCase Report\nA 32-year-old woman with a history of end-stage non-ischemic cardiomyopathy on chronic home milrinone therapy and chronic migraines was admitted to the hospital for cardiogenic shock. An intra-aortic balloon pump was placed as a bridge to orthotopic heart transplantation owing to persistent hypotension despite dual-ionotropic support. She experienced intermittent bouts of her typical migraine headaches consisting of a prodrome of kaleidoscope-like visual disturbances. Her symptoms were generally well controlled with sumatriptan when administered at the advent of her prodrome. However, given the patient’s underlying cardiac complications, intravenous Divalproex sodium was instituted as abortive therapy (continued oral Divalproex sodium for migraine prophylaxis) with successful resolution. After a suitable donor heart was obtained, she underwent orthotopic heart transplantation. Her anti-rejection (immunosuppressive) therapy consisted of mycophenolate mofetil, Prednisone, and tacrolimus. Five days following initiation of tacrolimus, she reported a severe headache that was without prodromal symptoms and was resistant to abortive migraine therapy. A few hours later, she had an episode of generalized tonic clonic seizures, which resolved spontaneously after 1 minute. While an emergent CT head was being performed, she suffered another episode of generalized tonic clonic seizure. This time, seizures subsided following administration of intravenous Ativan. No evidence of bleeding or infarct was noted on the CT head. Vital signs were unremarkable except for a significantly elevated systolic blood pressure of 180/90 mmHg. A comprehensive neurological exam was performed and was noted to be unremarkable without any focal neurologic deficits. Complete blood count and complete metabolic panel were within normal limits. Serum tacrolimus level and magnesium levels were 2·8 ng/ml and 1·5 mg/dl, respectively. She received a loading dose of Divalproex sodium intravenously for seizure prophylaxis and an anti-epileptic regimen was instituted. An electroencephalogram (EEG) demonstrated mild-to-moderate generalized slowing without clear epileptiform discharges. An MRI showed areas of subcortical FLAIR hyperintensity in the bilateral frontal, parietal, and occipital lobes, as well as the cerebellum, consistent with PRES (Figure 1). After the patient regained baseline mentation, she described transient visual disturbances (with patches of green in her visual fields). Considering MRI findings and the recent use of tacrolimus, PRES was our leading hypothesis. Therefore, tacrolimus was switched to cyclosporine. Hypertension was addressed with intravenous hydralazine with a systolic blood pressure goal of less than 140 mmHg, and magnesium was supplemented. Over the course of 3 days, her headache and visual disturbances gradually resolved. A follow-up MRI after 6 weeks demonstrated resolution of previous FLAIR signal abnormalities, with no abnormal post-contrast enhancement, corroborating the diagnosis of PRES. No further episodes of seizures were reported after the discontinuation of her anti-epileptic regimen following radiological resolution.\n\nDiscussion\nHinchey and colleagues were the first to describe posterior reversible encephalopathy syndrome (PRES) in 1996 in 15 patients, most of whom were on immunosuppressive therapy [4]. PRES is a clinico-neuroradiological syndrome that commonly manifests as seizures (77.5%), encephalopathy (62%), headache (29.6%), visual disturbances (22.5%), or focal neurological symptoms (22.5%). A wide range of neurological symptoms are reported with PRES, from mild transient reversible neurological symptoms to severe and debilitating, occasionally resulting in permanent neurologic sequelae. A literature review by Song and colleagues discovered that 89.3% of patients with CNI-associated PRES had a full recovery and an additional 10.7% recovered with neurological sequelae [3]. Patients with notable hemorrhagic lesion on imaging recovered with neurological sequelae. The patho-physiological mechanism underlying PRES is not fully understood. Postulated hypotheses include medication-induced endothelial damage and hypo- or hyperperfusion due to disruption of cerebral autoregulation precipitated by uncontrolled hypertension. Regardless of the underlying mechanism, transient vasogenic edema occurs, which can be detected on MRI. Delayed diagnosis can offset cytotoxic edema and result in permanent neurological sequelae. Frequently implicated triggers are eclampsia, hypertensive emergency, or exposure to immunosuppressive therapy (as reported in our case), as well as numerous other uncommon causes. Commonly implicated immunosuppressant medications are calcineurin inhibitors (e.g., cyclosporine and tacrolimus). Growing numbers of organ transplantations and use of calcineurin inhibitors inadvertently resulted in an escalating incidence of their neurotoxic adverse effects. According to a recent case report, sirolimus has joined this group of implicated medications, although at a much lower frequency [5].\n\nPRES is extensively described in the literature in patients who underwent solid organ and hematopoietic stem cell transplantation. Bartynski et al., studying 4222 patients who underwent solid organ transplantation (SOT) and on immunosuppressive therapy (especially with calcineurin inhibitors), reported that in kidney and liver transplant patients the incidence of PRES was around 0.49% and 0.84%, respectively [2]. The mean time of onset of the toxicity (following transplantation or initiation of immunosuppressant therapy) also varied between different SOT subtypes. When immunosuppressive therapy is the causative factor, dose reduction, switching medication, or discontinuation of the medication were all reasonably successful strategies. Tacrolimus-related PRES was noted to be unrelated to the drug levels. Therapeutic drug monitoring is recommended to prevent tacrolimus toxicity but PRES is known to occur even at normal therapeutic drug levels. Clinical recovery was noted to occur within a few days, while radiological recovery took days to weeks. Hypertension, elevated serum creatinine or CKD/Dialysis, solid organ or hematopoietic stem cell transplantation, hypomagnesemia, pregnancy, and sepsis are among the comorbid conditions associated with PRES. Management of hypertension and hypomagnesemia are noted to be important in the recovery of these patients.\n\nPRES is a neuro-radiological phenomenon characterized by bilateral and symmetric vasogenic edema involving subcortical white matter. It is diagnosed by a FLAIR hyperintensity signal, which has the ability detect even subtle PRES lesions, noted on T-2 weighted images, typically involving the parieto-occipital areas (posterior circulation) on MRI. Supplemental diffusion-weighted imaging (D-WI) and apparent diffusion coefficient (ADC) mapping helps differentiate reversible vasogenic edema (represented by iso-/hyperintense D-WI and hyper-intense ADC correlating with areas of FLAIR hyperintensity) from irreversible cytotoxic edema (hypointense ADC) [6]. Complete reversibility of all these changes on subsequent imaging is a unique characteristic of PRES and is often diagnostic (Figure 1). Rarely, hemorrhages and micro-ischemic infarcts are the residual findings noted on MRI. These changes are associated with residual neurological deficits.\n\nAtypical PRES denotes involvement of areas of the brain other than posterior circulation. Involvement of frontal and fronto-parietal lobes, thalami, internal capsule, isolated brainstem, cerebellum, cortical grey matter, unilateral lesions, foci of permanent injury, and hemorrhage into lesions demonstrable on MRI constitute atypical neuro-imaging findings. Since atypical PRES is more common, the term PRES is essentially considered a misnomer.\n\nConclusions\nDrug-induced PRES can occur in solid-organ transplant patients as early as the first week of initiation of immunosuppressant therapy. Early diagnosis followed by discontinuation of the causative agent, dose reduction, or switching immunosuppressant regimen can result in complete resolution of symptoms. This can also be demonstrated by the resolution of radiological findings on follow-up MRI.\n\nConflicts of interest\n\nNo conflicts of interest to declare.\n\nFigure 1. (A, B) Represent initial MRI brain findings (immediate post-seizure imaging): Areas of subcortical FLAIR hyperintensity in the bilateral parietal and occipital lobes (arrows) consistent with posterior reversible encephalopathy syndrome. (C, D) Represent follow-up MRI brain findings (6 weeks after switching tacrolimus to cyclosporine): Resolution of the previous FLAIR hyperintensity signal abnormality.\n==== Refs\nReferences:\n1. Song T Rao Z Tan Q Calcineurin inhibitors associated posterior reversible encephalopathy syndrome in solid organ transplantation: Report of 2 cases and literature review Medicine (Baltimore) 2016 95 e3173 27057842 \n2. Bartynski WS Tan HP Boardman JF Posterior reversible encephalopathy syndrome after solid organ transplantation Am J Neuroradiol 2008 29 924 30 18272559 \n3. Wu Q Marescaux C Wolff V Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation Eur Neurol 2010 64 169 77 20699617 \n4. Barbas AS Rege AS Castleberry AW Posterior reversible encephalopathy syndrome independently associated with tacrolimus and sirolimus after multivisceral transplantation Am J Transplant 2013 13 808 10 23331705 \n5. Hinchey J Chaves C Appignani B A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996 334 494 500 8559202 \n6. Lee VH Wijdicks EF Manno EM Rabinstein AA Clinical spectrum of reversible posterior leukoencephalopathy syndrome Arch Neurol 2008 65 20 10\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "18()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000328:Adult; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D054038:Posterior Leukoencephalopathy Syndrome; D016559:Tacrolimus", "nlm_unique_id": "101489566", "other_id": null, "pages": "487-490", "pmc": null, "pmid": "28465499", "pubdate": "2017-05-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "23331705;20699617;18268188;8559202;18272559;27057842", "title": "Posterior Reversible Encephalopathy Syndrome After Orthotopic Heart Transplantation: A Case Report.", "title_normalized": "posterior reversible encephalopathy syndrome after orthotopic heart 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{ "abstract": "Omphalocele, exstrophy of the bladder, imperforate anus and spinal defect (OEIS) complex is a rare congenital multisystemic malformation representing unique anomalies. It was first reported in 1978 through a series of cases with an abnormality of body wall development. We are reporting a case of an infant of 36 weeks gestation, with a family history of consanguinity and oral contraceptive pill intake that was discontinued when the mother was 1-month pregnant. The neonatal examination revealed findings that were consistent with OEIS complex along with the presence of genital anomalies. The infant required multi-staged surgical intervention. We conclude that this case report might illustrate some of the possible risk factors and variability of OEIS complex.", "affiliations": "Department of Pediatrics, University of Dammam-King Fahd Hospital of the University, Al Khobar, Saudi Arabia.;Department of Pediatrics, University of Dammam-King Fahd Hospital of the University, Al Khobar, Saudi Arabia.;Department of Surgery, University of Dammam-King Fahd Hospital of the University, Al Khobar, Saudi Arabia.", "authors": "Al-Qurashi\|Faisal Othman\|FO\|;Al-Hareky\|Thammer Saad\|TS\|;Al-Buainain\|Hussah Mohammed\|HM\|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/1658-631X.194258", "fulltext": "\n==== Front\nSaudi J Med Med SciSaudi J Med Med SciSJMMSSaudi Journal of Medicine & Medical Sciences1658-631X2321-4856Medknow Publications & Media Pvt Ltd India SJMMS-5-6710.4103/1658-631X.194258Case ReportOmphalocele, Exstrophy of Bladder, Imperforate Anus and Spinal Defect Complex with Genital Anomalies in a Late Preterm Infant Al-Qurashi Faisal Othman Al-Hareky Thammer Saad Al-Buainain Hussah Mohammed 1Department of Pediatrics, University of Dammam-King Fahd Hospital of the University, Al Khobar, Saudi Arabia1 Department of Surgery, University of Dammam-King Fahd Hospital of the University, Al Khobar, Saudi ArabiaCorrespondence: Dr. Faisal Othman Al-Qurashi, P.O. Box 11286, Dammam 31453, Saudi Arabia. E-mail: [email protected] 2017 16 11 2016 5 1 67 70 Copyright: © 2017 Saudi Journal of Medicine & Medical Sciences2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Omphalocele, exstrophy of the bladder, imperforate anus and spinal defect (OEIS) complex is a rare congenital multisystemic malformation representing unique anomalies. It was first reported in 1978 through a series of cases with an abnormality of body wall development. We are reporting a case of an infant of 36 weeks gestation, with a family history of consanguinity and oral contraceptive pill intake that was discontinued when the mother was 1-month pregnant. The neonatal examination revealed findings that were consistent with OEIS complex along with the presence of genital anomalies. The infant required multi-staged surgical intervention. We conclude that this case report might illustrate some of the possible risk factors and variability of OEIS complex.\n\nملخص البحث:\nتعتبر عقدة الاكشاف المذرقي واحدة من التشوهات الخلقية المتعددة الأجهزة النادرة، وتمثل مجموعة من التشوهات الخلقية المميزة وهي : القيلة السرية، الاكشاف المثاني، والرتق الشرجي وخلل في العمود الفقري. تاريخيا، تم تشخيص أول حالات هذه العقدة في عام 1978 ميلادية من خلال عدد من الحالات التي أظهرت خللا خلقيا في بنية الجدار البطني. يعرض الباحثون حالة خديج في السادس وثلاثين أسبوعا من الحمل ، بتاريخ عائلي من زواج الأقارب، وتناول الأم لحبوب منع الحمل لشهر واحد عند بداية حملها. اثبت فحص الرضيع السريري وجود علامات متماشية مع تشخيص العقدة بالإضافة إلى وجود أعضاء تناسلية ملتبسة . تطلب علاج هذه الحالة إلى تدخل جراحي متعدد المستويات. واستنادا على هذا التقرير، فإننا نخلص إلى أن هذه الحالة النادرة قد توضح بعض عوامل الأخطار المحتملة وتباين عرض عقدة الاكشاف المذرقي. \n\nKey words:\nCloacal exstrophyexstrophy of the bladderomphalocele\n==== Body\nINTRODUCTION\nOmphalocele, exstrophy of the bladder, imperforate anus and spinal defect (OEIS) complex is one of the rarest multisystemic congenital malformations representing unique and characteristic anomalies. It counts for approximately 1:200,000 live births. In 1978, Carey et al. reported a series of cases with an abnormality of body wall development known then by many names, most commonly “exstrophy of the cloaca.” They proposed the term OEIS complex because the term is simple and recalls all of the defects present.[1] Due to the rarity and lack of comprehensive background of such a diagnosis, our aim is to illustrate some of the possible risk factors and the variable presentations of OEIS complex.\n\nCASE REPORT\nA late preterm infant of 36 weeks gestation, product of spontaneous vaginal delivery with Apgar Score of 5 and 7 at 1 and 5 minutes respectively and admitted initially, was admitted initially as a case of multiple congenital anomalies with genital anomalies.\n\nThe infant was born to a 23-year-old Saudi female, G3 P1 + 1, who was not known to have any chronic medical illnesses, but with a history of a previous infant that had died of complicated surgically-corrected diaphragmatic hernia. She was on regular antenatal care follow-up in a private hospital. She had no history of pregnancy-related illnesses or exposure to radiation. There was a history of desogestrel/ethinyl estradiol oral contraceptive pills intake of 3 months duration that was discontinued by the mother who was 1 month pregnant. Regarding the family, there is the first-degree consanguinity between the parents (i.e., cousins), with no similar conditions being reported in the family.\n\nAt 28 weeks gestation, an ultrasound study revealed the presence of fetal omphalocele and accordingly she was referred to our hospital for feto-maternal services. The repeated ultrasound scan was of a limited anomaly. Amniocentesis was tried but failed due to advanced gestation.\n\nThe delivery went smoothly with the cephalic presentation of the infant and complete placental appearance with three umbilical cord vessels (two arteries/one vein). On examination, the infant looked pale but not cyanosed or jaundiced, with no apparent dysmorphic features. Central nervous system examination revealed an active infant moving upper and lower limbs freely, with myelomeningocele at the lumbosacral area (2 cm × 2 cm) that was covered by intact skin. The cardiovascular and respiratory examination was normal. Gastrointestinal and urinary systems examination revealed omphalocele minor below the umbilicus with an intact sac containing only the bowel. The central area of defect was identified as the caecal plate with a dilated prolapsed terminal ileum with the length of 4–5 cm presenting as characteristic “elephant trunk deformity.” There was a small pinhole-sized opening in the proximal ventral aspect of the prolapsed terminal ileum, which noted to be passing the meconium. On lateral aspects, there were exstrophy bladder plates with two hemispheric bladders, each of which contained a visible ureteric orifice. An imperforate anus with an anal dimple was noticed. The genital system examination revealed multiple genital anomalies in the form of asymmetrical widely bifid sacrolabial folds that were hyperpigmented. The gonad was palpable in the left side only with absent phallus and absent urethral opening [Figure 1].\n\nFigure 1 The central area of defect was identified as caecal plate “C” with a dilated prolapsed terminal ileum “I” with the length of 4–5 cm presenting as characteristic “elephant trunk deformity.” A small sized opening on the prolapsed terminal ileum which noted to be passing meconium (arrow). On lateral aspects, there were exstrophy bladder plates with two hemispheric bladders “H” each of which contains a visible ureteric orifice “*”. Genital anomalies with asymmetrical widely bifid sacro labial folds that were hyperpigmented. The gonad was palpable in the left side with absent phallus.\n\nInvestigations were performed, including radiographic studies and chromosomal analysis. Echocardiography showed a normal study. The chromosomal study revealed a normal male karyotype of 46, XY with no numerical or structural abnormalities discernible. A computed tomography (CT) scan revealed mildly balanced congenital scoliosis, widening of symphysis pubis indicating an open book pelvic deformity and evidence of congenital bilateral hip dislocation. A multilevel vertebral failure of formation and segmentation with hemivertebra were noted at the mid-thoracic and lower lumbosacral regions. A posterior spinal dysraphism at the lower lumbosacral region was noted that was associated with a low-lying spinal cord that herniates dorsally with skin coverage representing a tethered cord with myelomeningocele [Figure 2].\n\nFigure 2 Computed tomography image showing widening of symphysis pubis indicating an open book pelvic deformity with bilateral congenital hip dislocation, mildly balanced congenital scoliosis, multilevel vertebral failure of formation and segmentation with hemivertebra seen at the midthoracic and lumbosacral regions, and posterior spinal dysraphism at the lower lumbosacral region, associated with low-lying spinal cord that herniates dorsally representing myelomeningocele.\n\nA multidisciplinary approach had been discussed with a multispecialty surgical team at our center. Due to the absence of a pediatric urology specialty in our hospital, the infant was transferred to a specialized center where the patient underwent a multi-staged surgical intervention to correct the complicated defect.\n\nDISCUSSION\nIn 1978, Carey et al. reported a series of cases with an abnormality of the body wall development. The term OEIS complex was proposed to describe their findings.[1] The description by Carey et al. was based on a retrospective search of medical records and identifying 175 infants with one or more of the above-mentioned malformations. Twenty-nine of these infants had two or more of the four cardinal defects and ten infants exhibited the full complex. Among those, genital anomalies were found in six, e.g., absence of external genitalia, ambiguous genitalia, abnormal phallus, epispadias or bifid scrotum. They assumed that these abnormal genital findings were regarded to be secondary features of the complex. The constellation of the complex findings has since then repeatedly been described in the literature and is regarded as an entity.[2] In our case, the cardinal defects of OEIS complex had been identified clinically with the presence of genital anomalies and variable degrees of spinal defects in the form of myelomeningocele, congenital scoliosis and double thoracic hemivertebrae. Based on histopathologic studies in human embryos, OEIS is most likely the result of a very early defect involving the caudal eminence as opposed to an abnormality related to premature rupture of the cloacal membrane. Anatomically, the cardinal findings of cloacal exstrophy include exstrophy of the hemibladders with hindgut extrusion and imperforate anus. The hemibladders flank the openings of the small intestine, blind-ending large intestine and containing the orifices of ureters and vasa deferentia in males and the uterovaginal canal in females [Figure 3].[3]\n\nFigure 3 Clinical presentation of cloacal exstrophy in a newborn.\n\nAlthough most cases occur sporadically, there have been several reports of recurrence in siblings suggesting that some cases may have a genetic basis.[4] In our review of the literature, we noted that due to its rarity, most of this complex-related knowledge is still under investigation and reporting, one of the complex's biggest challenges is identifying its related risk factors. We believe that parental consanguinity and use of desogestrel/ethinylestradiol oral contraceptive pills during pregnancy may play a role in the etiology of OEIS complex. In one study, Stoll et al. estimated the risk of congenital malformations in consanguineous marriages and found that birth defects in consanguineous couples are 10.3 times more frequent than in offspring of non-consanguineous couples.[5] In another study, Li et al. conducted a case–control study of the relationship between oral contraceptive use after conception to the occurrence of congenital urinary tract anomalies (CUTAs) and found that their results were compatible with the hypothesis that oral contraceptive use after conception predisposes the offspring to the development of CUTAs.[6]\n\nThe prevalence of OEIS has been estimated at 1:200,000 live births; however, the real incidence is unknown since many cases are incorrectly diagnosed prenatally, or the majority of these pregnancies is terminated or ends with in utero fetal demise.[7]\n\nCONCLUSION\nOEIS complex is a congenital multisystemic syndromic entity that should be considered as a medical challenge. Although it was thought to be associated with high mortality risk, this is no longer the case. A crucial modifying step in the management of this complex is its early antenatal diagnosis and detection, where it should be considered as a medical urgency once the diagnosis is reached. A highly specialized multispecialty medical facility is the point of referral where the management must be started initially with stabilizing the patient, then considering either a single-staged or multi-staged surgical intervention. However, given that those patients will have a poor quality of life, such intervention will support the patient's well-being rather than being viewed as active management. As part of our objectives for this case report, identifying unrecognized risk factors will add to the present knowledge of this complex and enhance the treatment that these patients can be offered. We also conclude that parental consanguinity and use of desogestrel/ethinyl estradiol oral contraceptive pills during pregnancy may play a role in the etiology of OEIS complex.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Carey JC Greenbaum B Hall BD The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects) Birth Defects Orig Artic Ser 1978 14 253 63 728566 \n2 Haldar A Sharma AK Phadke SR Jain A Agarwal SS OEIS complex with craniofacial anomalies – Defect of blastogenesis? Am J Med Genet 1994 53 21 3 7802030 \n3 van der Putte SC Spliet WG Nikkels PG Common (“classical”) and covered cloacal exstrophy: A histopathological study and a reconstruction of the pathogenesis Pediatr Dev Pathol 2008 11 430 42 18078363 \n4 Smith NM Chambers HM Furness ME Haan EA The OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): Recurrence in sibs J Med Genet 1992 29 730 2 1433234 \n5 Stoll C Alembik Y Roth MP Dott B Parental consanguinity as a cause for increased incidence of births defects in a study of 238,942 consecutive births Ann Genet 1999 42 133 9 10526655 \n6 Li DK Daling JR Mueller BA Hickok DE Fantel AG Weiss NS Oral contraceptive use after conception in relation to the risk of congenital urinary tract anomalies Teratology 1995 51 30 6 7597655 \n7 Soper RT Kilger K Vesico-intestinal fissure J Urol 1964 92 490 501 14226477\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "2321-4856", "issue": "5(1)", "journal": "Saudi journal of medicine & medical sciences", "keywords": "Cloacal exstrophy; exstrophy of the bladder; omphalocele", "medline_ta": "Saudi J Med Med Sci", "mesh_terms": null, "nlm_unique_id": "101675905", "other_id": null, "pages": "67-70", "pmc": null, "pmid": "30787756", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "10526655;14226477;1433234;18078363;728566;7597655;7802030", "title": "Omphalocele, Exstrophy of Bladder, Imperforate Anus and Spinal Defect Complex with Genital Anomalies in a Late Preterm Infant.", "title_normalized": "omphalocele exstrophy of bladder imperforate anus and spinal defect complex with genital anomalies in a late preterm infant" }	[ { "companynumb": "SA-NOVAST LABORATORIES, LTD-SA-2017NOV000048", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DESOGESTREL\\ETHINYL ESTRADIOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "091234", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "201401", "drugenddateformat": "610", "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201310", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DESOGESTREL\\ETHINYL ESTRADIOL" } ], "patientagegroup": null, "patientonsetage": "0", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "2.7", "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cloacal exstrophy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201310" } }, "primarysource": { "literaturereference": "AL-QURASHI FO, AL-HAREKY TS, AL-BUAINAIN HM. OMPHALOCELE, EXSTROPHY OF BLADDER, IMPERFORATE ANUS AND SPINAL DEFECT COMPLEX WITH GENITAL ANOMALIES IN A LATE PRETERM INFANT. SAUDI-J-MED-MED-SCI. 2017;5(1):67-70", "literaturereference_normalized": "omphalocele exstrophy of bladder imperforate anus and spinal defect complex with genital anomalies in a late preterm infant", "qualification": "1", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20171030", "receivedate": "20170808", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13842656, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180320" }, { "companynumb": "SA-MYLANLABS-2017M1040525", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DESOGESTREL\\ETHINYL ESTRADIOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "202296", "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": "DESOGESTREL/ETHINYL ESTRADIOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Congenital spinal cord anomaly", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Congenital genitourinary abnormality", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Congenital scoliosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Congenital ectopic bladder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Developmental hip dysplasia", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Meningomyelocele", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Anal atresia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal drugs affecting foetus", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Exomphalos", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AL-QURASHI FO, AL-HAREKY TS, AL-BUAINAIN HM. OMPHALOCELE, EXSTROPHY OF BLADDER, IMPERFORATE ANUS AND SPINAL DEFECT COMPLEX WITH GENITAL ANOMALIES IN A LATE PRETERM INFANT. SAUDI-J-MED-MED-SCI 2017;5(1):67-70.", "literaturereference_normalized": "omphalocele exstrophy of bladder imperforate anus and spinal defect complex with genital anomalies in a late preterm infant", "qualification": "1", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20170711", "receivedate": "20170711", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13741691, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]
{ "abstract": "Topiramate is used to treat a variety of neurologic and psychiatric diseases due to its benign safety profile. Data regarding the toxicity and toxicokinetics of topiramate in acute overdose are limited. A case of massive, acute ingestion resulting in the highest reported topiramate level is presented, including toxicokinetic evaluation. A 37-year-old woman presented with coma unresponsive to naloxone following topiramate ingestion. She had normal vital signs without respiratory depression. She was intubated for airway protection, given 3.5 mg lorazepam IV for facial and neck muscle twitching, and transferred to our facility. No additional sedation was required for 18 h on the ventilator. Following mental status improvement, the patient was extubated. Confusion, dysarthria, and imbalance resolved over the next 2 days. Nonanion gap metabolic acidosis persisted for 3 days. Peak serum topiramate level was 356.6 microg/ml (reference range, 5-20 microg/ml). Massive topiramate ingestion led to prolonged coma with normal vital signs and nonanion gap metabolic acidosis. Coma of this severity has not been previously reported. Serum half-life, which has not been studied after overdose, was 16 h. Despite the large ingestion and significant presenting symptoms, the patient recovered fully with supportive intensive care alone. Massive acute topiramate ingestion may lead to nonanion gap metabolic acidosis and prolonged coma which resolves with intensive supportive care. Toxicokinetic data following large, suicidal ingestion of topiramate were similar to previously published pharmacokinetic information.", "affiliations": "Division of Medical Toxicology, Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. [email protected]", "authors": "Lynch\|Michael J\|MJ\|;Pizon\|Anthony F\|AF\|;Siam\|Mohamed G\|MG\|;Krasowski\|Matthew D\|MD\|", "chemical_list": "D000927:Anticonvulsants; D006993:Hypnotics and Sedatives; D000077236:Topiramate; D005632:Fructose; D008140:Lorazepam", "country": "United States", "delete": false, "doi": "10.1007/s13181-010-0065-y", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-9039", "issue": "6(2)", "journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology", "keywords": null, "medline_ta": "J Med Toxicol", "mesh_terms": "D000138:Acidosis; D000328:Adult; D000927:Anticonvulsants; D001714:Bipolar Disorder; D001784:Blood Gas Analysis; D003128:Coma; D003422:Critical Care; D062787:Drug Overdose; D005260:Female; D005632:Fructose; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006993:Hypnotics and Sedatives; D008140:Lorazepam; D012121:Respiration, Artificial; D000077236:Topiramate", "nlm_unique_id": "101284598", "other_id": null, "pages": "135-8", "pmc": null, "pmid": "20376593", "pubdate": "2010-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": null, "title": "Clinical effects and toxicokinetic evaluation following massive topiramate ingestion.", "title_normalized": "clinical effects and toxicokinetic evaluation following massive topiramate ingestion" }	[ { "companynumb": "US-GLENMARK PHARMACEUTICALS-2017GMK027690", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "077627", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 UNK, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscle twitching", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Clonus", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Unresponsive to stimuli", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LYNCH M J, PIZON A F, SIAM M G, KRASOWSKI M D.. CLINICAL EFFECTS AND TOXICOKINETIC EVALUATION FOLLOWING MASSIVE TOPIRAMATE INGESTION. AMERICAN COLLEGE OF MEDICAL TOXICOLOGY. 2010;6:135-138", "literaturereference_normalized": "clinical effects and toxicokinetic evaluation following massive topiramate ingestion", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170602", "receivedate": "20170602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13604764, "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": "Type 1 reactions, characterized by increasing lesion erythema, pain, and nerve damage, commonly complicate leprosy. Dapsone hypersensitivity syndrome (DHS) is a potentially fatal reaction occurring 6-8 weeks into dapsone therapy. We present a case of intercurrent Type 1 reaction and DHS in a multibacillary leprosy patient recently started on multidrug treatment.", "affiliations": "Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada.;Department of Pediatrics, University of Toronto, Toronto, Canada.;Faculty of Medicine, University of Toronto, Toronto, Canada.;Public Health Ontario Laboratory, Public Health Ontario, Toronto, Canada.", "authors": "Craig\|Jeffrey\|J\|;MacRae\|Cara\|C\|;Melvin\|Rochelle G\|RG\|;Boggild\|Andrea K\|AK\|", "chemical_list": "D007917:Leprostatic Agents; D003622:Dapsone", "country": "United States", "delete": false, "doi": "10.4269/ajtmh.18-0953", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9637", "issue": "100(5)", "journal": "The American journal of tropical medicine and hygiene", "keywords": null, "medline_ta": "Am J Trop Med Hyg", "mesh_terms": "D003622:Dapsone; D004342:Drug Hypersensitivity; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007917:Leprostatic Agents; D056006:Leprosy, Multibacillary; D008297:Male; D008875:Middle Aged; D009166:Mycobacterium leprae; D012871:Skin Diseases; D062606:Tertiary Care Centers; D016896:Treatment Outcome", "nlm_unique_id": "0370507", "other_id": null, "pages": "1145-1148", "pmc": null, "pmid": "30915953", "pubdate": "2019-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "8698924;23614255;14707226;12592301;16889287;10575418;2913915;23761718;24587958;12721394;23060374;15401496;24152261;22307940;28167593;2491425;29507748;30326738", "title": "Case Report: A Case of Type 1 Leprosy Reaction and Dapsone Hypersensitivity Syndrome Complicating the Clinical Course of Multibacillary Leprosy.", "title_normalized": "case report a case of type 1 leprosy reaction and dapsone hypersensitivity syndrome complicating the clinical course of multibacillary leprosy" }	[ { "companynumb": "CA-VIRTUS PHARMACEUTICALS, LLC-2019VTS00021", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DAPSONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "204074", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEPROSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DAPSONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEPROSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VITAMIN D NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN D NOS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEPROSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEPROSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "065", "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": "UNSPECIFIED PROTON PUMP INHIBITOR" } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CRAIG J., MACRAE C., MELVIN R.G., BOGGILD A.K. CASE REPORT: A CASE OF TYPE 1 LEPROSY REACTION AND DAPSONE HYPERSENSITIVITY SYNDROME COMPLICATING THE CLINICAL COURSE OF MULTIBACILLARY LEPROSY. [ARTICLE IN PRESS] AM. J. TROP. MED. HYG.. 2019", "literaturereference_normalized": "case report a case of type 1 leprosy reaction and dapsone hypersensitivity syndrome complicating the clinical course of multibacillary leprosy", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190429", "receivedate": "20190429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16251142, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" } ]
{ "abstract": "We performed a prospective study to evaluate the efficacy and safety of secondary antifungal prophylaxis (SAP) for patients with a history of invasive pulmonary aspergillosis (IPA) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, the prophylactic agents used were chosen based on treatment response to initial antifungal therapy. One hundred and thirty-six patients undergoing allo-HSCT with prior IPA were enrolled in this multicenter study. The agents of SAP included itraconazole in 24, voriconazole in 74, caspofungin in 32, and liposomal amphotericin B in 6. Eighty-eight patients had stable IPA and 48 had active IPA at the time of transplantation. The success rate of SAP was 91.2%. Twelve patients developed breakthrough invasive fungal disease (IFD), and none discontinued antifungal agents because drug-related adverse events. The incidence of breakthrough IFD was neither different among the different antifungal agents (P = .675) nor between patients with active and stable IPA (P = .080). The 1-year cumulative incidence of IFD and IPA relapse was 27.3% ± 4.5% and 24.7% ± 4.4%, respectively. Our data indicate that SAP with antifungal agents based on initial antifungal therapy has favorable efficacy and safety in allo-HSCT recipients with prior IPA. Active IPA might not increase the risk of breakthrough IFD after transplantation.", "affiliations": "Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: [email protected].;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Guangzhou General Hospital of Guangzhou Command, Guangzhou, China.;Department of Hematology, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Guangzhou General Hospital of Guangzhou Command, Guangzhou, China.;Department of Hematology, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.", "authors": "Liu\|Qifa\|Q\|;Lin\|Ren\|R\|;Sun\|Jing\|J\|;Xiao\|Yang\|Y\|;Nie\|Danian\|D\|;Zhang\|Yu\|Y\|;Huang\|Fen\|F\|;Fan\|Zhiping\|Z\|;Zhou\|Hongsheng\|H\|;Jiang\|Qianli\|Q\|;Zhang\|Fuhua\|F\|;Zhai\|Xiao\|X\|;Xu\|Dan\|D\|;Wei\|Yongqiang\|Y\|;Song\|Jiayin\|J\|;Li\|Yiqing\|Y\|;Feng\|Ru\|R\|", "chemical_list": "D000935:Antifungal Agents", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "20(8)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": "Allogeneic hematopoietic stem cell transplantation; Antifungal prophylaxis; Invasive pulmonary aspergillosis", "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D055732:Pulmonary Aspergillosis; D012307:Risk Factors; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "9600628", "other_id": null, "pages": "1198-203", "pmc": null, "pmid": "24769013", "pubdate": "2014-08", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Antifungal agents for secondary prophylaxis based on response to initial antifungal therapy in allogeneic hematopoietic stem cell transplant recipients with prior pulmonary aspergillosis.", "title_normalized": "antifungal agents for secondary prophylaxis based on response to initial antifungal therapy in allogeneic hematopoietic stem cell transplant recipients with prior pulmonary aspergillosis" }	[ { "companynumb": "CN-JNJFOC-20140716324", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "020657", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unspecified", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Systemic mycosis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood bilirubin increased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LIU Q, LIN R, SUN J, XIAO Y, NIE D, ZHANG Y, ET AL. ANTIFUNGAL AGENTS FOR SECONDARY PROPHYLAXIS BASED ON RESPONSE TO INITIAL ANTIFUNGAL THERAPY IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS WITH PRIOR PULMONARY ASPERGILLOSIS. BIOL BLOOD MARROW TRANSPLANT 2014;20:1198-1203.", "literaturereference_normalized": "antifungal agents for secondary prophylaxis based on response to initial antifungal therapy in allogeneic hematopoietic stem cell transplant recipients with prior pulmonary aspergillosis", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20140801", "receivedate": "20140801", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10357893, "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\nThe cetuximab plus platinum-based chemotherapy regimen is a standard of care in the treatment of recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The feasibility in the elderly population is currently unknown.\n\n\nMETHODS\nWe performed a retrospective study in order to assess the efficacy and safety of the cetuximab plus platinum-based chemotherapy regimen in patients >65 years with recurrent or metastatic HNSCC. We performed a retrospective review of all medical records from recurrent or metastatic HNSCC patients >65 years treated with the cetuximab plus platinum-based chemotherapy regimen between September 2008 and December 2013 in our institution (Centre Paul Strauss, Strasbourg, France).\n\n\nRESULTS\nA total of 59 patients were identified. Carboplatin in combination with 5-fluorouracil (FU) was the only cetuximab-associated chemotherapy regimen used for treating elderly patients. The median progression-free survival was 4 months (95% confidence interval [CI]: 2.9-4.7), and the median overall survival was 9.1 months (95% CI: 6.5-13.1). Grade 3 or 4 toxicity adverse events occurred in 52% (n = 31) of the patients (mostly hematologic toxicities and infections).\n\n\nCONCLUSIONS\nThis retrospective study suggests that the cetuximab plus carboplatin-5FU chemotherapy is an effective treatment option for elderly patients with recurrent or metastatic HNSCC.", "affiliations": "Medical Oncology Department, Centre Paul Strauss, Strasbourg, France.", "authors": "Burgy\|Mickaël\|M\|;Barthélémy\|Philippe\|P\|;Lefevre\|François\|F\|;Dupret-Bories\|Agnès\|A\|;Truntzer\|Pierre\|P\|;Korenbaum\|Clement\|C\|;Flesch\|Henri\|H\|;Bronner\|Guy\|G\|;Borel\|Christian\|C\|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D016190:Carboplatin; D002945:Cisplatin; D005472:Fluorouracil", "country": "Switzerland", "delete": false, "doi": "10.1159/000454732", "fulltext": null, "fulltext_license": null, "issn_linking": "0030-2414", "issue": "93(1)", "journal": "Oncology", "keywords": "Cetuximab; Chemotherapy; Elderly patients; Recurrent or metastatic head and neck squamous-cell carcinoma", "medline_ta": "Oncology", "mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil; D005602:France; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D016896:Treatment Outcome", "nlm_unique_id": "0135054", "other_id": null, "pages": "11-17", "pmc": null, "pmid": "28423384", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": null, "title": "Cetuximab-Carboplatin-5-Fluorouracil Regimen in Elderly Patients with Recurrent or Metastatic Head and Neck Squamous-Cell Carcinoma: A French Retrospective Survey.", "title_normalized": "cetuximab carboplatin 5 fluorouracil regimen in elderly patients with recurrent or metastatic head and neck squamous cell carcinoma a french retrospective survey" }	[ { "companynumb": "FR-CIPLA LTD.-2017FR08302", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/M2/DAY FROM DAY 1 TO DAY 4", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077383", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AUC 5 ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "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": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "250 MG/M2, WEEKLY DOSES FOR MAXIMUM OF 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "400 MG/M2, UNK, INITIAL DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BURGY M, BARTHELEMY P, LEFEVRE F, DUPRET-BORIES A, TRUNTZER P, KORENBAUM C, ET AL;. CETUXIMAB-CARBOPLATIN-5-FLUOROURACIL REGIMEN IN ELDERLY PATIENTS WITH RECURRENT OR METASTATIC HEAD AND NECK SQUAMOUS-CELL CARCINOMA: A FRENCH RETROSPECTIVE SURVEY. 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CETUXIMAB-CARBOPLATIN-5-FLUOROURACIL REGIMEN IN ELDERLY PATIENTS WITH RECURRENT OR METASTATIC HEAD AND NECK SQUAMOUS-CELL CARCINOMA: A FRENCH RETROSPECTIVE SURVEY. ONCOLOGY. 2017;1 TO 7", "literaturereference_normalized": "cetuximab carboplatin 5 fluorouracil regimen in elderly patients with recurrent or metastatic head and neck squamous cell carcinoma a french retrospective survey", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170509", "receivedate": "20170509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13527122, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "FR-CIPLA LTD.-2017FR08303", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "400 MG/M2, UNK, INITIAL DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "250 MG/M2, WEEKLY DOSES FOR MAXIMUM OF 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077383", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AUC 5 ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "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": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/M2/DAY FROM DAY 1 TO DAY 4", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BURGY M, BARTHELEMY P, LEFEVRE F, DUPRET-BORIES A, TRUNTZER P, KORENBAUM C, ET AL;. CETUXIMAB-CARBOPLATIN-5-FLUOROURACIL REGIMEN IN ELDERLY PATIENTS WITH RECURRENT OR METASTATIC HEAD AND NECK SQUAMOUS-CELL CARCINOMA: A FRENCH RETROSPECTIVE SURVEY. ONCOLOGY. 2017;1 TO 7", "literaturereference_normalized": "cetuximab carboplatin 5 fluorouracil regimen in elderly patients with recurrent or metastatic head and neck squamous cell carcinoma a french retrospective survey", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170509", "receivedate": "20170509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13527135, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "FR-CIPLA LTD.-2017FR08322", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077383", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AUC 5 ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "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": "1", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "400 MG/M2, INITIAL DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/M2/DAY FROM DAY 1 TO DAY 4", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "250 MG/M2, WEEKLY DOSES FOR MAXIMUM OF 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BURGY M, BARTHELEMY P, LEFEVRE F, DUPRET-BORIES A, TRUNTZER P, KORENBAUM C, ET AL;. CETUXIMAB-CARBOPLATIN-5-FLUOROURACIL REGIMEN IN ELDERLY PATIENTS WITH RECURRENT OR METASTATIC HEAD AND NECK SQUAMOUS-CELL CARCINOMA: A FRENCH RETROSPECTIVE SURVEY. ONCOLOGY. 2017;1 TO 7", "literaturereference_normalized": "cetuximab carboplatin 5 fluorouracil regimen in elderly patients with recurrent or metastatic head and neck squamous cell carcinoma a french retrospective survey", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170509", "receivedate": "20170509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13527123, "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": "This study was designed to characterize failure-free survival (FFS) as a novel end point for clinical trials of chronic graft-versus-host disease (GVHD). The study cohort included 400 consecutive patients who received initial systemic treatment of chronic GVHD at our center. FFS was defined by the absence of second-line treatment, nonrelapse mortality, and recurrent malignancy during initial treatment. The FFS rate was 68% at 6 months and 54% at 12 months after initial treatment. Multivariate analysis identified 4 risk factors associated with treatment failure: time interval <12 months from transplantation to initial treatment, patient age ≥60 years, severe involvement of the gastrointestinal tract, liver, or lungs, and Karnofsky score <80% at initial treatment. Initial steroid doses and the type of initial treatment were not associated with risk of treatment failure. Lower steroid doses after 12 months of initial treatment were associated with long-term success in withdrawing all systemic treatment. FFS offers a potentially useful basis for interpreting results of initial treatment of chronic GVHD. Incorporation of steroid doses at 12 months would increase clinical benefit associated with the end point. Studies using FFS as the primary end point should measure changes in GVHD-related symptoms, activity, damage, and disability as secondary end points.", "affiliations": "Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Departments of Medicine.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Departments of Medicine.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Pediatrics, and.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Departments of Medicine.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Biostatistics, University of Washington School of Medicine, Seattle, WA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Departments of Medicine.", "authors": "Inamoto\|Yoshihiro\|Y\|http://orcid.org/0000-0003-4881-0427;Flowers\|Mary E D\|ME\|http://orcid.org/0000-0003-1631-0911;Sandmaier\|Brenda M\|BM\|http://orcid.org/0000-0002-9767-9739;Aki\|Sahika Z\|SZ\|;Carpenter\|Paul A\|PA\|http://orcid.org/0000-0001-9810-1798;Lee\|Stephanie J\|SJ\|http://orcid.org/0000-0003-2600-6390;Storer\|Barry E\|BE\|http://orcid.org/0000-0003-1565-435X;Martin\|Paul J\|PJ\|http://orcid.org/0000-0001-9051-1215", "chemical_list": "D013256:Steroids", "country": "United States", "delete": false, "doi": "10.1182/blood-2014-03-563544", "fulltext": null, "fulltext_license": null, "issn_linking": "0006-4971", "issue": "124(8)", "journal": "Blood", "keywords": null, "medline_ta": "Blood", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D064591:Allografts; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D033581:Stem Cell Transplantation; D013256:Steroids; D015996:Survival Rate; D013997:Time Factors", "nlm_unique_id": "7603509", "other_id": null, "pages": "1363-71", "pmc": null, "pmid": "24876566", "pubdate": "2014-08-21", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "21464398;16338616;10204198;3042041;24152907;21493797;12720215;22683612;21467544;11400948;20601033;16503494;23321253;22576252;19470693;22058206;19896545;15292060;19270260;12070007;11090092;21633087;21689773;21621629;18621929", "title": "Failure-free survival after initial systemic treatment of chronic graft-versus-host disease.", "title_normalized": "failure free survival after initial systemic treatment of chronic graft versus host disease" }	[ { "companynumb": "US-JNJFOC-20141010643", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "INAMOTO Y, FLOWERS MD, SANDMAIER B, AKI S, CARPENTER P, LEE S, ET AL. FAILURE-FREE SURVIVAL AFTER INITIAL SYSTEMIC TREATMENT OF CHRONIC GRAFT-VERSUS-HOST DISEASE. BLOOD 21-AUG-2014;124 (8):1363-1371.", "literaturereference_normalized": "failure free survival after initial systemic treatment of chronic graft versus host disease", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150525", "receivedate": "20150404", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10987709, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]
{ "abstract": "Patients with upper-tract carcinoma in situ (UT-CIS) that have failed treatment with BCG are recommended for radical nephroureterectomy (RNU). We describe a cohort of patients with BCG-refractory UT-CIS that were treated with docetaxel, a novel agent in the approach to topical therapy.\n\n\n\nPatients with pathologically proven UT-CIS from 2012 to 2020 with an imperative indication for organ preservation and history of BCG-refractory disease were included. Each patient underwent ureteroscopy with biopsy and selective cytology pre- and postinduction, and after each maintenance course. Complete response (CR) was defined as the absence of visualized lesions on ureteroscopy, negative selective cytology, and absence of clinical progression. No response (NR) was defined as persistence of lesions after induction or absence of visualized lesions with persistently positive cytology.\n\n\n\nSeven patients and 10 renal units were treated. Six of the 10 renal units had initial CR (60%). Three patients with NR went on to have RNU, one of which subsequently died due to cancer-specific mortality. One patient with bilateral disease had NR in 10 renal unit and cure in the other. This patient subsequently developed recurrence in his remaining renal unit. A second patient had CR in both kidneys for 6 years, but 1 year after finishing maintenance regimen developed HG disease in 1 ureter. Average follow-up was 33 months.\n\n\n\nThis study demonstrates efficacy of docetaxel as a treatment option for patients with UT-CIS with a contraindication to RNU after failing BCG. Response rates of 60% appear to be similar to those of BCG-refractory bladder CIS.", "affiliations": "Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY. Electronic address: [email protected].;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.", "authors": "Katims\|Andrew B\|AB\|;Tam\|Andrew W\|AW\|;Rosen\|Daniel C\|DC\|;Zampini\|Anna M\|AM\|;Atallah\|William\|W\|;Mehrazin\|Reza\|R\|;Gupta\|Mantu\|M\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.urolonc.2020.08.002", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1439", "issue": "39(4)", "journal": "Urologic oncology", "keywords": "Chemotherapy; Topical therapy; Upper tract; Urothelial carcinoma", "medline_ta": "Urol Oncol", "mesh_terms": null, "nlm_unique_id": "9805460", "other_id": null, "pages": "234.e9-234.e13", "pmc": null, "pmid": "32958446", "pubdate": "2021-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Novel treatment of upper tract urothelial carcinoma in situ with docetaxel in BCG refractory patients.", "title_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients" }	[ { "companynumb": "US-009507513-2105USA006744", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "102821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INSTILLATION FLUID", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT CARCINOMA IN SITU", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICE BCG" } ], "patientagegroup": null, "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB., TAM AW., ROSEN D C., ZAMPINI AM., ATALLAH W, MEHRAZIN R.. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. 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NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY. 2020 AUG 02?39(4):234. E9?234 E 13. 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NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. 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NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. 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NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. 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NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY: SEMINARS AND ORIGINAL INVESTIGATIONS. 2021?39(4):234E9?13", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20210604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19373232, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-MYLANLABS-2021M1037819", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "208859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM 6 WEEKS INDUCTION THERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "208859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM, QW, MAINTENANCE THERAPY; FOR THREE WEEKS AT 3, 6, 12, 18, 24, AND 36 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BCG VACCINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL 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": "BCG" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB, TAM AW, ROSEN DC, ZAMPINI AM, ATALLAH W, MEHRAZIN R, ET AL. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROL?ONCOL 2021?39(4):234.E9?234.E13.", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210630", "receivedate": "20210630", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19477220, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2021-00860", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "205934", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT CARCINOMA IN SITU", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL, UNKNOWN" } ], "patientagegroup": "6", "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastatic neoplasm", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS A, TAM A, ROSEN D, ZAMPINI A, ATALLAH W, MEHRAZIN R. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY. 2020 AUG 02?39(4):234. E9?234 E 13. DOI:10.1016/J.UROLONC.2020.08.002", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210707", "receivedate": "20210707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19499165, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-009507513-2105USA007535", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "102821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INSTILLATION FLUID", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLADDER CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICE BCG" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB., TAM AW., ROSEN DC., ZAMPINI AM., ATALLAH W, MEHRAZIN R.. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY: SEMINARS AND ORIGINAL INVESTIGATIONS. 2021?39(4):234E9?13", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20210604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19373231, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-009507513-2105USA007533", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "102821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INSTILLATION FLUID", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLADDER TRANSITIONAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICE BCG" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB., TAM AW., ROSEN DC., ZAMPINI AM., ATALLAH W, MEHRAZIN R.. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY: SEMINARS AND ORIGINAL INVESTIGATIONS. 2021?39(4):234E9?13", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20210604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19373183, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-MYLANLABS-2021M1037821", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": "208859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM, QW MAINTENANCE THERAPY; FOR THREE WEEKS AT 3, 6, 12, 18, 24, AND 36 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": "208859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM INDUCTION THERAPY 6 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BCG VACCINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL 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": "BCG" } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB, TAM AW, ROSEN DC, ZAMPINI AM, ATALLAH W, MEHRAZIN R, ET AL. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROL?ONCOL 2021?39(4):234.E9?234.E13.", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210630", "receivedate": "20210630", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19477253, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2021-00858", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "205934", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION TREATMENT, SIX WEEKLY INSTILLATIONS", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT CARCINOMA IN SITU", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL, UNKNOWN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "205934", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE THERAPY: WEEKLY FOR THREE WEEKS AT 3, 6, 12, 18, 24, AND 36 MONTHS FOLLOWING INDUCTION.", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL, UNKNOWN" } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS A, TAM A, ROSEN D, ZAMPINI A, ATALLAH W, MEHRAZIN R. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY. 2020 AUG 02?39 (4):234. E9?234 E 13. DOI:10.1016/J.UROLONC.2020.08.002", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210710", "receivedate": "20210710", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19513683, "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": "A 54-year-old man with a long history of severe haemophilia A treated prophylactically with efmoroctocog alpha (3,000 IU twice weekly) was diagnosed with COVID-19 infection. He had multiple risk factors for COVID-19 severity including obesity, diabetes mellitus and hypertension. He required prolonged intensive care unit (ICU) stay due to the severity of respiratory failure until his death on day 24. During his ICU stay, he received a continuous infusion of efmoroctocog alpha in order to maintain factor VIII activity between 80 and 100%, together with therapeutic doses of low-molecular-weight heparin targeting anti-Xa activity above 0.5 IU/mol. He tolerated numerous invasive procedures without bleeding. At post-mortem examination, there was no evidence for thrombosis or haemorrhage in the different organs.", "affiliations": "Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium, [email protected].;Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Haematology, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Haematology, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.", "authors": "Pinto Pereira\|João\|J\|;Hantson\|Philippe\|P\|;Gerard\|Ludovic\|L\|;Wittebole\|Xavier\|X\|;Laterre\|Pierre-François\|PF\|;Lambert\|Catherine\|C\|;Hermans\|Cédric\|C\|", "chemical_list": "D006495:Heparin, Low-Molecular-Weight; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C587014:factor VIII-Fc fusion protein; D005169:Factor VIII", "country": "Switzerland", "delete": false, "doi": "10.1159/000510591", "fulltext": null, "fulltext_license": null, "issn_linking": "0001-5792", "issue": "144(3)", "journal": "Acta haematologica", "keywords": "COVID-19; Coagulopathy; Haemophilia", "medline_ta": "Acta Haematol", "mesh_terms": "D001780:Blood Coagulation Tests; D000086382:COVID-19; D005169:Factor VIII; D006467:Hemophilia A; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D007141:Immunoglobulin Fc Fragments; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins; D000086402:SARS-CoV-2; D012720:Severity of Illness Index", "nlm_unique_id": "0141053", "other_id": null, "pages": "319-321", "pmc": null, "pmid": "32980842", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": null, "title": "Management of COVID-19 Coagulopathy in a Patient with Severe Haemophilia A.", "title_normalized": "management of covid 19 coagulopathy in a patient with severe haemophilia a" }	[ { "companynumb": "BE-APPCO PHARMA LLC-2121063", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE SULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210441", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE SULFATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SUFENTANIL CITRATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "2", "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": "SUFENTANIL CITRATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONIDINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "2", "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": "CLONIDINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "2", "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": "PROPOFOL" }, { "actiondrug": "5", "activesubstance": null, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "2", "drugcumulativedosagenumb": null, 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"804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3800", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "2", "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": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Pereira JP, Hantson P, Gerard L, Wittebole X, Laterre PF, Lambert C, Hermans C. Management of COVID-19 Coagulopathy in a Patient with Severe Haemophilia A. Acta haematologica. 2021; 144(3):317-9. DOI: 10.1159/000510591", "literaturereference_normalized": "management of covid 19 coagulopathy in a patient with severe haemophilia a", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20211027", "receivedate": "20211027", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 20002752, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "BE-SA-2020SA123498", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USE IN UNAPPROVED INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EFMOROCTOCOG ALFA" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3000 IU; TWICE A WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FACTOR VIII DEFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3000", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELOCTA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PINTO PEREIRA J, HANTSON P, GERARD L, WITTEBOLE X, LATERRE PF, LAMBERT C, EL AT.. MANAGEMENT OF COVID-19 COAGULOPATHY IN A PATIENT WITH SEVERE HAEMOPHILIA A.. ACTA HAEMATOL.. 2020?UNK:UNK", "literaturereference_normalized": "management of covid 19 coagulopathy in a patient with severe haemophilia a", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20201207", "receivedate": "20200513", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17779451, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210113" } ]
{ "abstract": "Favipiravir is a novel antiviral drug approved for influenza treatment in Japan. Little is known about favipiravir pharmacokinetics in critically ill patients. Here, we report a patient with influenza treated with favipiravir and undergoing continuous venovenous haemofiltration (CVVH) on the Intensive Care Unit of a tertiary hospital in the Netherlands. Pharmacokinetic analyses showed increased clearance and decreased plasma levels compared to healthy volunteers. CVVH has no clinically relevant contribution to total clearance. Despite susceptibility to favipiravir, the influenza virus was not cleared. A multi-disciplinary approach is needed to ensure optimal favipiravir treatment in critically ill patients.", "affiliations": "Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, the Netherlands.;Laboratory of Medical Microbiology and Immunology, St Elisabeth Hospital Tilburg, Tilburg, the Netherlands.;Centre for Infectious Diseases Research, Diagnostics and Screening, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.;Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, the Netherlands.;Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, the Netherlands.;Intensive Care, University Medical Center Utrecht, Utrecht, the Netherlands.", "authors": "Favié\|Laurent Ma\|LM\|;Murk\|Jean-Luc\|JL\|;Meijer\|Adam\|A\|;Nijstad\|A Laura\|AL\|;van Maarseveen\|Erik M\|EM\|;Sikma\|Maaike A\|MA\|", "chemical_list": "D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D053139:Oseltamivir; C462182:favipiravir", "country": "England", "delete": false, "doi": "10.3851/IMP3210", "fulltext": null, "fulltext_license": null, "issn_linking": "1359-6535", "issue": "23(5)", "journal": "Antiviral therapy", "keywords": null, "medline_ta": "Antivir Ther", "mesh_terms": "D000577:Amides; D000998:Antiviral Agents; D016638:Critical Illness; D017809:Fatal Outcome; D006440:Hemofiltration; D006801:Humans; D007251:Influenza, Human; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D053139:Oseltamivir; D011719:Pyrazines; D062606:Tertiary Care Centers", "nlm_unique_id": "9815705", "other_id": null, "pages": "457-461", "pmc": null, "pmid": "29185991", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza.", "title_normalized": "pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza" }	[ { "companynumb": "NL-ROCHE-2244417", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FAVIPIRAVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3600 MILLIGRAM DAILY; LOADING DOSE ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAVIPIRAVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OSELTAMIVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021087", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM DAILY; LOADING DOSE ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "H1N1 INFLUENZA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OSELTAMIVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OSELTAMIVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021087", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MILLIGRAM DAILY; MAINTENANCE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OSELTAMIVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FAVIPIRAVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MILLIGRAM DAILY; MAINTENANCE DOSE; HALF OF THE MAINTENANCE DOSE WAS GIVEN BECAUSE OF UNKNOWN EFF", "drugenddate": null, "drugenddateformat": null, "drugindication": "H1N1 INFLUENZA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAVIPIRAVIR" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "67", "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FAVIE L, MURK J-L, MEIJER A, LAURA NIJSTAD A, VAN MAARSEVEEN EM, SIKMA MA. PHARMACOKINETICS OF FAVIPIRAVIR DURING CONTINUOUS VENOVENOUS HAEMOFILTRATION IN A CRITICALLY ILL PATIENT WITH INFLUENZA.. ANTIVIRAL-THER 2018?23 (5):457-461.", "literaturereference_normalized": "pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15835894, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-TEVA-2018-NL-991717", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OSELTAMIVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "211125", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM DAILY; LOADING DOSE ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "H1N1 influenza", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OSELTAMIVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OSELTAMIVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "211125", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MILLIGRAM DAILY; MAINTENANCE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OSELTAMIVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FAVIPIRAVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3600 MILLIGRAM DAILY; LOADING DOSE ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "H1N1 influenza", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1800", "drugstructuredosageunit": "003", "drugtreatmentduration": "4", "drugtreatmentdurationunit": "804", "medicinalproduct": "FAVIPIRAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FAVIPIRAVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MILLIGRAM DAILY; MAINTENANCE DOSE; HALF OF THE MAINTENANCE DOSE WAS GIVEN BECAUSE OF UNKNOWN EFF", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": "4", "drugtreatmentdurationunit": "804", "medicinalproduct": "FAVIPIRAVIR" } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "67", "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Favie LMA, Murk J-L, Meijer A, Laura Nijstad A, Van Maarseveen EM, Sikma MA. Pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza. Antiviral-Ther 2018;23(5):457-461.", "literaturereference_normalized": "pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20220304", "receivedate": "20220222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20503586, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220423" } ]
{ "abstract": "BACKGROUND\nEarly detection and monitoring for malignant arrhythmias is fundamental to prenatal care in long QT syndrome (LQTS). Recently, we studied the feasibility of isolating the fetal electrocardiogram (fECG) and measuring electrocardiographic intervals with a noninvasive fECG device using blind source separation with reference signal. Our aim was to evaluate the ability of fECG to diagnose LQTS.\n\n\nMETHODS\nWe identified 3 cases of clinically suspected LQTS based on fetal echocardiogram (2 had sinus bradycardia, 1 had second-degree atrioventricular block with negative maternal anti-SSA/SSB antibody titers). With institutional review board approval, these patients were prospectively enrolled for fECG acquisition. Offline post-processing generated fECG waveforms and calculated QT intervals. Case 1 and 3 had a maternal history of LQTS. Two of the three fetuses with suspected LQTS had confirmed LQTS by postnatal ECG and genetic testing. FECG was able to identify a prolonged corrected QT interval in both cases. One of these also had fetal magnetocardiography (fMCG), which yielded similar findings to the fECG. The third fetus had a normal fECG; fMCG and postnatal ECG were also normal.\n\n\nCONCLUSIONS\nIn 3 cases, fECG findings corroborated the diagnosis of LQTS. Noninvasive fECG may offer a novel method for fECG that is portable and more clinically accessible.", "affiliations": "Division of Cardiology, Children's National Hospital, Washington, District of Columbia, USA, [email protected].;Department of Advanced Interdisciplinary Biomedical Engineering, Tohoku University School of Medicine, Sendai-shi, Miyagi, Japan.;Division of Cardiology, Children's National Hospital, Washington, District of Columbia, USA.;Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, District of Columbia, USA.;Division of Cardiology, Children's National Hospital, Washington, District of Columbia, USA.;Biomagnetism Laboratory, University of Wisconsin-Madison, Madison, Wisconsin, USA.;Division of Cardiology, Herma Heart Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.;Division of Cardiology, Children's National Hospital, Washington, District of Columbia, USA.;Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.;Department of Advanced Interdisciplinary Biomedical Engineering, Tohoku University School of Medicine, Sendai-shi, Miyagi, Japan.;Division of Cardiology, Children's National Hospital, Washington, District of Columbia, USA.", "authors": "Sethi\|Neeta\|N\|;Funamoto\|Kiyoe\|K\|;Ingbar\|Catherine\|C\|;Mass\|Paige\|P\|;Moak\|Jeffrey\|J\|;Wakai\|Ronald\|R\|;Strasburger\|Janette\|J\|;Donofrio\|Mary\|M\|;Khandoker\|Ahsan\|A\|;Kimura\|Yoshitaka\|Y\|;Krishnan\|Anita\|A\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000508043", "fulltext": null, "fulltext_license": null, "issn_linking": "1015-3837", "issue": "47(9)", "journal": "Fetal diagnosis and therapy", "keywords": "Arrhythmias; Congenital long QT syndrome; Noninvasive fetal electrocardiography; Prenatal diagnosis", "medline_ta": "Fetal Diagn Ther", "mesh_terms": "D000328:Adult; D004562:Electrocardiography; D005260:Female; D005318:Fetal Heart; D006340:Heart Rate, Fetal; D006801:Humans; D008133:Long QT Syndrome; D053798:Magnetocardiography; D011247:Pregnancy; D011295:Prenatal Care; D011296:Prenatal Diagnosis; D055815:Young Adult", "nlm_unique_id": "9107463", "other_id": null, "pages": "711-716", "pmc": null, "pmid": "32615554", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "21908954;22776830;24858320;11920893;19731233;12767447;25640061;29654130;10962758;24218437;24763516;17260855;31172229;18486565;22717013;27539165;12478635;28491768", "title": "Noninvasive Fetal Electrocardiography in the Diagnosis of Long QT Syndrome: A Case Series.", "title_normalized": "noninvasive fetal electrocardiography in the diagnosis of long qt syndrome a case series" }	[ { "companynumb": "US-PFM-2022-03516", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Long QT syndrome", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "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": "PROPRANOLOL" } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Sethi N, Funamoto K, Ingbar C, Mass P, Moak J, Wakai R et al. Noninvasive fetal electrocardiography in the diagnosis of long QT syndrome: A case series. Fetal diagnosis and therapy. 2020;47(9):711-6", "literaturereference_normalized": "noninvasive fetal electrocardiography in the diagnosis of long qt syndrome a case series", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220614", "receivedate": "20220614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20958066, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]
{ "abstract": "Pneumocystis jirovecii is a common cause of pneumonia in patients with advanced HIV. In a lot of cases, there is a concomitant pulmonary infection. Cryptococcosis presents as a common complication for people with advanced HIV. However, it usually presents as meningitis rather than pneumonia. We present a case of a patient with coinfection by P. jirovecii and Cryptococcus spp without neurological involvement and a single nodular pulmonary lesion.", "affiliations": "Internal Medicine Department, Centro Medico ABC, Ciudad de México, Mexico [email protected].;Internal Medicine Department, Centro Medico ABC, Ciudad de México, Mexico.;Escuela de Medicina, Instituto Tecnologico y de Estudios Superiores de Monterrey Campus Ciudad de Mexico, Tlalpan, Mexico.", "authors": "Valente-Acosta\|Benjamin\|B\|http://orcid.org/0000-0001-9885-3594;Padua-Garcia\|José\|J\|;Tame-Elorduy\|Andrés\|A\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/bcr-2019-233607", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "13(4)", "journal": "BMJ case reports", "keywords": "Cryptococcus; HIV / AIDS; cryptococcosis; pneumonia (infectious disease)", "medline_ta": "BMJ Case Rep", "mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D060085:Coinfection; D003453:Cryptococcosis; D003454:Cryptococcus; D015658:HIV Infections; D006801:Humans; D008168:Lung; D008297:Male; D008800:Mexico; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32295797", "pubdate": "2020-04-14", "publication_types": "D002363:Case Reports", "references": null, "title": "Pulmonary coinfection by Pneumocystis jirovecii and Cryptococcus species in a patient with undiagnosed advanced HIV.", "title_normalized": "pulmonary coinfection by pneumocystis jirovecii and cryptococcus species in a patient with undiagnosed advanced hiv" }	[ { "companynumb": "MX-GILEAD-2020-0467218", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EMTRICITABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "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": "EMTRIVA" }, { "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": "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": "VIREAD" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOLUTEGRAVIR" }, "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": "DOLUTEGRAVIR" } ], "patientagegroup": "5", "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VALENTE-ACOSTA B., PADUA-GARCIA J., TAME-ELORDUY A.. PULMONARY COINFECTION BY PNEUMOCYSTIS JIROVECII AND CRYPTOCOCCUS SPECIES IN A PATIENT WITH UNDIAGNOSED ADVANCED HIV. BMJ CASE REPORTS. 2020?13 (4):NO PAGINATION", "literaturereference_normalized": "pulmonary coinfection by pneumocystis jirovecii and cryptococcus species in a patient with undiagnosed advanced hiv", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20200519", "receivedate": "20200519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17804294, "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" } ]
{ "abstract": "BACKGROUND\nTacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT).\n\n\nMETHODS\nTwenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A53 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake.\n\n\nRESULTS\nThirteen patients had a CYP3A53/3 genotype, and 11 patients had a CYP3A51/1 or 1/3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A53/3 allele than with the CYP3A51 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A53/3 were significantly lower than those with the CYP3A51 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A53/3 than with the CYP3A51 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A53/3 than the CYP3A51 allele.\n\n\nCONCLUSIONS\nCYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.", "affiliations": "Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan. [email protected].;Department of Pharmacy, Akita University Hospital, Akita, Japan.;Department of Pharmacy, Akita University Hospital, Akita, Japan.;Department of Pharmacy, Akita University Hospital, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.", "authors": "Yamashita\|Takaya\|T\|;Fujishima\|Naohito\|N\|;Miura\|Masatomo\|M\|;Niioka\|Takenori\|T\|;Abumiya\|Maiko\|M\|;Shinohara\|Yoshinori\|Y\|;Ubukawa\|Kumi\|K\|;Nara\|Miho\|M\|;Fujishima\|Masumi\|M\|;Kameoka\|Yoshihiro\|Y\|;Tagawa\|Hiroyuki\|H\|;Hirokawa\|Makoto\|M\|;Takahashi\|Naoto\|N\|", "chemical_list": "D000935:Antifungal Agents; D001393:Azoles; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus", "country": "Germany", "delete": false, "doi": "10.1007/s00280-016-3060-4", "fulltext": "\n==== Front\nCancer Chemother PharmacolCancer Chemother. PharmacolCancer Chemotherapy and Pharmacology0344-57041432-0843Springer Berlin Heidelberg Berlin/Heidelberg 306010.1007/s00280-016-3060-4Original ArticleEffects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation Yamashita Takaya Fujishima Naohito [email protected] Miura Masatomo Niioka Takenori Abumiya Maiko Shinohara Yoshinori Ubukawa Kumi Nara Miho Fujishima Masumi Kameoka Yoshihiro Tagawa Hiroyuki Hirokawa Makoto Takahashi Naoto Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan Division of Blood Transfusion, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543 Japan Department of Pharmacy, Akita University Hospital, Akita, Japan Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan 23 5 2016 23 5 2016 2016 78 111 118 15 12 2015 10 5 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.Background\nTacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT).\n\nDesign and methods\nTwenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A53 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake.\n\nResults\nThirteen patients had a CYP3A53/3 genotype, and 11 patients had a CYP3A51/1 or 1/3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A53/3 allele than with the CYP3A51 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A53/3 were significantly lower than those with the CYP3A51 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A53/3 than with the CYP3A51 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A53/3 than the CYP3A51 allele.\n\nConclusions\nCYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1007/s00280-016-3060-4) contains supplementary material, which is available to authorized users.\n\nKeywords\nOnce-daily tacrolimus formulationCYP3A5 polymorphismAzole antifungal agentPharmacokineticsHematopoietic stem cell transplantationissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2016\n==== Body\nIntroduction\nTacrolimus has been widely used to prevent graft rejection following solid organ transplantation and hematopoietic stem cell transplantation (HSCT). Tacrolimus plus methotrexate is regarded as one of the standard methods of graft-versus-host disease (GVHD) prophylaxis after allogeneic HSCT. Given that tacrolimus has a narrow therapeutic window and that there are inter- and intra-individual variations in pharmacokinetics, blood concentrations of tacrolimus are usually monitored to maintain adequate exposure and to prevent drug-related toxicities [1].\n\nTacrolimus is given intravenously in the early phase after HSCT and then switched to oral administration. Oral tacrolimus was first developed as a twice-daily (BID: bis in die) formulation (Tac-BID). Then, a once-daily modified-release (QD: quaque die) formulation of tacrolimus (Tac-QD) was developed to provide more convenient dosing and to improve patient adherence [2]. In solid organ transplantation, initial clinical trials showed that the pharmacokinetic parameters of Tac-BID and Tac-QD were equivalent on a mg for mg basis, and Tac-QD was well tolerated with similar efficacy and safety profiles to Tac-BID [3–6]. However, studies of the pharmacokinetics of Tac-QD administration in the HSCT setting are few in number compared with solid organ transplantation. Thus, the pharmacokinetics of inter-individual variations of blood concentration of tacrolimus in transplant patients with Tac-QD after HSCT are yet to be determined.\n\nMany clinical and genetic factors affect the pharmacokinetics of tacrolimus [7]. Cytochrome P450 (CYP) 3A4, CYP3A5 and ATP-binding cassette subfamily B member 1 (ABCB1) reportedly contribute to inter-individual variability in the absorption, metabolism and tissue distribution of tacrolimus. Moreover, CYP3A5 may play a dominant role over that of CYP3A4 in the metabolism of tacrolimus in individuals who express the CYP3A5 enzyme [8–12]. CYP3A5 is polymorphically expressed, and more than 10 single nucleotide polymorphisms (SNPs) have been identified [9]. The most important SNP related to functional variation is CYP3A5 6986A > G, in which the wild-type allele is CYP3A51 and the variant allele is CYP3A53 [13]. Homozygous carriers of the CYP3A53 gene (CYP3A53/3) should lack functional CYP3A5 protein [14–18]. There are racial differences in the frequencies of CYP3A5 polymorphisms [15, 19–21]. The frequencies of CYP3A53/3 were reported to be 56.7–60.5 % in Japanese, 86 % in Caucasians and 23 % in the African-American population. Although there are many genetic variants of CYP3A4 and ABCB1, the majority of studies have failed to find an association between the CYP3A4 or ABCB1 genotypes and tacrolimus pharmacokinetics [9]. These studies have demonstrated that trough blood concentrations or area under the blood concentration–time curve (AUC) of tacrolimus was higher in patients with the CYP3A53/3 genotype than those with the CYP3A51 allele, and the required daily dosage of tacrolimus was significantly reduced.\n\nOur colleagues have previously reported the impact of CYP3A5 polymorphism on the pharmacokinetics of tacrolimus in kidney transplantation patients receiving Tac-QD administration [22–25]. However, the effect of the CYP3A5 genotype on the pharmacokinetics of Tac-QD in HSCT patients has yet to be clarified [13]. Although azole antifungal agents (AZ) are most often used for the prevention as well as the treatment of these infections in HSCT patients, these agents interfere with the metabolism and transport of tacrolimus [26]. In addition, the magnitude of drug interactions between AZs and tacrolimus differs between AZs (itraconazole = voriconazole > fluconazole) [27, 28]. Here, we investigated the safety and efficacy of Tac-QD in HSCT patients. We focused on CYP3A5 polymorphism and the interaction of Tac-QD with AZ.\n\nMethods\nRecipients and protocols of transplantation\nThis study was conducted as a single-institution, prospective cohort study to evaluate the safety and efficacy of Tac-QD in allogeneic HSCT patients. The eligibility criteria for the present study were as follows: (1) HSCT patients were given the same immunosuppressive regimens for the prophylaxis of GVHD; (2) age > 16 years; (3) no hypersensitivity to tacrolimus (Prograf® or Graceptor®); (4) no liver dysfunction [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level < fivefold the upper normal range and total bilirubin level < 2.0 mg/dL]; (5) no renal dysfunction (serum creatinine level < 2.0 mg/dL or creatinine clearance > 30 mL/min); and (6) no consumption of drugs or food affecting CYP3A and ABCB1 function. Twenty-four patients (17 males and 7 females) who underwent allogeneic HSCT at Akita University Hospital between April 2012 and October 2014 were enrolled in this study.\n\nProphylaxis regimens against GVHD included tacrolimus and methotrexate in the majority of patients, or variations including mycophenolate mofetil. Continuous infusion of 0.03 mg/kg/day tacrolimus was administered from the day prior to stem cell infusion. Tacrolimus administration was converted from intravenous administration to once-daily oral intake after adequate oral intake was observed. A quadruple dose of intravenous daily dose as an initial Tac-QD was administrated orally. The target whole blood concentrations of tacrolimus were 10–20 ng/mL with continuous infusion and 5–10 ng/mL after switching to oral administration. The whole blood concentrations of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay (CMIA).\n\nIntravenous infusion of micafungin was given to prevent fungal infection during the neutropenic phase. Seven days after switching from tacrolimus continuous infusion to Tac-QD, antifungal agents were switched from intravenous micafungin to oral AZ.\n\nThis study was approved by the Ethics Committee of the Akita University School of Medicine, and each patient provided written informed consent in accordance with the Declaration of Helsinki.\n\nGenotyping\nDNA was extracted from a peripheral blood sample using the QIAamp Blood kit (Qiagen, Hilden, Germany) and stored at −80 °C until analysis. The CYP3A53 allele was detected using a PCR-restriction fragment length polymorphism (RFLP) method [20]. The results obtained from PCR–RFLP analyses were confirmed using a fully automated SNP detection system (prototype i-density™; ARKRAY, Kyoto, Japan). The results of CYP3A5 genotyping were not used to adjust Tac-QD dosage or to score acute GVHD.\n\nBlood concentration of tacrolimus\nWhole blood samples were collected with EDTA just prior to the morning administration of Tac-QD 4–7 days after switching from continuous infusion to Tac-QD. Also, samples were collected 4–7 days after switching from intravenous micafungin to oral AZ. During both periods, whole blood tacrolimus concentrations were measured every day to confirm the stability of tacrolimus trough concentrations. Whole blood tacrolimus concentrations were determined using CMIA on the Architect-i1000® system (Abbott Laboratories, Abbott Park, IL) according to the manufacturer’s instructions. The Architect tacrolimus assay is a semiautomated, robust and highly sensitive immunoassay. It represents an alternative approach for laboratories that are not equipped with an LC-MSMS, and it meets the 1 ng/mL LOQ recommendation of the European Consensus Conference on Tacrolimus Optimization [29]. LOQ values for CMIA are reported to be 0.5–0.8 ng/mL, and CMIA exhibits cross-reactivity of 94 % to the tacrolimus active metabolite, 31-O-demethyl tacrolimus (M-II) [29, 30]. The reliable range of determination of tacrolimus with the Architect-i1000® instrument is between 0.5 and 30 ng/mL [31, 32].\n\nDefinition of acute kidney injury\nAcute kidney injury (AKI) was defined according to CTCAE version 4.0: serum creatinine increased 0.3 mg/dL or more, or more than 1.5 times from the baseline of serum creatinine. Baseline serum creatinine was the value obtained before the start of conditioning therapy.\n\nStatistical analyses\nThe primary endpoint of this study was the analysis of the pharmacokinetic behavior of Tac-QD based on CYP3A5 polymorphisms. The secondary endpoints were the assessments of the development of acute GVHD and the transplantation-related mortality on day 100. The Kolmogorov–Smirnov test was used to assess distribution. The clinical characteristics of the HSCT patients, dose-adjusted blood concentrations and changes in these parameters were expressed as medians (quartiles 1–3). The Chi-square test was used to examine differences in categorical data, except when the expected number of cells was <5, in which case the Fisher’s exact test was used. The Mann–Whitney U test was used to determine the significance of difference between continuous values between the groups. The Wilcoxon paired signed-rank test was used to determine the significance of differences in continuous values within each patient. A receiver operating characteristic (ROC) curve was used to determine the best cutoff values for predictive factors that had a minimum distance from the upper left corner to a point on the ROC curve. The proportion of patients showing no clinical events was estimated using the Kaplan–Meier method. The time to clinical events was compared between the groups using the stratified log-rank test. A P value <0.05 was considered to be statistically significant. For post hoc power analysis, an effect size was calculated in comparison with clinical characteristics between recipients with or without AKI after co-administration of AZs. An effect size >0.5 was considered clinically meaningful. Statistical analyses were performed using SPSS version 20.0 software for Windows (SPSS IBM Japan, Tokyo, Japan). Power was calculated using GPower version 3.1 software.\n\nResults\nCYP3A5 genetic polymorphism and outcome after HSCT\nThe characteristics of patients are given in Table 1. The CYP3A5 genotype frequency was in Hardy–Weinberg equilibrium [19]. Eleven patients had either the CYP3A51/1 or 1/3 genotype, and 13 patients had the CYP3A53/3 genotype. There was no significant difference in the ages, body weights, underlying diseases, pre-HSCT disease status, graft sources, extents of HLA allele matching or conditioning regimens between the two groups. Three patients could not switch to oral AZ due to severe infection. Fluconazole was used in 15 of 21 patients who were given oral AZ. Three patients received itraconazole, whereas another 3 patients were treated with voriconazole.Table 1 Characteristics of HSCT recipients\n\nCharacteristics\t\nCYP3A5\n\t\nCYP3A5\n\t\nP value\t\n\n1/1 or 1/3\n\t\n3/3\n\t\nNumber of recipients\t11\t13\t\t\nMale/female\t8/3\t9/4\t\t\nAge [years, median (range)]\t39 (21–63)\t55 (36–65)\t0.124\t\nBody weight [kg, median (range)]\t51 (49–66)\t61 (49–69)\t0.825\t\nDiagnosis\t\t\t0.622\t\n AML/MDS\t8\t11\t\t\n ALL\t3\t2\t\t\nState before HSCT\t\t\t0.265\t\n CR1\t2\t4\t\t\n CR2 or CR3\t3\t5\t\t\n Non-remission\t6\t4\t\t\nGraft source\t\t\t0.247\t\n BM from unrelated donors\t10\t8\t\t\n PBSC from sibling donors\t0\t2\t\t\n Umbilical cord blood\t1\t3\t\t\nHLA allele matching\t\t\t0.543\t\n 5/8\t1\t2\t\t\n 6/8\t2\t0\t\t\n 7/8\t2\t7\t\t\n 8/8\t6\t4\t\t\nConditioning\t\t\t0.271\t\n Reduced intensity\t3\t7\t\t\n Myeloablative\t8\t6\t\t\nGVHD prophylaxis\t\t\t0.397\t\n MTX\t11\t11\t\t\n MMF\t0\t1\t\t\n MTX + MMF\t0\t1\t\t\nIn combination with AZ\t\t\t0.855\t\n Fluconazole\t7\t8\t\t\n Itraconazole\t1\t2\t\t\n Voriconazole\t1\t2\t\t\n\nAML acute myeloid leukemia, MDS myelodysplastic syndrome, ALL acute lymphoblastic leukemia, HSCT hematopoietic stem cell transplantation, CR complete remission, BM bone marrow, PBSC peripheral blood stem cell, HLA human leukocyte antigen, GVHD graft-versus-host disease, MTX methotrexate, MMF mycophenolate mofetil, AZ azole antifungal agent\n\n\n\nThere was no transplantation-related mortality on day 100 in the present study cohort (Table 2). Two patients with relapse of the underlying disease and two patients with fungal infection were noted. There was a significant difference in the cumulative incidence of grade III–IV severe acute GVHD between the patients with the CYP3A51 allele and the CYP3A53/3 allele (36 vs. 0 %, P = 0.017). The incidence of AKI was higher in the CYP3A53/3 group than in the 1 allele group (46 vs. 9 %, respectively, P = 0.046).Table 2 Acute GVHD, TRM, relapse, fungal infection and AKI during the first 100 days\n\n\nCYP3A5 genotype\t\n1/1 or 1/3 (n = 11)\t\n3/3 (n = 13)\t\nP value\t\nAcute GVHD\t\t\t0.173\t\n Grade 0\t5\t8\t\t\n Grade 1\t1\t1\t\t\n Grade 2\t1\t4\t\t\n Grade 3\t3\t0\t\t\n Grade 4\t1\t0\t\t\nAcute GVHD\t\t\t0.017\t\n Grade 0–2\t7\t13\t\t\n Grade 3–4\t4\t0\t\t\nTRM\t0\t0\t\t\nRelapse\t1\t1\t0.902\t\nFungal infection\t1\t1\t0.902\t\nAKI\t1\t6\t0.046\t\n\nGVHD graft-versus-host disease, TRM transplantation-related-mortality, AKI acute kidney injury\n\n\n\nPharmacokinetics of Tac-QD during administration of oral AZ\nWithout co-administration of oral AZ, neither the tacrolimus C0 nor the median daily dose of tacrolimus differed between the CYP3A53/3 and the CYP3A51 allele groups (3.5 vs. 3.3 mg/day, respectively, P = 0.965 or 7.9 vs. 4.9 ng/mL, P = 0.053) (Fig. 1a). On the other hand, in the presence of AZ, tacrolimus C0 values were higher in patients with the CYP3A53/3 than with the CYP3A51 allele (10.1 vs. 7.4 ng/mL, respectively, P = 0.034) (Fig. 1b). The daily dose of tacrolimus was significantly lower in patients with the CYP3A53/3 allele than with the 1 allele (2.0 vs. 4.0 mg/day, respectively, P = 0.041).Fig. 1 Comparison of doses (box and whiskers plots) and the tacrolimus trough levels (open circles) between the CYP3A511 + 1/3 group and the 3/3 group. a Before co-administration of AZ and b after co-administration of AZ. Graphical analysis was performed using an SPSS box and whiskers plot. The box spans data between two quartiles (IQR), with the median represented as a bold horizontal line. The ends of the whiskers (vertical lines) represent the smallest and largest values that were not outliers. The gray circles represent the outlier of dose. AZ azole antifungal agent\n\n\n\nAKI occurred in the CYP3A53/3 group after co-administration of AZ\nSeven patients developed AKI in the present study. In order to properly study the impact of Tac-QD and co-administration of AZ, we excluded the three patients who did not receive AZ and the one patient who developed AKI prior to the administration of Tac-QD (Table 3). The median tacrolimus C0 with administration of AZ in patients with AKI was about twice that of patients without AKI (16.3 vs. 8.6 ng/mL, P = 0.020, effect size = 0.517). Furthermore, only the patients with the CYP3A53/3 developed AKI (6/6 vs. 6/14 patients, P = 0.024, effect size = 0.535). AKI occurred within 14 days of starting co-administration of AZ (Supplementary Fig. 1).Table 3 Comparison of clinical characteristics between recipients with or without AKI after co-administration of azole antifungal agents\n\n\tWith AKI\tWithout AKI\t\nP value\t\nSex\t\t\t0.613\t\n Male\t4\t10\t\t\n Female\t2\t4\t\t\nCYP3A5 genotypes\t\t\t0.024\t\n 1/1 or 1/3\n\t0\t8\t\t\n 3/3\n\t6\t6\t\t\nAge [years, median (range)]\t60 (39–63)\t53 (37–61)\t0.353\t\nBody weight [kg, median (range)]\t55.1 (46.8–63.3)\t61.5 (48.6–75.0)\t0.097\t\nIn combination with\t\t\t0.239\t\n Fluconazole\t4\t11\t\t\n Itraconazole\t2\t1\t\t\n Voriconazole\t0\t2\t\t\nDose of tacrolimus (mg/day)\t2.0 (1.5–5.0)\t3.5 (3.0–4.0)\t0.659\t\nTacrolimus C0 (ng/mL)\t16.3 (13.4–16.4)\t8.6 (6.8–9.1)\t0.020\t\n\nAKI acute kidney injury\n\n\n\nThe tacrolimus C0 value was higher after co-administration of AZ in most patients than without, and AKI was observed only after co-administration of AZ (Fig. 2). The area under the ROC for the tacrolimus C0 to develop AKI after co-administration of AZ was 0.833, which gave the best sensitivity (83.3 %) and specificity (85.7 %) at a tacrolimus C0 threshold of 10.1 ng/mL (data not shown).Fig. 2 Comparisons of the tacrolimus trough levels according to the presence or absence of a co-administered AZ. Circles fluconazole; triangles voriconazole; boxes itraconazole; closed figures patients with AKI. AZ azole antifungal agent, AKI acute kidney injury\n\n\n\nEighty percent of the CYP3A53/3 group were required to reduce the daily dose of Tac-QD by 50 % or more within 14 days of co-administration of AZ (Fig. 3). The reduction in the Tac-QD dosage in patients with the CYP3A53/3 was significantly faster than those with the CYP3A51 allele (P = 0.020).Fig. 3 Cumulative incidence of dose attenuation of tacrolimus from baseline (<50 %) after co-administration of AZ. Solid line, CYP3A511 + 1/3; dotted line, CYP3A53/3. Median time to reduction in tacrolimus dosage was 8.0 days in the CYP3A53/3 group and not reached in the CYP3A511 + 1/3 group. AZ azole antifungal agent\n\n\n\nDiscussion\nThis is the first study to assess the inter-individual variability of tacrolimus blood concentrations in allogeneic HSCT patients who were given Tac-QD. The results were clearly dependent upon the CYP3A5 polymorphism. There are three clinically important findings in the present study. First, the CYP3A5 polymorphism had a great influence on the blood concentrations of tacrolimus, even when the once-daily modified-release formulation was used. Second, the blood concentrations of tacrolimus in patients with CYP3A53/3 was elevated markedly after co-administration of AZ, even when the patients had been given fluconazole, which is recognized as having the lowest CYP3A4 inhibitory activity among AZs. Finally, the CYP3A53/3 group with AZ developed AKI when the blood concentrations of tacrolimus were over 10.1 ng/mL.\n\nOur colleagues previously reported that the CYP3A5 polymorphism had no impact on the dose-adjusted AUC0–24 of tacrolimus during continuous intravenous infusion in kidney transplantation patients. However, the bioavailability of oral tacrolimus was higher for the CYP3A53/3 group than for the CYP3A51 allele group [33]. Also in the present study, we investigated the pharmacokinetics of tacrolimus when switching from intravenous infusion to oral administration and antifungal agents. AZ has a stronger inhibitory effect on CYP3A4 activity than on CYP3A5 in the small intestine [27, 28], and tacrolimus is metabolized by CYP3A4 in patients expressing CYP3A53/3. As a result of CYP3A4 inhibition with AZ in the small intestine, we found that the C0 of tacrolimus was elevated markedly in CYP3A53/3 patients after co-administration of AZ (Fig. 1). It has been reported that the blood concentration of tacrolimus was higher in patients with the CYP3A53/3 than those with the CYP3A51 allele in the absence of co-administration of AZ in HSCT and kidney transplantation [17, 34]. We previously confirmed that the influence of CYP3A5 polymorphism on the tacrolimus dosage became evident 14 days after kidney transplantation [35]. Between the two genotypes, we did not observe a significant difference in the C0 value of tacrolimus or daily doses of Tac-QD before co-administration of oral AZ. However, it may be too short a time to observe differences in the blood concentration and doses of tacrolimus after switching to oral tacrolimus.\n\nCYP3A5 is expressed in the liver and small intestine [8, 36, 37], and it plays a key role in the small intestine [15]. The interaction between tacrolimus and AZ is depicted in Fig. 3. In patients with the CYP3A51 allele, tacrolimus can be metabolized by CYP3A5 in the intestinal epithelium when oral AZ is given, resulting in inhibition of CYP3A4 activity. In contrast, the metabolism of tacrolimus in the CYP3A53/3 group proceeds only through CYP3A4 in the presence of oral AZ. Since HSCT recipients are at high risk of developing invasive fungal infection [23], antifungal agents are commonly used therapeutically and/or prophylactically. Many factors contribute to variability in the clinical significance of drug interactions between tacrolimus and AZ [27, 34, 38, 39]. Although the strong inhibition of CYP3A4 and P-glycoprotein by itraconazole is well known, many reports suggested that the influence of fluconazole on CYP3A4 may be less than other AZ agents [26–28]. In the present study, 15 patients were given fluconazole and eight of them carried the CYP3A53/3. Four patients who were given fluconazole in the CYP3A53/3 group showed nephrotoxicity (Fig. 2). Kuypers et al. [40] reported similar results, in that the CYP3A53/3 patients who were given fluconazole were more frequently exposed to supra-therapeutic tacrolimus C0. Our study suggests that co-administration of fluconazole with Tac-QD in the CYP3A53/3 may cause not only elevation of tacrolimus blood concentrations but also kidney injury.\n\nTacrolimus has a narrow therapeutic window in HSCT, and Yano et al. [41] reported that the modification of Tac-QD to maintain a whole tacrolimus C0 above 7.5 ng/mL may be as effective as Tac-BID, and no patient developed grade III–IV acute GVHD. On the other hand, we demonstrated that nephrotoxicity of tacrolimus may increase when tacrolimus C0 was above 10.1 ng/mL (Fig. 2). By maintaining the tacrolimus C0 under 10 ng/mL, we may prevent nephrotoxicity in patients who are given Tac-QD with AZ. As Ram et al. reported [1], a higher mean blood concentration of tacrolimus during the second week following HSCT was also correlated with protection against grade III–IV acute GVHD (Supplementary Fig. 2). The number of subjects was quite small, and we could not identify the clinical significance of the blood concentration of tacrolimus and CYP3A5 genotype. Studies consisting of a large number of subjects will be needed.\n\nUnlike kidney transplantation, the administration of antifungal agents is usually required for allogeneic HSCT. CYP3A5 genotyping may be useful for determination of the appropriate dose of Tac-QD and the selection of AZ, in order to avoid AKI as well as severe acute GVHD. We need further prospective study to determine whether appropriate therapeutic drug monitoring based on stratified doses of tacrolimus in the setting of CYP3A5 polymorphism can prevent AKI.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary Fig. 1. Cumulative incidence of AKI after co-administration of AZ in the CYP3A511 + 1/3 group and the 3/3 group with AZ. Solid line, the CYP3A511 + 1/3 group; dotted line, the CYP3A53/3 group. AZ: azole antifungal agent, AKI: acute kidney injury (TIFF 25 kb)\n\n Supplementary Fig. 2. Cumulative incidence of grade III–IV GVHD after hematopoietic stem cell transplantation in the CYP3A511 + 1/3 group and the 3/3 group with AZ. Solid line, the CYP3A511 + 1/3 group; dotted line, the CYP3A53/3 group. GVHD: graft-versus-host disease (TIFF 41 kb)\n\n \n\nAuthor contributions\nTY and NF performed the research, designed the study, collected and analyzed the data, and wrote the paper; MM, TN, MH and NT analyzed the data and revised the manuscript; MA, YS, KU, MN, MF, YK and HT collected and analyzed the data, and revised the manuscript. All authors are responsible for the scientific content of this manuscript and approved the manuscript to be published.\n\nCompliance with ethical standards\nConflict of interest\nThe authors reported no potential conflict of interest.\n==== Refs\nReferences\n1. Ram R Storer B Mielcarek M Association between calcineurin inhibitor blood concentrations and outcomes after allogeneic hematopoietic cell transplantation Biol Blood Marrow Transplant 2012 18 414 422 10.1016/j.bbmt.2011.08.016 21875504 \n2. 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Nara M Takahashi N Miura M Effect of itraconazole on the concentrations of tacrolimus and cyclosporine in the blood of recipients receiving allogeneic hematopoietic stem cell transplants Eur J Clin Pharmacol 2013 69 1321 1329 10.1007/s00228-013-1471-2 23354810 \n40. Kuypers DR de Jonge H Naesens M Vanrenterghem Y Effects of CYP3A5 and MDR1 single nucleotide polymorphisms on drug interactions between tacrolimus and fluconazole in renal allograft recipients Pharmacogenet Genomics 2008 18 861 868 10.1097/FPC.0b013e328307c26e 18704002 \n41. Yano S Mori S Saito T Pharmacokinetics for once-daily modified release formulation of tacrolimus hydrate in unrelated hematopoietic stem cell transplantation Ann Hematol 2015 94 491 496 10.1007/s00277-014-2233-7 25325985\n\n", "fulltext_license": "CC BY", "issn_linking": "0344-5704", "issue": "78(1)", "journal": "Cancer chemotherapy and pharmacology", "keywords": "Azole antifungal agent; CYP3A5 polymorphism; Hematopoietic stem cell transplantation; Once-daily tacrolimus formulation; Pharmacokinetics", "medline_ta": "Cancer Chemother Pharmacol", "mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000483:Alleles; D000935:Antifungal Agents; D001393:Azoles; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies; D016559:Tacrolimus; D055815:Young Adult", "nlm_unique_id": "7806519", "other_id": null, "pages": "111-8", "pmc": null, "pmid": "27217047", "pubdate": "2016-07", "publication_types": "D018848:Controlled Clinical Trial; D016428:Journal Article", "references": "20840481;12242601;19258928;12406645;23354810;21875504;20534291;15502717;25801146;20818295;12228187;17125435;20216110;21861541;23955548;20840480;20170205;1385058;17635182;18704002;23733010;25565672;16501005;25325985;16205037;14961555;17049058;26218924;23073468;12966368;21168673;25594874;21158926;25429674;25303300;19142177;17965516;12490779;21102498;21528942;10709776", "title": "Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation.", "title_normalized": "effects of cyp3a5 polymorphism on the pharmacokinetics of a once daily modified release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation" }	[ { "companynumb": "JP-JNJFOC-20160824119", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS\\TACROLIMUS ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".03", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROGRAF" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "020083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MICAFUNGIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "MICAFUNGIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GRACEPTOR" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAKAYA Y, NAOHITO F, MASATOMO M, TAKENORI N, MAIKO A, YOSHINORI S, ET AL. EFFECTS OF CYP3A5 POLYMORPHISM ON THE PHARMACOKINETICS OF A ONCE-DAILY MODIFIED-RELEASE TACROLIMUS FORMULATION AND ACUTE KIDNEY INJURY IN HEMATOPOIETIC STEM CELL TRANSPLANTATION. CANCER CHEMOTHERAPY AND PHARMACOLOGY 23-MAY-2016;78:111-118. TAKAYA Y, FUJISHIMA N, MIURA M, NIIOKA T, ABUMIYA M, TESHIMA K, ET AL. INFLUENCE OF CYP3A5 GENE POLYMORPHISMS ON PHARMACOKINETICS OF TACROLIMUS MODUFIED-RELEASE ONCE-DAILY AFTER HEMATOPO", "literaturereference_normalized": "effects of cyp3a5 polymorphism on the pharmacokinetics of a once daily modified release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161018", "receivedate": "20160829", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12695158, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "JP-JNJFOC-20160610788", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GRACEPTOR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MICAFUNGIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "MICAFUNGIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "020083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS\\TACROLIMUS ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".03", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROGRAF" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAKAYA Y, NAOHITO F, MASATOMO M, TAKENORI N, MAIKO A, YOSHINORI S, ET AL. EFFECTS OF CYP3A5 POLYMORPHISM ON THE PHARMACOKINETICS OF A ONCE-DAILY MODIFIED-RELEASE TACROLIMUS FORMULATION AND ACUTE KIDNEY INJURY IN HEMATOPOIETIC STEM CELL TRANSPLANTATION. CANCER CHEMOTHERAPY AND PHARMACOLOGY 23-MAY-2016;78:111-118. YAMASHITA T, FUJISHIMA N, MIURA M, NIIOKA T, ABUMIYA M, NARA M. INFLUENCE OF CYP3A5 GENE POLYMORPHISMS ON PHARMACOKINETICS OF MODIFIED-RELEASE TACROLIMUS. THE JAPANESE JOURNAL OF CLINICA", "literaturereference_normalized": "effects of cyp3a5 polymorphism on the pharmacokinetics of a once daily modified release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160829", "receivedate": "20160623", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12493616, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" } ]
{ "abstract": "Objectives: Cranial neuropathies (CNs) can be due to a wide spectrum of causes, and the differential diagnosis is particularly challenging in patients with positive history of hematological malignancies, when neoplastic meningitis (NM) must be excluded.Patients and Methods: We retrospectively selected a series of twelve haematological patients with isolated cranial neuropathies (ICNs) or multiple cranial neuropathies (MCNs). among 71 patients that developed neurologic symptoms during different stages of the cancer, between 1 January, 2010 and 31 December, 2017. Brain and cauda equina magnetic resonance imaging (MRI) with gadolinium, cerebrospinal fluid (CSF) analysis, including flow cytometry for cell immunophenotyping and microbiological exams were performed in all patients.Results: Patients developed signs and symptoms of involvement of isolated (n = 11) or multiple (n = 1) cranial nerves, at different stages of the primary disease, and, in 5 of these cases in complete remission after hematopoietic stem cell transplantation. Among the 5 cases that eventually were diagnosed as having NM, cerebrospinal fluid was positive for neoplastic cells in 3, and MRI gadolinium-enhancement was present in 3. The other episodes were attributed to heterogeneous pathologies that were unrelated to meningeal infiltration by neoplastic cells.Conclusions: Our observations confirm that NM in haematological malignancies can yield insidious isolated signs of cranial nerves. Only a multidisciplinary approach allows prompt recognition of these conditions through a challenging process of differential diagnosis, and proper therapies.", "affiliations": "IRCCS C. Mondino Foundation, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.;Department of Microbiology and Virology, Molecular Virology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.;Transplantation Unit, Department of Hematology and Oncology, Foundation IRCCS, Policlinico San Matteo, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.", "authors": "Diamanti\|Luca\|L\|;Berzero\|Giulia\|G\|;Franciotta\|Diego\|D\|;Bini\|Paola\|P\|;Furione\|Milena\|M\|;Farina\|Lisa Maria\|LM\|;Bastianello\|Stefano\|S\|;Colombo\|Anna Amelia\|AA\|;Marchioni\|Enrico\|E\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/00207454.2019.1705810", "fulltext": null, "fulltext_license": null, "issn_linking": "0020-7454", "issue": "130(8)", "journal": "The International journal of neuroscience", "keywords": "Cranial neuropathies; leukemia; lymphoma; neoplastic meningitis", "medline_ta": "Int J Neurosci", "mesh_terms": "D000328:Adult; D001921:Brain; D002420:Cauda Equina; D003389:Cranial Nerve Diseases; D003937:Diagnosis, Differential; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia; D008223:Lymphoma; D008279:Magnetic Resonance Imaging; D008297:Male; D055756:Meningeal Carcinomatosis; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies", "nlm_unique_id": "0270707", "other_id": null, "pages": "777-780", "pmc": null, "pmid": "31906752", "pubdate": "2020-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Cranial nerve palsies in patients with hematological malignancies: a case series.", "title_normalized": "cranial nerve palsies in patients with hematological malignancies a case series" }	[ { "companynumb": "IT-MYLANLABS-2020M1074367", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMATINIB MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "204644", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC MYELOID LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB." } ], "patientagegroup": null, "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blindness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Optic neuritis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DIAMANTI L, BERZERO G, FRANCIOTTA D, BINI P, FURIONE M, FARINA LM, ET AL. CRANIAL NERVE PALSIES IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES: A CASE SERIES. INT?J?NEUROSCI 2020?130(8):777?780.", "literaturereference_normalized": "cranial nerve palsies in patients with hematological malignancies a case series", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200826", "receivedate": "20200826", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18198754, "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-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-259840", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018374", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "SULPHAMETHOXAZOLE/TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxoplasmosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DIAMANTI L, BERZERO G, FRANCIOTTA D, BINI P, FURIONE M, FARINA LM, ET AL. CRANIAL NERVE PALSIES IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES: A CASE SERIES. INT J NEUROSCI. 2020?777?780:130(8)", "literaturereference_normalized": "cranial nerve palsies in patients with hematological malignancies a case series", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200902", "receivedate": "20200902", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18220516, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "IT-EMA-DD-20220117-singh_p11-162626", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "206547", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic myeloid leukaemia", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" } ], "patientagegroup": "5", "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blindness", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Optic neuritis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Diamanti L, Berzero G, Franciotta D, Bini P, Furione M, Farina LM, et al. Cranial nerve palsies in patients with hematological malignancies: a case series. Int-J-Neurosci 2020;130(8):777-780.", "literaturereference_normalized": "cranial nerve palsies in patients with hematological malignancies a case series", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20220129", "receivedate": "20220129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20394382, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-260086", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "078340", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic myeloid leukaemia", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" } ], "patientagegroup": null, "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuritis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Iatrogenic injury", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Diamanti L, Berzero G, Franciotta D, Bini P, Furione M, Farina LM, et al. Cranial nerve palsies in patients with hematological malignancies: a case series. Int J Neurosci. 2020;130(8):777-780", "literaturereference_normalized": "cranial nerve palsies in patients with hematological malignancies a case series", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20220209", "receivedate": "20200903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18227282, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]
{ "abstract": "Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.", "affiliations": "Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Postgraduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Postgraduate School in Clinical Pharmacology and Toxicology, University of Campania \"L. Vanvitelli\", 80138 Naples, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Postgraduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy.;Postgraduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Postgraduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.", "authors": "Conti\|Valeria\|V\|;De Bellis\|Emanuela\|E\|;Manzo\|Valentina\|V\|;Sabbatino\|Francesco\|F\|;Iannello\|Francesco\|F\|;Dal Piaz\|Fabrizio\|F\|;Izzo\|Viviana\|V\|0000-0001-6066-7569;Charlier\|Bruno\|B\|;Stefanelli\|Berenice\|B\|;Torsiello\|Martina\|M\|;Iannaccone\|Teresa\|T\|;Coglianese\|Albino\|A\|;Colucci\|Francesca\|F\|;Pepe\|Stefano\|S\|;Filippelli\|Amelia\|A\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/jpm10030113", "fulltext": "\n==== Front\nJ Pers Med\nJ Pers Med\njpm\nJournal of Personalized Medicine\n2075-4426 MDPI \n\n32899374\n10.3390/jpm10030113\njpm-10-00113\nReview\nA Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature\nConti Valeria 12 De Bellis Emanuela 3 Manzo Valentina 123* Sabbatino Francesco 14 Iannello Francesco 5 Dal Piaz Fabrizio 12 https://orcid.org/0000-0001-6066-7569Izzo Viviana 12 Charlier Bruno 12 Stefanelli Berenice 3 Torsiello Martina 3 Iannaccone Teresa 1 Coglianese Albino 1 Colucci Francesca 3 Pepe Stefano 14 Filippelli Amelia 12 1 Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; [email protected] (V.C.); [email protected] (F.S.); [email protected] (F.D.P.); [email protected] (V.I.); [email protected] (B.C.); [email protected] (T.I.); [email protected] (A.C.); [email protected] (S.P.); [email protected] (A.F.)\n2 Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy\n3 Postgraduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy; [email protected] (E.D.B.); [email protected] (B.S.); [email protected] (M.T.); [email protected] (F.C.)\n4 Oncology Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy\n5 Postgraduate School in Clinical Pharmacology and Toxicology, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; [email protected]\n* Correspondence: [email protected]; Tel.: +39-089-672-424\n03 9 2020 \n9 2020 \n10 3 11305 8 2020 01 9 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/).Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.\n\nDPDDPYD polymorphismspharmacogeneticsfluoropyrimidinespersonalised medicinetherapeutic drug monitoring\n==== Body\n1. Introduction\nFluoropyrimidines (FP), including 5-fluorouracil (5-FU) and its oral prodrug capecitabine, are cytotoxic antineoplastic agents belonging to the class of antimetabolites. They are commonly used to treat solid cancer types such as gastrointestinal, head-neck and breast cancers associated or not to other chemotherapeutics and both cytotoxic and biologic drugs [1,2]. The administration of the FP may cause severe, even life-threatening, adverse drug reactions (ADR), including myelosuppression, mucositis/stomatitis, diarrhoea and hand–foot syndrome (HFS). Indeed, it has been estimated that an increased risk of severe ADR (grade > 2) involves 10–30% of treated patients, although these data greatly depend on the therapeutic regimen used [1,3,4].\n\nThe rate-limiting step of FP catabolism is the conversion of fluorouracil to dihydrofluorouracil, which is catalysed by an enzyme called dihydropyrimidine dehydrogenase (DPD), encoded by a highly polymorphic gene (i.e., DPYD). Several single-nucleotide polymorphisms (SNPs) have been associated to an alteration of the DPYD sequence, and some of them may determine a partial or complete DPD deficiency, leading to FP severe toxicity [1].\n\nThe Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) [5,6] have published guidelines for FP dosing based on the pharmacogenetic testing of four DPYD polymorphisms that are DPYD2A (rs3918290), DPYD13 (rs55886062), DPYD c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182 and HapB3). The latter is the most common variant, with ~4% allelic frequency; the DPYD2A, c.2846A>T and DPYD13 are present in ~2.0%, 1.4% and 0.1%, respectively, of Caucasian patients [5]. Recently, a new polymorphism, DPYD6 (rs1801160), has been associated with both gastrointestinal and haematological FP-ADR [7].\n\nNotably, other DPYD genetic variants may lead to dangerous clinical consequences, although their frequency is very low [5,6,8].\n\nWith the main aim of reducing the risk of severe FP-induced toxicity, the CPIC and DPWG have implemented a gene activity score (DPYD-AS), which ranges from 0 (complete DPD deficiency) to 2 (normal DPD activity). In patients who are homozygous for one or more of the aforementioned SNPs, the recommendation is to avoid the use of FP. However, if alternative drugs are not considered a suitable option, the FP dosage should be markedly reduced while establishing a therapeutic drug-monitoring (TDM) approach. Patients who are heterozygous should receive a 50% dose reduction at the first cycle of chemotherapy, followed by a titration dose, while monitoring the patient’s clinical conditions and possibly performing TDM [5,6].\n\nHowever, it has been estimated that 30–50% of the patients experience severe ADR, despite not having a DPD deficit associated with such DPYD polymorphisms. In fact, there are several factors, including comorbidities, polytherapy, other variants in the DPYD and other genes, that can play an important role [9]. Besides DPYD polymorphisms, two SNPs in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene [10] and a tandem repeat in the thymidylate synthase enhancer region (TYMS-TSER) could concur in predicting FP-related toxicity [11]. Moreover, a SNP in glutathione S-transferase-p1 (GSTP1) has been suggested as a genetic factor able to influence the response to oxaliplatin, a drug frequently administered with FP [12].\n\nSeveral strategies complementing the DPYD pharmacogenetics (DPYD-PGx) have been proposed to prevent FP-related severe ADR associated with DPD deficit. Among others, the measurement of the plasmatic dihydrouracil/uracil ratio (UH2/U) and the monitoring of 5-FU clearance are considered valid approaches [13,14]. Here, we reported clinical cases in whom a combined genotyping/phenotyping approach, together with careful clinical monitoring was used to optimise the FP-based treatment. In addition, we performed a systematic review of the literature concerning the use of DPYD-PGx, together with phenotyping methods to personalise such chemotherapy.\n\n2. Materials and Methods\n2.1. Case Series\nWe describe the cases of eleven oncological patients of the Campania Region (Italy) treated with FP-based chemotherapy. They were enrolled in an ongoing study (ethics committee approval n. 4_r.p.s.o.) whose main aim was to investigate the association between DPYD SNPs and other genetic variants with FP-related severe toxicity. To manage the therapy of these eleven patients, we used a combined genotyping/phenotyping approach with clinical monitoring.\n\nA careful clinical monitoring was carried out by interviewing patients and checking the results of their blood counts at each cycle of chemotherapy. The ADR were recorded and graded according to the Common Terminology Criteria for Adverse Events (CTC-AE) version 5.0 [15]. The Response evaluation criteria in solid tumors (RECIST) were used to assess the treatment response [16].\n\nAll enrolled patients were genotyped for the recommended DPYD SNPs (DPYD2A, DPYD13, DPYD 2846A>T and c.1129-5923C>G) as part of the clinical practice. Besides this pharmacogenetic testing (DPYD-PGx) performed by real-time PCR with allelic discrimination, the SNPs MTHFR-C677T and -A1298C were analysed using pyrosequencing technology and the TYMS-TSER variant by classical PCR and agarose gel-based electrophoresis.\n\nA phenotyping analysis was carried out by determining the plasmatic UH2/U ratio, as an indirect measurement of DPD activity, using high-performance liquid chromatography (HPLC) [17]. Moreover, in three patients, a 5-FU pharmacokinetic analysis was also performed to determine the plasmatic 5-FU clearance by using ultra-high-performance liquid chromatography combined with tandem mass spectrometry (UHPLC-MS/MS) [18]. Written informed consent was obtained from the patients for participation in the study, as well as publication of their data.\n\n2.2. Systematic Review\n2.2.1. Search Strategy\nA systematic review was performed using the PubMed, Scopus and Cochrane databases from inception to 3 July 2020. The following keywords and Medical Subject Headings (MeSH) terms were used for the search: DPYD polymorphism, dihydropyrimidine dehydrogenase deficiency, 5-FU clearance and dihydrouracil/uracil ratio.\n\nThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were applied [19]. A total of 1932 studies were retrieved from the searched databases. After the removal of duplicates and then article types such as reviews, metanalyses, case reports, etc., 112 articles were screened. Afterward, considering the inclusion and exclusion criteria, 22 articles were included in the analysis. The flowchart of the literature screening is reported in Figure 1.\n\n2.2.2. Eligibility Criteria\nThe search was limited to studies conducted in human beings and published in the English language. Both observational and randomised clinical studies were eligible. Only the studies enrolling patients treated with FP and showing results of DPYD-PGx, analysing at least one of the four SNPs recommended in the CPIC and DPWG guidelines, have been included in the analysis.\n\n2.2.3. Article Selection\nFirst, articles were selected by reading their titles and abstracts. Then, the full text of all articles considered eligible was read. The authors (Valeria Conti and Berenice Stefanelli) carried out this work independently and discussed when there was a disagreement about the relevance of an article.\n\n2.2.4. Data Extraction\nClinical, genetic and biochemical data were extracted from the articles. The factors considered were: study design, sample size, DPYD genotyping combined with phenotyping methods and/or clinical monitoring.\n\n3. Results\n3.1. Cases Presentation\nCase 1 was a Caucasian 55-year-old male former smoker with a history of hypertension. The patient had stage IV colorectal adenocarcinoma with metastases in the lymph nodes, lungs, liver and kidneys. The tumour mutational profile identified no mutations in the KRAS, NRAS or BRAF genes. The patient was treated with the combination of 5-FU, leucovorin and oxaliplatin (FOLFOX6) regimen, plus cetuximab. After three cycles of chemotherapy, the patient reported grade 1 thrombocytopenia and paraesthesia; grade 2 stomatitis, rash and leukopenia and grade 3 neutropenia and mucositis.\n\nA post-therapeutic DPYD-PGx was performed, revealing that the patient was heterozygous for DPYD2A. Moreover, the patient was homozygous (TT) for MTHFR-C677T, homozygous TYMS-TSER-2R/2R and homozygous (AA) for GSTP1-A313G. The plasmatic UH2/U ratio was 4.52. Based on these results and the reported toxicity, both the 5-FU and cetuximab doses were reduced. Specifically, the total dosage of 5-FU was reduced to 50%, according to the CPIC and DPWG guidelines.\n\nAt the fourth cycle of therapy, the pharmacokinetic analysis revealed a trough 5-FU plasma concentration of 950 ng/mL. The CT scan demonstrated an overall stable disease, according to the RECIST criteria v1.1. The patient was still treated with the same doses of 5-FU. At the sixth cycle of therapy, the 5-FU plasma concentration was 400 ng/mL. The following cycles (fifth to eighth) of chemotherapy were administered at the same drug doses. A new CT scan demonstrated no evidence of disease progression. The ADR were grade 1 leukopenia, neutropenia, thrombocytopenia and mucositis and grade 2 HFS. Following a further two cycles of therapy, the reported ADR were grade 1 paraesthesia, erythematous maculopapular rash and grade 2 cutaneous and mucous fissures. Lastly, following a further two treatment cycles, a new CT scan showed disease progression. The treatment was stopped, and the administration of a new chemotherapeutic regimen was planned. Sadly, the patient died before starting a second line of treatment.\n\nCase 2 was a Caucasian 48-year-old male with no comorbidity. He had stage IV colorectal adenocarcinoma with metastases in the lymph nodes and liver. The tumour mutational profile highlighted the presence of a KRAS mutation; thus, a treatment with the FOLFOX6 regimen plus bevacizumab was planned. A pretherapeutic DPYD-PGx was requested, and the patient was identified as DPYD2A heterozygous. In addition, he was wild type for MTHFR-C677T and MTHFR-A1298C, heterozygous TYMS TSER-2R/3R and homozygous (GG) for GSTP1-A313G. The plasmatic UH2/U ratio was 3.22. Based on these results, a 50% dose reduction of 5-FU was planned for the first cycle of FOLFOX administration, according to the CPIC and DPWG guidelines. After the first cycle of treatment, the plasmatic 5-FU clearance was 474 ng/mL. Following three cycles of therapy, a stable disease was found, according to the RECIST criteria v1.1, and no adverse events were reported. The patient was still treated with the same doses of chemotherapeutic agents for an additional seven cycles of therapy. Grade 1 paraesthesia and mucositis and grade 2 HFS but no severe ADR were reported, and the CT scan demonstrated a stable disease. Afterward, the patient was treated up to the twelfth cycle with a FOLFOX regimen plus bevacizumab, still obtaining, at revaluation, a stable disease. Then, he was a candidate for a maintenance therapy with capecitabine plus bevacizumab. Following 16 cycles of this therapy, the patient reported grade 1 paraesthesia and mucositis, and no severe ADR were recorded.\n\nCase 3 was a Caucasian 60-year-old male former smoker with no comorbidities. He had stage IV rectal adenocarcinoma with liver metastases. The tumour mutational profile did not identify mutations in either KRAS, NRAS or BRAF. Based on the tumour profile and stage, the patient was a candidate for a FOLFOX regimen plus cetuximab. A pretherapeutic DPYD-PGx was performed, and the patient was found heterozygous for DPYD c2846A>T SNP. Therefore, according to the CPIC and DPWG guidelines, he started chemotherapy with a 50% dose reduction of 5-FU. Moreover, he was homozygous (TT) for MTHFR-C677T, heterozygous TYMS TSER-2R/3R and heterozygous for GSTP1-A313G. The plasmatic UH2/U ratio was 1.77.\n\nA grade 2 diffuse maculopapular rash was reported, and, based on such an ADR, the dose of cetuximab was also reduced to 50% for the second cycle of therapy. The plasmatic 5-FU clearance was 811 ng/mL—still high, notwithstanding the 5-FU dose reduction. The patient reported no improvement of the skin rash and grade 2 diarrhoea. At the third cycle of therapy with the same drugs doses, the 5-FU plasma level was 1093 ng/mL. Grade 1 nausea and grade 3 diarrhoea were reported. Based on these results, the 5-FU dose was further reduced by an additional 10% at the fourth cycle of therapy. However, the 5-FU plasma concentration was still high (1048 ng/mL), and grade 4 diarrhoea was reported. Hence, it was decided not to administer 5-FU in a continuous infusion, leaving the administration of 5-FU in bolus. Nevertheless, the 5-FU plasma concentration was still high (i.e., 934 ng/mL), and grade 3 diarrhoea was reported.\n\nA CT scan showed a partial response according to the RECIST criteria with a reduction of hepatic lesions. It was decided to carry out a further cycle with oxaliplatin plus cetuximab.\n\nAfter this cycle, the hepatic lesions were resected. After one month from surgery, a CT scan demonstrated the development of a new hepatic lesion. The patient was a candidate to start a new treatment with 5-FU plus irinotecan as a modified 5-FU, leucovorin and irinotecan (FOLFIRI) regimen, since 5-FU was administered with a 50% dose reduction and without continuous infusion. The patient performed six cycles of FOLFIRI plus bevacizumab. Grade 3 diarrhoea was reported. As a consequence, the 5-FU administration was stopped, and only irinotecan and bevacizumab were further administered. After four cycles of this treatment, the CT scan demonstrated a progression of the disease. The patient died after 11.2 months from starting treatment with irinotecan plus bevacizumab.\n\nTable 1 and Table 2 report the main characteristics and the occurrence of grade ≥ 3 ADR of 3/11 and 8/11 clinical cases, respectively. Table 1 describes three clinical cases for whom either pretherapeutic DPYD-PGx or post-therapeutic DPYD-PGx were performed. As phenotypic characteristics, the UH2/U ratio values and plasmatic 5-FU clearance were reported.\n\nA pretherapeutic DPYD-PGx was performed in two out of three cases, while one patient (case 1) had already started chemotherapy before requesting DPYD-PGx. Importantly, the patients were monitored during all treatment cycles.\n\nBesides these three clinical cases, the history of other eight patients is briefly reported below, and their main characteristics are listed in Table 2.\n\nAll subjects were monitored for at least four treatment cycles. In two out of eight subjects, the DPYD-PGx was required after the occurrence of severe toxicity (post-therapeutic DPYD-PGx), while in six out of eight, pharmacogenetic testing was performed before the treatment started (pretherapeutic DPYD-PGx). All patients were identified as carriers of DPYD variants—precisely, four out of eight were DPYD2A heterozygous, and four out of eight were DPYD c.2846 heterozygous.\n\nThe two patients for whom the DPYD-PGx was performed after 5-FU administration experienced grade 3 ADR with a different timing, and both were then revealed as DPYD-variant carriers. More in detail, one patient with stage III gastric cancer, treated with FOLFOX, suffered from grade 3 vomit after the second cycle; he was then identified as DPYD2A heterozygous and continued to be treated only with oxaliplatin. Moreover, the patient was homozygous (TT) for MTHFR-C677T, homozygous TYMS TSER-3R/3R and homozygous (AA) for GSTP1-A313G.\n\nThe other one with stage IV colon cancer, treated with FOLFIRI plus bevacizumab, showed grade 3 vomit after the eighth cycle of chemotherapy. The patient was identified as DPYD c.2846 heterozygous, and the 5-FU dosage was halved. With regards to the other SNPs, the patient was homozygous (TT) for MTHFR-C677T, heterozygous TYMS TSER-2R/3R and wild type for UGT1A128 SNP. The latter polymorphism is routinely analysed in patients treated with irinotecan.\n\nConversely, in the other patients, a pretherapeutic DPYD-PGx was performed; thus they were treated with a starting halved dose of 5-FU, and no severe ADR were reported.\n\n3.2. Systematic Review\nA systematic review was performed to analyse the studies investigating the variability of responses to FP-based chemotherapy by DPYD genotyping combined with phenotyping methods and/or clinical monitoring.\n\nOf the potential 112 articles assessed for eligibility, after considering the inclusion and exclusion criteria, 22 studies were included in the analysis [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41]. Table 3 shows such studies subdivided with respect to the analysed DPYD polymorphisms (DPYD-PGx), the used phenotyping methods and the presence of clinical monitoring. A DPYD-PGx/clinical monitoring combination was present in 11, and DPYD-PGx/phenotyping in three, surveys. A DPYD-PGx/phenotyping/clinical monitoring combined approach was made in eight studies (Table 3). \n\nAmong the studies with a DPYD-PGx/clinical monitoring combination, five out of eleven studies confirmed the importance of DPYD variants in predicting FP-related toxicity, although a too-short clinical monitoring was performed (only two treatment cycles) [21,23,29,31,39]. Two studies [24,34] analysed only DPYD2A of the DPYD SNPs currently recommended. The first confirmed a strong association between DPYD2A and a severe and potentially fatal toxicity [24]. The second did not analyse this type of association because of the too-low DPYD2A allelic frequency found in the study population [34].\n\nLee et al., by testing 2886 patients, reported a significant association between DPYD2A and DPYD c.2846A>T and grade ≥3 FP ADR [26]. Similarly, Cremolini et al., in a large cohort of colon cancer patients who were treated with FOLFIRI or FOLFOXIRI plus bevacizumab, demonstrated that DPYD2A and DPYD c.2846A>T predicted FP-associated clinically relevant ADR [36]. Iachetta et al. analysed 668 out of 1827 patients enrolled in their study. The authors, first, confirmed the clinical relevance of DPYD c.2846A>T and DPYD13 in predicting FP safety. Second, they found a significant association between DPYD6 and severe neutropenia. Notably, no patients carrying DPYD2A (1.7%) had started a FP-based treatment [38]. Negarandeh et al. screened the presence of DPYD c.2846A>T, DPYD6 and DPYD2A in a population of 73 Iranian patients. DPYD c.2846A>T and DPYD6 were not found in the patient population analysed. However, a high allelic frequency for DPYD2A (5.5%) was reported. Surprisingly, Negarandeh et al. did not find any significant association between DPYD2A and severe toxicity [40]. \n\nA DPYD-PGx/phenotyping combined approach was performed in three studies that underlined the importance of complementing the DPYD-PGx with a phenotyping analysis. Gentile et al., by measuring the 5-FUDR (degradation rate) in peripheral blood mononuclear cells (PBMCs) utilising HPLC with MS/MS, found a significant correlation between several polymorphisms, including DPYD2A and DPYD c.2846A>T, and this phenotyping marker [27]. Jacobs et al. determined 5-FU clearance in the plasma of patients treated with capecitabine, finding that the presence of DPYD2A led to a 21.5% reduction in 5-FU elimination. Pallet et al. evaluated an approach based on the combination of the plasmatic UH2/U ratio and uracil concentration with genotyping of the four recommended DPYD SNPs. The main finding of this study was that complementing the DPYD-PGx with the plasmatic UH2/U ratio increased the possibility to identify patients at higher risks of severe FP-related toxicity [41]. Among the studies that performed a DPYD-PGx/phenotyping approach with clinical monitoring, four out of eight studies reported information about FP-related ADR until a maximum of three treatment cycles. \n\nJoerger et al. confirmed the importance of DPYD genotyping to identify patients at high risks of severe FP-related toxicity. Unfortunately, because of the low sample size of the study, they did not show conclusive results about the usefulness of plasmatic 5-FU clearance determination in improving the predictive potential of DPYD-PGx [28]. \n\nGalarza et al. found that salivary and plasmatic UH2 concentrations were inversely correlated with the ADR grade. However, given the low number of patients enrolled in the study, no DPYD variant allele carriers were identified [30].\n\nBoisdron et al. conducted a phase II study in 85 patients to test the efficacy of a pharmacogenetic-guiding dosing approach combined with the UH2/U ratio measurement. Despite a very large increase in drug dosages, a low incidence of severe ADR was shown in patients who used a guiding dosing approach. However, also in this case, it was not possible to conclude if this phenotyping analysis enhanced the predictability of DPYD genotyping because of the low sample size of the study [32]. Etienne et al. failed to demonstrate a correlation between DPYD variants and the plasmatic UH2/U ratio values. The authors concluded that only an extension of the genetic panel may improve the performance of DPYD-PGx for predicting severe and life-threatening ADR associated with capecitabine [33]. \n\nKuilenburg et al. measured the UH2/U ratio in PBMCs as an indirect assessment of DPYD activity. They demonstrated that patients with a low DPD activity experienced a more rapid onset of toxicity as compared to those with a normal enzymatic activity. Moreover, grade 4 neutropenia occurred in a substantial percentage (55%) of the patients with a decreased DPD activity as compared to that (13%) of subjects with a normal DPD activity. Notably, eleven out of fourteen patients suffering from severe ADR with a decreased enzymatic activity were identified as carriers of DPYD polymorphisms. In particular, six, four and one out of eleven patients carried DPYD2A, DPYD9A and DPYD6 in homozygosis, respectively [20]. Kristensen et al. also showed a significant correlation between the plasmatic UH2/U ratio and the presence of DPYD2A [22].\n\nFinally, in a prospective study, Henricks et al. analysed all the four recommended DPYD SNPs and performed two phenotyping tests by measuring the UH2/U ratio in PBMCs and plasmatic 5-FU pharmacokinetics (PK) by UHPLC-MS/MS. The patients carrying DPYD c.1236G>A and DPYD c.2846A>T were more likely to manifest FP-related severe toxicity as compared to wild-type subjects. In addition, the mean DPD enzyme activity was significantly lower in patients bearing these two genetic variants, as well as DPYD2A, as compared to other patients. Only one patient carrying DPYD13 showed a 60% DPD activity reduction. This patient was treated with a reduced 5-FU dosage for three treatment cycles, and no severe ADR occurred. Based on these results, the authors confirmed that a dose reduction of 50% in DPYD2A and DPYD13 carriers is appropriate, as issued in the PGx guidelines [35].\n\n4. Discussion\nFluoropyrimidines (FP) are the most-prescribed antineoplastic drugs in the world and represent the mainstay therapy for colorectal cancer. Unfortunately, 10–30% of the treated patients suffer from severe FP-related ADR [1].\n\nThe association between four DPYD variants and FP toxicity is now widely recognised, and it is also largely accepted that the pretherapeutic guiding dosing model based on the DPYD-PGx is a valid and cost-effective approach to manage FP-based chemotherapy. As a matter of fact, FP are included among the drugs with a pharmacogenetic warning [5], and the CPIC and DPWG guidelines are now followed in several countries, including Italy.\n\nHowever, DPYD-PGx is not yet routinely performed, and one of the aims of these consortia is to overcome the barriers preventing the implementation of the PGx into clinical practice. In March 2019, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommended to perform DPYD-PGx before starting treatment with FP. As in the CPIC and DPWG guidelines, the PRAC stated that 5-FU, capecitabine or tegafur must be avoided in the presence of a complete DPD deficiency. In the case of a partial DPD deficit, a reduced starting dose of FP should be considered [42].The PRAC recommendation was transferred to the Committee for Medicinal Products for Human Use (CHMP), and, on 7 July 2020, the EMA Commission raised a final decision that the DPYD-PGx should be performed in naïve oncological patients prior to starting a treatment with FP [43].\n\nA substantial percentage of patients with a DPYD variant associated with a deficit of DPD activity show grade > 2 toxicity [9]. For instance, it has been estimated that 73% of the patients who are carriers of DPYD2A suffer from grade ≥ 3 toxicity [24]. Therefore, the upfront DPYD-PGx has a crucial impact on the management of chemotherapy given that it may prevent 20–30% of life-threatening or lethal FP-related toxicity in Caucasian patients, revealing also a cost-effective approach [24,44].\n\nIn this regard, case 1 suffered from grade 3 neutropenia and grade 3 mucositis before the DPYD-PGx was required, which then revealed the presence of DPYD2A SNP. Notably, once the PGx results were obtained, the patient received 50% of the 5-FU dosage, and at the fourth and following cycles, there was no evidence for severe ADR.\n\nThe importance of performing a pretherapeutic DPYD-PGx is confirmed by the history of two other patients who had experienced grade 3 toxicity, with a different timing, before the test was requested. One of them was identified as DPYD2A heterozygous and the other one as DPYD c.2846 heterozygous. It is possible to conclude that FP-related severe toxicity may occur anytime during the therapy. The DPYD2A, which is a no-function variant, could be associated with a more premature ADR when compared with DPYD c.2846A>T SNP, which is classified as reduced-function variant. In fact, the subject bearing the DPYD2A suffered from grade 3 vomit at the second cycle, while the other patient, who was the carrier of the DPYD c.2846, suffered from the same toxicity but at the eighth cycle of chemotherapy.\n\nNotably, it has been estimated that a 30–50% of the patients treated with FP have no DPD deficit attributable to the four recommended DPYD SNPs, yet suffer from severe ADR [45]. In fact, several factors concur to determine the variability of responses to FP-based treatments. Among them, other polymorphisms in DPYD, and in other genes encoding enzymes involved in the pathway of the FP and, also, FP-associated drugs, may play an important role. In this regard, several studies have shown an association between the TYM-TSER 28-bp variant (in the gene encoding the FP molecular target) and FP-related toxicity [12,46]. Moreover, an increased risk of severe toxicity has been shown in patients carrying rs183205964 in the promoter enhancer region of TYMS [46].\n\nFinding the relationship between FP and specific ADR can be very difficult also, because FP are often administered with both traditional and biologic antineoplastic agents, such as cetuximab and bevacizumab. These drugs, as well as oxaliplatin and irinotecan, can cause diarrhoea and myelosuppression [47,48,49,50] similar to FP, and, as already mentioned, there are several genetic variants that are associated to these ADR and others.\n\nThe MTHFR is a critical enzyme involved in the synthesis of purine and thymidine and, in general, folate homeostasis. Two common SNPs (i.e., MTHFR-C677T and -A1298C), associated with a decrease of the MTHFR enzymatic activity, have been proposed as predictive factors of the response to cytotoxic agents, including FP, raltitrexed and methotrexate [51]. In addition, these two SNPs may exert a synergistic effect on the MTHFR activity [11]. A recent metanalysis failed to recognise the MTHFR polymorphisms (neither MTHFR-C677T nor -A1298C) as predicting factors for the response to FP-based treatment [52]. The data often contrast each other because of several reasons, including the type of cancer, dietary folate levels, therapy regimen and saturation level of the enzyme [51].\n\nOxaliplatin is mainly metabolised by glutathione-S-transferase P1 (GSTP1), and the SNP in this gene (i.e., GSTP1 A313G, Ile105val and rs1695) has been associated with severe ADR. Most of the evidence regards the occurrence of cumulative neuropathy associated with such a polymorphism [12,53], but the presence of at least one variant allele has been associated also with grade 3 or 4 gastrointestinal and haematological toxicity [54].\n\nIn a recent metanalysis, Lv et al. found an association between the GSTP1 rs1695 SNP and granulocytopenia induced by platinum derivatives [55]. Another metanalysis failed to demonstrate that this polymorphism can be considered a reliable predictive factor of oxaliplatin-related severe neurotoxicity [56]. At present, the data are inconclusive; therefore, only large, well-designed clinical trials will be able to clarify this issue.\n\nThe TYMS-TSER 28-bp tandem repeat is one of the more promising candidates as a genetic factor responsible for FP-related ADR. However, as reported in the last CPIC update, its clinical relevance is still debated [5].\n\nLecomte et al. found that patients who were carriers of the double-repeat allele (i.e., TYMS-TSER-2R) had more severe FP-associated ADR than the homozygous -3R/3R. In particular, the authors reported that patients bearing the -2R/2R genotype were 20 times more likely to suffer from severe toxicity compared with those who are carriers of the -3R/3R genotype. This could be related to a decreased TYMS mRNA expression in the normal tissue of subjects bearing a 2R/2R genotype that may lead to increased thymidylate synthase (TS) inhibition by FP treatment [11]. These findings refer to the somatic variant, while the data regarding the same germline polymorphism, which is identifiable by means of a peripheral blood sample, are inconclusive. Obviously, if the germline variant could be considered a predictive parameter like the somatic ones, a less-invasive method would be available to individualise the FP-based treatment in naïve patients. Several recent studies have suggested that the TYMS TSER germline polymorphism may be useful to prevent toxicity [57], such as hand-foot syndrome and other ADR types, including haematological and gastrointestinal ones [58]. With regards to the clinical cases described in Table 1, case 1 was homozygous TYMS TSER-2R/2R and case 2 and 3 were heterozygous 2R/3R.\n\nUndoubtedly, a larger panel of genetic variants is needed. On the other hand, further studies should be performed to support the regulatory authorities to decide whether and which new polymorphisms should be added to the four recommended DPYD SNPs in the PGx guidelines. Researchers’ efforts are addressed to find the best phenotyping methods to complement the DPYD-PGx. Among the different approaches proposed until now, the analysis of the 5-FU pharmacokinetic parameters was evaluated even before the DPYD-PGx introduction. In the eighties, in fact, a high individual variability of the plasmatic 5-FU clearance was demonstrated, and the existence of a correlation between the 5-FU levels and FP-related toxicity had already been highlighted [59].\n\nNowadays, it is possible to determine the 5-FU clearance using sophisticated techniques, such as HPLC coupled with tandem mass spectrometry (LC-MS/MS), which provides the precious opportunity to carry out TDM to adjust the therapy cycle-by-cycle where appropriate. Nonetheless, this approach is not always feasible in hospital settings and is unable to detect a DPD deficit prior to starting the treatment, thus preventing an early severe toxicity. Moreover, a 5-FU pharmacokinetic analysis aims at measuring the area under the curve (AUC) of the 5-FU plasma levels at the steady state (i.e., 2 h after the drug administration) and requires collecting multiple blood samples [14].\n\nThe CPIC and DPWG guidelines recommend to perform the DPYD-PGx and to treat the heterozygous patients with a dose reduction at the first cycle of chemotherapy and then titrate the dosage while performing a careful clinical monitoring and possibly TDM [5,6].\n\nAn ideal management workflow should consent to optimise FP-based therapy before treatment using the least invasive method; therefore, the researchers’ efforts have been addressed in this direction.\n\nThe measure of the plasmatic UH2/U ratio has been proposed as a suitable approach, but its validity is brought up for discussion. Indeed, some studies have demonstrated that this parameter well-correlates with 5-FU clearance and FP-related toxicity [22], while others have suggested that it can be considered a valid predictive factor during 5-FU administration alone [25]. Notably, determining the UH2/U ratio in peripheral blood mononuclear cells (PBMCs) seems to be the best method, but, unfortunately, it is a time-consuming procedure and requires radiolabelled reagents and large volumes of blood [20,35,60].\n\nImportantly, it seems that only a low plasmatic UH2/U ratio is a good predictive factor. For instance, Gamelin et al. suggested that a value less than 1.8 really helps to identify the patients at higher risk of FP-related toxicity [61]. To this line, Kristensen et al. studied 24 patients treated with FP who experienced FP severe-related toxicity, finding that 21 out of 24 subjects had a UH2/U ratio ≤4. They stated that the average UH2/U ratio decreased with the toxicity grade and proposed the value of 4 as the cut-off value [22]. Other authors have fixed the cut-off value at 6, specifying that the patients carrying one functional and one nonfunctional allele of DPYD (i.e., heterozygous) have a UH2/U ratio ranging from 1.5 to 6, while those who are carriers of two nonfunctional alleles (i.e., homozygous) have a value close to 0, corresponding to a complete DPD deficiency [62].\n\nBesides the patients described in Table 1, we have measured the plasmatic UH2/U ratio in another eight subjects who are all heterozygous for DPYD2A or DPYD c.2846A>T. We did not perform the pharmacokinetic analysis on these patients for several reasons (e.g., unavailability of the patients consents and changes of the therapy). It is important to underline that in six out of eight patients for whom a pretherapeutic DPYD-PGx was performed and the starting 5-FU dosage was halved, no severe toxicity was recorded (Table 2).\n\nIn the 11 patients we examined, the UH2/U ratio ranged between 1.77 and 7.38.\n\nThe fluctuation of the UH2/U ratio values as a predictive factor could reflect the variability of the DPD deficit that may range from 30% to 70% in the heterozygous patients. Nonetheless, the plasmatic UH2/U ratio could contribute to identifying, before beginning treatment, the subjects who are at-risk of severe or life-threatening ADR. Case 3 (reported in Table 1) exemplifies the complexity of the management of FP-based therapy. In fact, he had a very low (i.e., 1.7) plasmatic UH2/U ratio and continued suffering from severe toxicity despite the reduction of the 5-FU dosage. It is mandatory to bear in mind that this ratio remains a surrogate marker of DPD activity, and even if it was a more sensitive and specific parameter, several other variables may influence both the efficacy and tolerability of FP-based chemotherapy.\n\nThis is the reason why a combined genotyping/phenotyping approach, together with careful clinical monitoring, is the best way to personalise and optimise the therapy. Several studies have used this kind of approach, suggesting that phenotyping analyses, especially those based on the plasmatic 5-FU clearance and/or UH2/U ratio measurement, could successfully complement the DPYD-PGx in predicting FP-related toxicity. This is clearly shown by our systematic literature search (Figure 1 and Table 3).\n\nAs shown in Table 3, eight studies have combined DPYD-PGx with phenotyping methods and clinical monitoring, but only two out of eight have provided satisfactory clinical monitoring [28,35]. Indeed, to perform daily careful, clinical monitoring during all patients’ treatment cycles is very arduous. In fact, among these studies, three out of eight reported ADR only for two cycles [22,25,33], one out of eight monitored the toxicity until the third cycle [30] and two out of eight made clinical monitoring for two-to-three months [20,32].\n\nMoreover, as shown in Table 3, three studies have performed a combined DPYD-PGx/phenotyping [27,37,41] approach, and eleven carried out the DPYD-PGx together with clinical monitoring. However, among these, only 2/11 genotyped all the four DPYD SNPs recommended in the CPIC and DPWG guidelines [29,39]; the other studies performed at least one of such SNPs, together with other DPYD genetic variants [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40].\n\nThe main limitations of the studies performed until now are the lack of clinical monitoring throughout the entire course of chemotherapy and the scarce sample size. Moreover, the missing of the screening of one or more of the four DPYD-SNPs now recommended and the heterogeneity in the choice of other polymorphisms potentially useful to implement genotyping do not allow reaching conclusive results.\n\n5. Conclusions\nThe pretherapeutic DPYD-PGx represents an essential approach to personalise FP-based chemotherapy, minimising the risk of severe and life-threatening toxicity. This is confirmed by both the clinical cases here described and the literature data.\n\nNowadays, the regulatory agencies recommend carrying out the DPYD-PGx, including four DPYD polymorphisms (i.e., rs3918290, rs55886062, rs67376798 and rs75017182, HapB3) in patients who need to be treated with FP.\n\nDespite that these DPYD variants are strongly associated with treatment toxicity, other genetic and nongenetic factors concur to determine the variable response to FP-based chemotherapy.\n\nInitiating the FP with a reduced dosage is not a suitable option, because DPD deficits may range from 30% to 70% in the heterozygous patients who would experience a dangerous period of undertreatment.\n\nA pretherapeutic DPYD-PGx offers the possibility to avoid early ADR. Nonetheless, severe and even fatal FP-related toxicity may happen anytime during the therapy also in subjects having no DPD deficit attributable to the four recommended DPYD SNPs.\n\nOn the other hand, measuring the plasmatic 5-FU clearance—currently, the best method to perform TDM—does not permit to diagnose a possible DPD deficit prior to starting the treatment.\n\nTherefore, because both genetic and phenotypic tests show advantages and disadvantages, a combined genotyping/phenotyping approach, together with careful and continuous clinical monitoring, is the best diagnostic method to optimise the therapy with FP (Figure 2).\n\nAn accurate genotypic/phenotypic characterisation of each patient is essential not only to prevent severe toxicity associated with the cytotoxic agents but, also, to determine patients’ benefit-risk profiles to begin early the best therapeutic approach. This is of particular interest considering the current possibility to treat certain patients with anticancer agents, such as immune checkpoint inhibitors, that are changing the cancer therapeutic paradigm.\n\nAcknowledgments\nWe thank the native English-speaker Jan Festa, who revised the manuscript.\n\nAuthor Contributions\nConceptualisation, A.F., V.C., F.S. and S.P.; methodology, V.M., E.D.B., F.D.P., F.I., M.T., B.C. and A.C.; validation, V.C., B.S. and F.C.; investigation, V.C., V.M., E.D.B. and A.F.; resources, A.F. and V.C.; data curation, E.D.B., B.S., V.C., F.I. and T.I.; writing—original draft preparation, V.C., E.D.B., V.M., V.I. and M.T.; writing—review and editing, V.C., A.F., F.S., V.I. and F.D.P.; supervision, V.C. and A.F.; project administration, V.C., V.M. and A.F. and funding acquisition, A.F. and V.C. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nItalian Medicines Agency (AIFA) AVPM/17806/A (Rome, Italy) and Reti Oncologiche, Campania Region (2018) fund to A.F. at University Hospital of Salerno (Salerno, Italy) and University ORSA175354 fund (University of Salerno, Italy) to V.C.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nAbbreviations\nFP\tFluoropyrimidines\t\nDPD\tDihydropyrimidine Dehydrogenase\t\nDPYD-PGx\tDPYD-Pharmacogenomics\t\nPCR\tPolymerase Chain Reaction\t\n5-FU\t5-Fluorouracil\t\nADR\tAdverse Drug Reaction\t\nHFS\tHand-Foot Syndrome\t\nSNPs\tSingle-Nucleotide Polymorphisms\t\nCPIC\tThe Clinical Pharmacogenetics Implementation Consortium\t\nDPWG\tDutch Pharmacogenetics Working Group\t\nDPYD-AS\tDPYD-Activity Score\t\nTDM\tTherapeutic Drug Monitoring\t\nMTHFR\tMethylene-Tetrahydrofolate Reductase\t\nTYMS-TSER\tThymidylate Synthase-Thymidylate Synthase Enhancer Region\t\nGSTP1\tGlutathione S-Trasferase-p1\t\nUH2/U ratio\tDihydrouracil/Uracil Ratio\t\nCTC-AE\tCommon Terminology Criteria for Adverse Events\t\nRECIST \tResponse Evaluation Criteria in Solid Tumours\t\nHPLC\tHigh-Performance Liquid Chromatography\t\nUHPLC-MS/MS\tUltra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry\t\nMeSH\tMedical Subject Heading\t\nPRISMA\tPreferred Reporting Items for Systematic reviews and Meta-Analyses\t\nFOLFOX\t5-FU, Leucovorin and Oxaliplatin\t\nCT scan\tComputed Tomography Scan\t\nFOLFIRI\t5-FU, Leucovorin and Irinotecan\t\nPRAC\tPharmacovigilance Risk Assessment Committee \t\nEMA\tEuropean Medicines Agency\t\nCHMP\tCommittee for Medicinal Products for Human Use \t\nAUC\tArea Under the Curve\t\nLC-MS/MS\tLiquid Chromatography-Tandem Mass Spectrometry\t\nPBMCs\tPeripheral Blood Mononuclear Cells\t\nFigure 1 Flowchart of the databases searched. Exclusion criteria: (1) studies not including at least one of the four recommended DPYD polymorphisms and (2) other study designs (e.g., allelic frequencies estimation, no patients and methods for genotyping).\n\nFigure 2 This figure illustrates the main enzymatic reactions involved in the fluoropyrimidines (FP) pathway. The importance to perform, together with careful clinical monitoring, a genotyping/phenotyping combined approach is shown by using panels and arrows. The four recommended DPYD-SNPs, including in the DPYD-PGx, are listed, together with the other polymorphisms proposed as potential predictive factors of FP-related toxicity. Phenotyping methods (e.g., UH2/U ratio measured in plasma or PBMCs), which potential in predicting FP safety are currently under evaluation, are also described. An ideal flowchart to manage patients eligible for FP-based therapy is shown at the bottom of the figure. DPYD-PGx and the plasmatic UH2/U ratio have to perform one time (continuous line), while the plasmatic 5-FU clearance is throughout the entire course of the therapy (dotted line). The numbers located on the panels are the same reported in the flowchart in order to underline which genotyping and phenotyping markers may be used together to optimise the diagnosis and management of patients. Abbreviations: DPD, dihydropyrimidine dehydrogenase; DPYD-PGx, DPYD-pharmacogenomics; 5-FU, fluorouracil; DHFU, 5-fluoro-dihydrouracil; TP, thymidine phosphorylase; TK, thymidine kinase; FdUMP, 5-fluorodeoxyuridine monophosphate; TS, thymidylate synthase; dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate; dTTP, deoxythymidine triphosphate; 5,10-methylene-THF, 5,10-methylene-tetrahydrofolate; H2PteGlu(n), dihydrofolic acid; MTHFR, methylene-tetrahydrofolate reductase; 5-methyl-THF, 5,10-methyl-tetrahydrofolate; NADPH, nicotinamide adenine dinucleotide phosphate and TYMS-TSER, thymidylate synthase-thymidylate synthase enhancer region.\n\njpm-10-00113-t001_Table 1Table 1 Reports of the main characteristics of three patients with the occurrence of grade ≥ 3 ADR.\n\nPt\tSex\tAge (years)\tTumor Type and Stage\tChemotherapy Regimen\tPre-Therapeutic\nDPYD-PGx\tPost-Therapeutic\nDPYD-PGx\tDPYD\nGenotype\tUH2/U Ratio\t5-FU Dosage\t5-FU Clearance\tADR ≥ 3\tTotal Toxicity\t\n1\tM\t55\tCRC\n(metastatic)\tFolfox plus cetuximab\t/\tYes (C4)\tHeterozygous for DPYD2A\t4.52\tC1-C3: 100% C4-C6: 50%\t950 ng/mL (C4)\n400 ng/mL (C6)\tG3 mucositis (C3) G3 neutropenia (C3) (neuthrophils: 830.58 /mm3)\t7\t\n2\tM\t48\tCRC\n(metastatic)\tFolfox plus bevacizumab\tYes\t/\tHeterozygous for DPYD2A\t3.22\tC1-C8: 50%\t474 ng/mL (C1)\t/\t6\t\n3\tM\t60\tRectal cancer (metastatic)\tFolfox plus cetuximab)\tYes\t/\tHeterozygous for c.2846A>T\t1.77\tC1-C3: 50% C4: 40%\nC5-C6: 40% (only bolus)\t811 ng/mL (C2) 1093 ng/mL (C3) 1048 ng/mL (C4) 934 ng/mL (C5)\tG3 diarrhoea (C3)\nG4 diarrhoea (C4)\nG3 diarrhoea (C5)\t3\t\nPt, patient; M, male; CRC, colorectal cancer; FOLFOX, 5-fluorouracil plus leucovorin plus oxaliplatin; DPYD-PGx, DPYD pharmacogenetics; 5-FU, 5-fluorouracil; C, cycle; plasmatic UH2/U ratio, dihydrouracil/uracil ratio; ADR, adverse drug reaction; G, grade and total toxicity, number of ADR regardless of the grade of severity.\n\njpm-10-00113-t002_Table 2Table 2 Reports of 8 clinical cases for whom either pretherapeutic DPYD-PGx or post-therapeutic DPYD-PGx were performed. As phenotypic characteristics, the UH2/U ratio values were reported.\n\nPt\tSex\tAge\n(Years)\tTumor Type and Stage\tChemotherapy Regimen\tPre-Therapeutic\nDPYD-PGx\tPost-Therapeutic\nDPYD-PGx\tDPYD\nGenotype\tUH2/U Ratio\t5-FU Dosage\tADR ≥3\t\n1\tF\t63\tStomach cancer\n(locally advanced)\tFolfox\t/\tYes (C2)\tHeterozygous for DPYD2A\t7.09\tC1-C2: 100% C3: 5-FU withdrawal\tG3 vomit (C2)\t\n2\tM\t43\tCRC\n(metastatic)\tFolfiri with bevacizumab\t/\tYes (C8)\tHeterozygous for c.2846A>T\t3.88\tC1-C8: 100% C9: 50%\tG3 vomit (C8)\t\n3\tM\t63\tKidney cancer\n(metastatic)\tXeloda\tyes\t/\tHeterozygous for c.2846A>T\t6.57\tC1-C6: 50%\t/\t\n4\tM\t68\tCRC\n(metastatic)\tXelox\tyes\t/\tHeterozygous for c.2846A>T\t4.4\tC1-C7: 50%\t/\t\n5\tM\t78\tCRC\n(local)\tXelox\tyes\t/\tHeterozygous for c.2846A>T\t3.37\tC1-C2: 50%\t/\t\n6\tM\t72\tCRC\n(locally advanced)\tXelox\tyes\t/\tHeterozygous for DPYD2A\t5.15\tC1-C8: 50%\t/\t\n7\tF\t52\tVulva carcinoma\n(local)\tXeloda with cisplatin\tyes\t/\tHeterozygous for DPYD2A\t7.38\tC1-C5: 50%\t/\t\n8\tM\t76\tRectosigmoid cancer (locally advanced)\tFolfox\tyes\t/\tHeterozygous for DPYD2A\t2.44\tC1-C5: 50%\t/\t\nPt, patient; M, male; F, female; CRC, ColoRectal Cancer; FOLFOX, 5-Fluorouracil plus leucovorin plus oxaliplatin; FOLFIRI, 5-Fluorouracil plus leucovorin plus irinotecan; XELOX, capecitabine plus oxaliplatin; XELODA, Capecitabine; DPYD-PGx, DPYD pharmacogenetics; UH2/U RATIO, dihydrouracil/uracil ratio; ADR, Adverse Drug Reaction; C, cycle; G, Grade.\n\njpm-10-00113-t003_Table 3Table 3 The table reports the studies included in the systematic review and subdivided into three groups: DPYD-PGx/clinical monitoring combination, DPYD-PGx/phenotyping and DPYD-PGx/phenotyping/clinical monitoring. Abbreviations: PBMC, peripheral blood mononuclear cells; HPLC-UV, high-performance liquid chromatography-UV detector; LC-MS/MS, liquid chromatography-tandem mass spectrometry; 5-FUDR, 5-FU degradation rate; UHPLC-MS/MS, ultra-high-performance liquid chromatography-tandem mass spectrometry; PK, pharmacokinetics; FP, fluoropyrimidines; DPD, dihydropyrimidine dehydrogenase; UH2/U ratio, dihydrouracil/uracil ratio and AAS, atomic absorption spectrometry.\n\nFirst Author‘s Name (Published Year)\tEnrolled Patients (n)\tOutcomes\tDPYD-PGx/Clinical Monitoring\tDPYD-PGx/Phenotyping\tDPYD-PGx/Phenotyping/Clinical Monitoring\t\nKuilenburg et al. (2000) [20]\t37\tDPD activity and overall toxicity; DPYD genotyping in patients with reduced DPD activity.\t\n\t\n\tDPYD2A, c.2846A>T, DPYD6, DPYD9A, c.496A>G/ UH2/U ratio in PBMC/ADR until two treatment months.\t\nSchwab et al. (2008) [21]\t683\tOverall toxicity; DPYD, TYMS, MTHFR genotyping; sequencing of DPYD exome; influence of sex and promoter methylation on DPD expression in human liver.\tDPYD2A, c.2846A>T, c.623G>T, DPYD4, DPYD6, and c.2858G>C/ ADR reported until the second cycle of treatment.\t\n\t\n\t\nKristensen et al.(2010) [22]\t68\tRelationship between UH2/U plasma ratio and 5-FU-related early toxicity; relationship between 5-FU concentration and toxicity; IVS14+1G>A mutation screening.\t\n\t\n\tDPYD2A/ UH2/U ratio in plasma 5-FU clearance by HPLC-UV/ ADR reported until the second cycle of treatment.\t\nDeenen et al. (2011) [23]\t568\tRelationships between SNPs and toxicity, SNPs and dose modification of capecitabine, DPYD haplotypes and toxicity, DPYD SNPs and haplotypes and survival.\tDPYD2A, c.2846A>T and c.1236G>A [HapB3]/ ADR reported until the second cycle of treatment.\t\n\t\n\t\nDeenen et al. (2016) [24]\t2038\tFeasibility, safety and cost of DPYD2A genotype-guided dosing.\tDPYD2A/ADR reported until the sixth cycle of treatment.\t\n\t\n\t\nSistonen et al. (2014) [25]\t28\tRelationship between UH2/U plasma ratio and DPYD genetic variation; plasma concentration of 5-FU and corresponding AUC; toxicity.\t\n\t\n\tc.234-123G>C, c.496A>G, c.775A>G, c.1129-5923C>G [Hap B3], DPYD13, DPYD2A and c.2846A>T/ UH2/U ratio in plasma- 5-FU clearance by LC-MS/MS/ ADR reported until the second cycle of treatment.\t\nLee et al.(2014) [26]\t2886\tRelationship between DPYD variants and toxicity.\tDPYD2A, DPYD13, c.2846A>T/ ADR until the twelfth cycle of treatment.\t\n\t\n\t\nGentile et al. (2015) [27]\t156\tCorrelation between degradation rate of 5-FU with detected SNPs.\t\n\tDPYD2A, DPYD13, c.2846A>T/5-FUDR assay in PBMC by HPLC-MS/MS\t\n\t\nJoerger et al. (2015) [28]\t140\tQuantitative effect of 44 gene polymorphism in 16 drug pathway associated genes on progression free survival (PFS), on chemotherapy toxicity, on objective response rate (ORR), on overall survival (OS).\t\n\t\n\tDPYD13, DPYD2A, c.2846A>T, DPYD9A, c.1896T>C/5-FU clearance by AAS and HPLC/ADR until disease progression.\t\nLunenburg et al. (2016) [29]\t275\tEvaluation of requests of prospective DPYD screening and results with a dose recommendation; estimation of the follow up of the dose recommendations.\tDPYD2A, DPYD13, c.2846A>T, c.1236G>A [HapB3]/ ADR reported until the second cycle of treatment.\t\n\t\n\t\nGalarza et al. (2016) [30]\t60\tEstimation of the use of plasma and saliva; Uracil to UH2 metabolic ratio and DPYD genotyping.\t\n\t\n\tDPYD 2A, 13, c.557A>G, DPYD 7/ UH2/U ratio in plasma/ ADR reported until the third cycle of treatment.\t\nMilano et al. (2016) [31]\t243\tSequencing of DPYD exome and frequence of G3, G4 toxicity over cycle 1-2.\tDPYD2A, DPYD13, c.2846A>T, c.1774C>T, c.1475C>T, D342G/ ADR reported until the second cycle of treatment.\t\n\t\n\t\nBoisdron-Celle et al.(2017) [32]\t85\tUGT1A1 and DPYD genotyping; UH2/U ratio; follow up of efficacy and tolerance.\t\n\t\n\tDPYD2A, DPYD13, c.2846A>T, DPYD7/ UH2/U ratio in plasma/ADR every two weeks until three months.\t\nEtienne-Grimaldi et al.(2017) [33]\t243\tDPYD sequencing; relationship between toxicity and DPYD variants; DPD phenotyping.\t\n\t\n\tDPYD2A, DPYD13, c.2846A>T/ UH2/U ratio in plasma/ ADR reported until the second cycle of treatment.\t\nLiu et al.(2017) [34]\t661\tRelationship between UGT1A1 and DPYD polymorphism and incidence of severe neutropenia and diarrhea; relationship between UGT1A1 and DPYD variants and objective response rate, disease control rate, overall and progression free survival.\tDPYD5, c.1896 T > C, and DPYD2A/ ADR reported every two-three cycles or whenever patient’s condition changed.\t\n\t\n\t\nHenricks et al.(2018) [35]\t1181\tFrequency of severe overall FP-related toxicity; pharmacokinetics of fluoropyrimidines in DPYD variant allele carriers; DPD enzyme activity; cost analysis on individualised dosing by upfront DPYD genotyping.\t\n\t\n\tDPYD2A, c.2846A>T, DPYD13 and c.1236G>A [Hap B3]/ UH2/U ratio in PBMC/PK data by UHPLC-MS/MS/ADR until toxicity resolution.\t\nCremolini et al. (2018) [36]\t443\tRelationship between DPYD and UGT1A1 genotyping and toxicity.\tDPYD2A, 13, c.2846A>T/ADR reported until the fourth cycle of treatment.\t\n\t\n\t\nJacobs et al.(2019) [37]\t237\tPharmacokinetics of capecitabine and 5-FU in DPYD variant allele carriers.\t\n\tDPYD2A, c.2846A>T, c.1236G>A [HapB3]/5-FU clearance by LC MS/MS.\t\n\t\nIachetta et al.(2019) [38]\t1827\tRelationship between DPYD and toxicity.\tDPYD13, DPYD2A, c.2846A>T, DPYD6 /ADR reported until the eleventh cycle of treatment.\t\n\t\n\t\nKleinjan et al. (2019) [39]\t185\tDPYD genotyping and toxicity.\tDPYD2A, c.2846A>T, DPYD13 and c.1236G>A [HapB3] /ADR reported until the second cycle of treatment.\t\n\t\n\t\nNegarandeh et al.(2020) [40]\t88\tRelationship between DPYD genotyping and toxicity.\tDPYD2A, c.2846A>T, DPYD6/ADR reported following 227 cycles for 88 patients.\t\n\t\n\t\nNicolas Pallet et al.(2020) [41]\t5886\tRelationship between DPYD genotyping and [U] and UH2/U ratio in plasma.\t\n\tDPYD2A, DPYD13, c.2846A>T, c.1236G>A [HapB3]/ [U] and UH2/U ratio in plasma.\n==== Refs\nReferences\n1. Longley D.B. Harkin D.P. Johnston P.G. 5-Fluorouracil: Mechanisms of Action and Clinical Strategies Nat. Rev. Cancer 2003 3 330 338 10.1038/nrc1074 12724731 \n2. Venook A.P. Niedzwiecki D. Lenz H.-J. Innocenti F. Fruth B. Meyerhardt J.A. Schrag D. Greene C. O’Neil B.H. Atkins J.N. 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Milano G. Link between Dihydropyrimidine Dehydrogenase Activity in Peripheral Blood Mononuclear Cells and Liver Clin. Cancer Res. 1996 2 507 510 9816197 \n61. Gamelin E. Boisdron-Celle M. Guérin-Meyer V. Delva R. Lortholary A. Genevieve F. Larra F. Ifrah N. Robert J. Correlation between Uracil and Dihydrouracil Plasma Ratio, Fluorouracil (5-FU) Pharmacokinetic Parameters, and Tolerance in Patients with Advanced Colorectal Cancer: A Potential Interest for Predicting 5-FU Toxicity and Determining Optimal 5-FU Dosage J. Clin. Oncol. 1999 17 1105 1110 10.1200/JCO.1999.17.4.1105 10561167 \n62. Thomas F. Hennebelle I. Delmas C. Lochon I. Dhelens C. Tixidre C.G. Bonadona A. Penel N. Goncalves A. Delord J.P. Genotyping of a Family with a Novel Deleterious DPYD Mutation Supports the Pretherapeutic Screening of DPD Deficiency with Dihydrouracil/Uracil Ratio Clin. Pharmacol. Ther. 2016 99 235 241 10.1002/cpt.210 26265035\n\n", "fulltext_license": "CC BY", "issn_linking": "2075-4426", "issue": "10(3)", "journal": "Journal of personalized medicine", "keywords": "DPD; DPYD polymorphisms; fluoropyrimidines; personalised medicine; pharmacogenetics; therapeutic drug monitoring", "medline_ta": "J Pers Med", "mesh_terms": null, "nlm_unique_id": "101602269", "other_id": null, "pages": null, "pmc": null, "pmid": "32899374", "pubdate": "2020-09-03", "publication_types": "D016428:Journal Article; D016454:Review", "references": "16707601;28632865;31745289;29487697;11304782;30238837;23695028;30858516;15355920;29152729;30628914;19097774;27181275;23856855;29906295;28481884;18299612;11156223;26573078;28395759;25555855;20362666;21498394;27399164;31838077;31652031;26099996;27454530;30131855;22454320;28637434;9816197;25677447;17064846;30510603;10561167;8630950;32595208;20926004;26216193;26189437;17115185;12724731;24923815;32546132;30723313;25381393;28024938;18635751;26265035;30348537;18781847;23604281;20530282;25410891", "title": "A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature.", "title_normalized": "a genotyping phenotyping approach with careful clinical monitoring to manage the fluoropyrimidines based therapy clinical cases and systematic review of the literature" }	[ { "companynumb": "IT-FRESENIUS KABI-FK202011881", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { 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"drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN CALCIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LYMPH NODES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM FOLINATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078811", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LYMPH NODES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Palmar-plantar erythrodysaesthesia syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stomatitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash erythematous", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash maculo-papular", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anal fissure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CONTI V, DE BELLIS E, MANZO V, SABBATINO F, IANNELLO F, PIAZ F. A GENOTYPING/PHENOTYPING APPROACH WITH CAREFUL CLINICAL MONITORING TO MANAGE THE FLUOROPYRIMIDINES-BASED THERAPY: CLINICAL CASES AND SYSTEMATIC REVIEW OF THE LITERATURE. JOURNAL OF PERSONALIZED MEDICINE. 2020?10(113):1-25.", "literaturereference_normalized": "a genotyping phenotyping approach with careful clinical monitoring to manage the fluoropyrimidines based therapy clinical cases and systematic review of the literature", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201111", "receivedate": "20201111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18490304, "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": "IT-TEVA-2020-IT-1849076", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES OF FOLFOX AND THEREAFTER ONE CYCLE WITH CETUXIMAB", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES EACH OF FOLFOX AND FOLFIRI", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES ALONG WITH FOLFOX REGIMEN AND THEREAFTER ONE CYCLE WITH OXALIPLATIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40333", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIATED AT 50% DOSE REDUCTION; RECEIVED 6 CYCLES EACH OF FOLFIRI AND FOLFOX REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5-FLUOROURACIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES OF FOLFIRI AND THEREAFTER CONTINUED WITH BEVACIZUMAB", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES ALONG WITH FOLFIRI AND THEREAFTER CONTINUED WITH IRINOTECAN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "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": "5", "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash maculo-papular", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CONTI V, DE BELLIS E, MANZO V, SABBATINO F, IANNELLO F, PIAZ FD, ET AL. A GENOTYPING/PHENOTYPING APPROACH WITH CAREFUL CLINICAL MONITORING TO MANAGE THE FLUOROPYRIMIDINES-BASED THERAPY: CLINICAL CASES AND SYSTEMATIC REVIEW OF THE LITERATURE. J-PERS-MED 2020?10(3):1-24.", "literaturereference_normalized": "a genotyping phenotyping approach with careful clinical monitoring to manage the fluoropyrimidines based therapy clinical cases and systematic review of the literature", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201201", "receivedate": "20201201", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18566676, "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": "IT-TEVA-2020-IT-1849073", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "40333", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5?FLUOROURACIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40333", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5?FLUOROURACIL" } ], "patientagegroup": "5", "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Palmar-plantar erythrodysaesthesia syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash erythematous", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin fissures", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash maculo-papular", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stomatitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CONTI V, DE BELLIS E, MANZO V, SABBATINO F, IANNELLO F, PIAZ FD, ET AL. A GENOTYPING/PHENOTYPING APPROACH WITH CAREFUL CLINICAL MONITORING TO MANAGE THE FLUOROPYRIMIDINES?BASED THERAPY: CLINICAL CASES AND SYSTEMATIC REVIEW OF THE LITERATURE. J?PERS?MED 2020?10(3):1?24.", "literaturereference_normalized": "a genotyping phenotyping approach with careful clinical monitoring to manage the fluoropyrimidines based therapy clinical cases and systematic review of the literature", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210121", "receivedate": "20201201", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18566679, "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": "IT-PFIZER INC-2020384474", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTRIC CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTRIC CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLINIC ACID" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078813", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTRIC CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CONTI, V.. A GENOTYPING/PHENOTYPING APPROACH WITH CAREFUL CLINICAL MONITORING TO MANAGE THE FLUOROPYRIMIDINES-BASED THERAPY: CLINICAL CASES AND SYSTEMATIC REVIEW OF THE LITERATURE. JOURNAL OF PERSONALIZED MEDICINE. 2020?10 (3):1-25", "literaturereference_normalized": "a genotyping phenotyping approach with careful clinical monitoring to manage the fluoropyrimidines based therapy clinical cases and systematic review of the literature", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201015", "receivedate": "20201008", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18362215, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]
{ "abstract": "Rituximab has been associated with the development of cytomegalovirus enterocolitis in immunosuppressed patients. A 51-year-old patient with diffuse large B-cell lymphoma who received a conditioning chemotherapy regimen (RCVP and RICE) consisting of rituximab before bone marrow transplantation went on to develop cytomegalovirus enterocolitis. This supports evidence from previously described cases that rituximab may be associated with cytomegalovirus enterocolitis.", "affiliations": null, "authors": "Seewoodhary\|Jason\|J\|", "chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab", "country": "United States", "delete": false, "doi": "10.3748/wjg.v12.i45.7391", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "12(45)", "journal": "World journal of gastroenterology", "keywords": null, "medline_ta": "World J Gastroenterol", "mesh_terms": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003586:Cytomegalovirus Infections; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D016896:Treatment Outcome", "nlm_unique_id": "100883448", "other_id": null, "pages": "7391", "pmc": null, "pmid": "17143963", "pubdate": "2006-12-07", "publication_types": "D002363:Case Reports; D016420:Comment; D016422:Letter", "references": "10458242;16610013", "title": "Cytomegalovirus enterocolitis in a patient with diffuse large B-cell lymphoma after chemotherapy with rituximab.", "title_normalized": "cytomegalovirus enterocolitis in a patient with diffuse large b cell lymphoma after chemotherapy with rituximab" }	[ { "companynumb": "GB-PFIZER INC-2009226220", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200408", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071868", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", 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{ "abstract": "Postoperative visual loss is a rare but devastating complication of non-ophthalmic surgery. Its aetiology is poorly understood and multiple associated factors have been proposed. We present a report of a 33-year-old female who developed irreversible diminution of vision on the right eye (non-arteritic-posterior-ischemic-optic-neuropathy) following general anaesthesia for pedicle screw fixation and plating for fracture vertebrae and hip in prone position and then screw placement for fracture calcaneum in supine position. The vision loss, limited to finger count close to face on the right eye, did not improve till follow-up at one-year. The combination of mild intraoperative hypotension, anaemia, prone positioning, prolonged surgery and anaesthesia may have contributed to postoperative visual loss in our patient. Keywords: ischaemic optic neuropathy; postoperative visual loss; spine surgery.", "affiliations": "Department of Anaesthesia and Intensive Care, Kathmandu Medical College, Sinamangal, Kathmandu, Nepal.;Department of Anaesthesia and Intensive Care, Kathmandu Medical College, Sinamangal, Kathmandu, Nepal.;Department of Anaesthesiology and Critical care, B.P. Koirala Insitute of Health Sciences, Dharan, Nepal.", "authors": "Bhandari\|Sabin\|S\|;Pokharel\|Krishna\|K\|;Sah\|Birendra Prasad\|BP\|", "chemical_list": null, "country": "Nepal", "delete": false, "doi": null, "fulltext": "\n==== Front\nJNMA J Nepal Med Assoc\nJNMA J Nepal Med Assoc\nJ Nepal Med Assoc\nJNMA\nJNMA: Journal of the Nepal Medical Association\n0028-2715\n1815-672X\nJournal of the Nepal Medical Association\n\n10.31729/jnma.4539\nCase Report\nPostoperative Visual Loss Following Spine Surgery: A Case Report\nBhandari Sabin 1\nPokharel Krishna 1\nSah Birendra Prasad 1\n1 Department of Anaesthesiology and Critical Care, B.P. Koirala Institute of Health Sciences, Dharan, Nepal\nCorrespondence: Dr. Sabin Bhandari, Department of Anaesthesiology and Critical Care, B. P. Koirala Institute of Health Sciences, Dharan, Nepal. Email: [email protected], Phone: +9779851161225.\n8 2019\n31 8 2019\n57 218 269271\n© The Author(s) 2018.\n2018\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open-Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nABSTRACT\n\nPostoperative visual loss is a rare but devastating complication of non-ophthalmic surgery. Its aetiology is poorly understood and multiple associated factors have been proposed. We present a report of a 33-year-old female who developed irreversible diminution of vision on the right eye (non-arteritic-posterior-ischemic-optic-neuropathy) following general anaesthesia for pedicle screw fixation and plating for fracture vertebrae and hip in prone position and then screw placement for fracture calcaneum in supine position. The vision loss, limited to finger count close to face on the right eye, did not improve till follow-up at one-year. The combination of mild intraoperative hypotension, anaemia, prone positioning, prolonged surgery and anaesthesia may have contributed to postoperative visual loss in our patient.\n\nKeywords\n\nischaemic optic neuropathy\npostoperative visual loss\nspine surgery\n==== Body\npmcINTRODUCTION\n\nPostoperative visual loss (POVL) is a rare, devastating complication of non-ophthalmic surgery. Its incidence is variable from 0.05 to 1.3% and mostly reported after cardiac (incidence 0.09%) and spinal (incidence 0.03%) surgery.1,2 However, the exact incidence and aetiology remains unknown as most cases of postoperative vision loss following spine surgery are mentioned as case reports, which are difficult to obtain as the cases are often subject to malpractice claims, resulting in a lack of public access to case reports.\n\nCASE REPORT\n\nA 33-year-old female, weighing 70 kg, was scheduled for pedicle screw fixation at T11-L3, open reduction internal fixation for fracture hip and closed reduction and cortico-cancellous screw for calcaneum fracture for a five-day-old traumatic anterior wedge compression fracture L1 vertebrae without neurological deficit, fracture left iliac blade and fracture calcaneum without distal neurovascular damage.\n\nHer pre-anaesthetic check-up revealed anaemia (hemoglobin 9.4 gm/dl). After induction of general anaesthesia, her eyes were padded with cotton gauze and she was placed prone. The head was placed on a horse shoe in a neutral position. We ensured that pressure was not exerted on the eyes. The abdomen was also checked for free movement. After three and half hours of prone positioning, she was made supine for surgery on the hip and calcaneum. We followed the routine departmental anaesthesia protocol for induction, maintenance and reversal of anaesthesia. We maintained mean arterial pressure (MAP) from 60 to 70 mmHg (20% below baseline) during the manipulation of spine with IV esmolol 5 mg boluses and IV nitroglycerin 50 -100 mcg boluses for two hours. MAP was maintained close to baseline for the remaining period. Heart rate was maintained at 100-120/min. Estimated blood loss was 700 ml. One unit of packed red cells was transfused after the hemostasis was secured. Urine output was 75–100 ml/h. The surgery lasted for four and half hours.\n\nIn the orthopaedics in-patient unit, the patient complained of painless diminution of vision in the right eye. An ophthalmologist was consulted. In the right eye, vision was limited to finger count close to face. Intraocular pressure was normal. A dense apparent pupillary defect was present. Anterior segments were normal. Fundal examination showed normal discs and maculae without swelling or pallor or retinal hemorrhage. Visual evoked potential showed perception of light with absent visual evoked response. There was no abnormality on the left eye. A diagnosis of non-arteritic posterior ischemic optic neuropathy of right eye was made. IV methylprednisolone 250 mg four times a day for three days followed by tapering dose of tab prednisolone over 15 days was administered. Other aspects of recovery from surgery was unremarkable. On regular follow-up for one year in the ophthalmology out-patient-service, her visual acuity did not improve.\n\nDISCUSSION\n\nThe aetiology of post-operative visual loss is poorly understood. Proposed risk factors include obesity, cardiovascular disease, hyper-lipidemia, diabetes, smoking, male gender, intraoperative hypotension, prone positioning, less usage of colloids, prolonged procedures and anaesthesia.3\n\nThe American Society of Anaesthesiologists (ASA) closed claim database analysis of 93 patients with postoperative visual loss after spine surgery from 1999 to June 2005 revealed 89% had ischaemic optic neuropathy (ION) while 10% had central retinal arterial occlusion. Among the patients developing ION, majority (60%) had posterior ischaemic optic neuropathy (PION).4\n\nOur patient was anaemic. We also induced deliberate hypotension (MAP 20 % below baseline but around 60 – 70 mm Hg) for two hours. Although these two are the most commonly blamed risk factors, the ASA report does not suggest any independent effect of anaemia or intraoperative mean arterial pressure drop of more than 40% below baseline for 30 congruent or additive minutes on postoperative blindness.5 Our patient did not have decreased urine output or ECG changes that may reflect reduced end organ perfusion due to hypotension.\n\nAnother risk factor for postoperative visual loss is increased intraocular tension by direct pressure on the globe or raised central venous pressure (CVP) due to head-down position, rotation of head or direct pressure on the abdomen during prone positioning. We had ensured that these factors were absent. However, the prone position itself can significantly increase intraocular pressure which could be normalized by 10° reverse trendelenberg position.6,7 We did not take this precaution. An analysis of the reports of spine procedures obtained from the Anaesthesia Closed Claims Project database (2000 to 2014) found that prone positioning and surgical duration of ≥4 hours were associated with permanent disabling injuries to nerves, spinal cord, and eyes or visual pathways.8 The duration of surgery in our patient was four and a half hours.\n\nIt is likely that the combination of preoperative anaemia, intraoperative mild to moderate hypotension, prone positioning, prolonged surgery and anaesthesia resulted in a reduced perfusion pressure to the optic nerve and hence, visual loss in our patient. We strongly feel that we should have corrected the preoperative anaemia and also staged the last part of surgery after a few days instead of performing it in a single setting. The practice of deliberate hypotension for all spine surgery in prone position also warrants some caution.\n\nIn conclusion, both anaesthesiologist and surgeon need to be aware that a number of risk factors which, when combined, can cumulatively increase the risk of postoperative visual loss. A thorough preoperative evaluation to identify high risk patients should be performed and they should be informed about the risk of POVL. Whenever possible, staged procedure to reduce surgical duration should be considered. During surgery, a 10° reverse trendelenburg position should be maintained with the neck in a neutral forward position. Direct ocular pressure must be prevented, and the anaesthesiologist should have unobstructed access to the patient's eyes for repeat positioning checks. Normocarbia should be maintained, prolonged decrease in blood pressure should be corrected and deliberate hypotension should only be used with extreme caution at high risk patients. Monitoring the haemoglobin values frequently and avoiding anaemia are other preventive measures. Postoperatively, the vision of a high-risk patient should be assessed once the patient becomes alert and if there is concern regarding potential visual loss, an urgent ophthalmologic consultation should be obtained. Also, maintaining 30–45° head-up position postoperatively, if feasible, to limit orbital oedema is another preventive measure.1,2,6,7,8,9,10\n\nConsent:\n\nJNMA Case Report Consent Formwas signed by the patient and the original is attached with the patient's chart.\n\nConflict of Interest:\n\nNone.\n==== Refs\nREFERENCES\n\n1. Kitaba A Martin DP Gopalakrishnan S Tobias JD Perioperative visual loss after nonocular surgery J Anesth 2013 Dec 27 6 919 26 10.1007/s00540-013-1648-y 23775280\n2. Chwalisz B Gilbert AL Gittinger JW Jr Perioperative Vision Loss after Non-Ocular Surgery Semin Ophthalmol 2018 33 1 17 22 10.1080/08820538.2017.1353807 28881162\n3. Mendel E Stoicea N Rao R Niermeyer W Revilla S Cluse M et al Revisiting Postoperative Vision Loss following Non-Ocular Surgery: A Short Review of Etiology and Legal Considerations Front Surg 2017 4 34 10.3389/fsurg.2017.00034 28695122\n4. Lee LA Roth S Posner KL Cheney FW Caplan RA Newman NJ et al The American Society of Anesthesiologists Postoperative Visual Loss Registry: analysis of 93 spine surgery cases with postoperative visual loss Anesthesiology 2006 Oct 105 4 652 9 10.1097/00000542-200610000-00007 17006060\n5. Postoperative Visual Loss Study Group Risk factors associated with ischemic optic neuropathy after spinal fusion surgery Anesthesiology 2012 Jan 116 1 15 24 10.1097/ALN.0b013e31823d012a 22185873\n6. Hunt K Bajekal R Calder I Meacher R Eliahoo J Acheson JF Changes in intraocular pressure in anaesthetised prone patients J Neurosurg Anesthesiol 2004 Oct 16 4 287 90 15557832\n7. Ozcan MS Praetel C Bhatti MT Gavenstein N Mahla ME Seubert CN The effect of body inclination during prone positioning on intraocular pressure in awake volunteers: a comparison of two operating tables Anesth Analg 2004 Oct 99 4 1152 8 10.1213/01.ANE.0000130851.37039.50 15385367\n8. Kutteruf R Wells D Stephens L Posner KL Lee LA Domino KB Injury and liability associated with spine surgery J Neurosurg Anesthesiol 2018 Apr 30 2 156 62 10.1097/ANA.0000000000000448 28763433\n9. American Society of Anesthesiologists Task Force on Perioperative Vision loss Practice advisory for perioperative vision loss associated with spine surgery: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Vision loss Anesthesiology 2012 Feb 116 2 274 85 10.1097/ALN.0b013e31823c104d 22227790\n10. Practice Advisory for Perioperative Visual Loss Associated with Spine Surgery 2019 An Updated Report by the American Society of Anesthesiologists Task Force on Perioperative Visual Loss, the North American Neuro-Ophthalmology Society, and the Society for Neuroscience in Anesthesiology and Critical Care Anesthesiology 2019 Jan 130 12 30 10.1097/ALN.0000000000002503 30531555\n\n", "fulltext_license": "CC BY", "issn_linking": "0028-2715", "issue": "57(218)", "journal": "JNMA; journal of the Nepal Medical Association", "keywords": null, "medline_ta": "JNMA J Nepal Med Assoc", "mesh_terms": "D000328:Adult; D000740:Anemia; D000768:Anesthesia, General; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018917:Optic Neuropathy, Ischemic; D056888:Patient Positioning; D065289:Pedicle Screws; D011183:Postoperative Complications; D013131:Spine; D014786:Vision Disorders", "nlm_unique_id": "0045233", "other_id": null, "pages": "269-271", "pmc": null, "pmid": "32323661", "pubdate": "2019", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Postoperative Visual Loss Following Spine Surgery: A Case Report.", "title_normalized": "postoperative visual loss following spine surgery a case report" }	[ { "companynumb": "NP-FRESENIUS KABI-FK201912728", "fulfillexpeditecriteria": "1", "occurcountry": "NP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ESMOLOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "040", "drugauthorizationnumb": "076573", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE MANAGEMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESMOLOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NITROGLYCERIN" }, "drugadditional": null, "drugadministrationroute": "040", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "50-100 MCG", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE MANAGEMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLYCERYL TRINITRATE" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "70", "reaction": [ { "reactionmeddrapt": "Optic ischaemic neuropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "BHANDARI S, POKHAREL K, PRASAD SAH B. POSTOPERATIVE VISUAL LOSS FOLLOWING SPINE SURGERY: A CASE REPORT. J NEPAL MED ASSOC. 2019?VOL. 57:269-271.", "literaturereference_normalized": "postoperative visual loss following spine surgery a case report", "qualification": "3", "reportercountry": "NP" }, "primarysourcecountry": "NP", "receiptdate": "20191118", "receivedate": "20191118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17043955, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]
{ "abstract": "Immunotherapy for cancer treatment continues to evolve, and immune checkpoints have proven successful therapeutic targets. With success has come the challenge of managing the commonly associated immune-related toxicities. Arthralgias and arthritis are a common immune-related adverse event (IrAE), well described in the literature (Pardoll Nat Rev Cancer 12:252-264, 2012; Diesendruck and Benhar Drug Resist Updat 30:39-47, 2017; Cappelli et al. Arthritis Care Res 69:1751-1763, 2017; Brahmer et al. J Clin Oncol 36:1714-1768, 2018; Smith and Bass (2017). The optimal management of immune checkpoint inhibitor (ICI)-induced arthritis remains unclear. We describe the first series using hydroxychloroquine as a first-line disease-modifying antirheumatic drug (DMARD) for patients without pre-existing autoimmune disease, who developed arthritis secondary to ICI's. This was a single-center retrospective observational study reporting all patients evaluated by rheumatologists affiliated with the University of Alberta, a large tertiary health care center in Northern Alberta, Canada, deemed to have inflammatory arthritis (IA) following ICIs. We identified 11 patients, without pre-existing autoimmune disease, who developed IA following ICIs. Most patients presented with a symmetrical polyarthritis with both large and small joint involvement. All patients were treated according to the outlined treatment protocol with hydroxychloroquine as a first-line steroid-sparing agent: either as monotherapy or in combination with tapering doses of systemic corticosteroids (3) or intra-articular steroid injections (6). One patient required the addition of methotrexate to control symptoms and none required biologic therapy. There were no reported adverse effects from hydroxychloroquine. Inflammatory arthritis is an important complication of ICIs leading to significant impact on patient quality of life. In our experience, in patients without pre-existing autoimmune disease, hydroxychloroquine is an effective first-line therapy for IA secondary to ICI therapy.", "affiliations": "Division of Rheumatology, Department of Medicine, Dalhousie University, Suite 245 Nova Scotia Rehabilitation Building, 1341 Summer Street, Halifax, NS, B3H 4K4, Canada. [email protected].;Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.;Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.;Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.;Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.;Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.;Division of Rheumatology, Department of Medicine, University of Alberta, 8-120 Clinical Sciences Building, 8440 112 St NW, Edmonton, AB, T6G 2G3, Canada.;Division of Rheumatology, Department of Medicine, University of Alberta, 8-120 Clinical Sciences Building, 8440 112 St NW, Edmonton, AB, T6G 2G3, Canada.", "authors": "Roberts\|Janet\|J\|http://orcid.org/0000-0002-3787-8541;Smylie\|Michael\|M\|;Walker\|John\|J\|;Basappa\|Naveen S\|NS\|;Chu\|Quincy\|Q\|;Kolinsky\|Michael\|M\|;Lyddell\|Christopher\|C\|;Ye\|Carrie\|C\|", "chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor; D006886:Hydroxychloroquine", "country": "Germany", "delete": false, "doi": "10.1007/s10067-019-04451-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0770-3198", "issue": "38(5)", "journal": "Clinical rheumatology", "keywords": "Autoimmune disease; Hydroxychloroquine; Immunotherapy; Inflammation; Neoplasms", "medline_ta": "Clin Rheumatol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000416:Alberta; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D060908:CTLA-4 Antigen; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D061026:Programmed Cell Death 1 Receptor; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D016896:Treatment Outcome", "nlm_unique_id": "8211469", "other_id": null, "pages": "1513-1519", "pmc": null, "pmid": "30701346", "pubdate": "2019-05", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": "4856023;28363334;29442540;27307501;28830882;29162153;28405474;28600350;21398612;22343096;26687632;26282644;29146737;28514612", "title": "Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor-induced inflammatory arthritis.", "title_normalized": "hydroxychloroquine is a safe and effective steroid sparing agent for immune checkpoint inhibitor induced inflammatory arthritis" }	[ { "companynumb": "CA-009507513-1906CAN004862", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEMBROLIZUMAB" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "125514", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KEYTRUDA" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune-mediated adverse reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Polyarthritis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ROBERTS J, SMYLIE M, WALKER J, BASAPPA NS, CHU Q, KOLINSKY M, ET AL.. HYDROXYCHLOROQUINE IS A SAFE AND EFFECTIVE STEROID-SPARING AGENT FOR IMMUNE CHECKPOINT INHIBITOR?INDUCED INFLAMMATORY ARTHRITIS. CLINICAL RHEUMATOLOGY. 2019?38(5):1513-9", "literaturereference_normalized": "hydroxychloroquine is a safe and effective steroid sparing agent for immune checkpoint inhibitor induced inflammatory arthritis", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190924", "receivedate": "20190614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16429188, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "CA-009507513-1906CAN004861", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PEMBROLIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "125514", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "UNK", "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": "KEYTRUDA" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune-mediated adverse reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Immune-mediated adverse reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Polyarthritis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ROBERTS J, SMYLIE M, WALKER J, BASAPPA NS, CHU Q, KOLINSKY M, ET AL.. HYDROXYCHLOROQUINE IS A SAFE AND EFFECTIVE STEROID-SPARING AGENT FOR IMMUNE CHECKPOINT INHIBITOR?INDUCED INFLAMMATORY ARTHRITIS. CLINICAL RHEUMATOLOGY. 2019?38(5):1513-9", "literaturereference_normalized": "hydroxychloroquine is a safe and effective steroid sparing agent for immune checkpoint inhibitor induced inflammatory arthritis", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190925", "receivedate": "20190614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16429128, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "CA-009507513-1906CAN004864", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PEMBROLIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125514", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KEYTRUDA" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune-mediated adverse reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oligoarthritis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ROBERTS J, SMYLIE M, WALKER J, BASAPPA NS, CHU Q, KOLINSKY M, ET AL.. HYDROXYCHLOROQUINE IS A SAFE AND EFFECTIVE STEROID-SPARING AGENT FOR IMMUNE CHECKPOINT INHIBITOR?INDUCED INFLAMMATORY ARTHRITIS. CLINICAL RHEUMATOLOGY. 2019?38(5):1513-9", "literaturereference_normalized": "hydroxychloroquine is a safe and effective steroid sparing agent for immune checkpoint inhibitor induced inflammatory arthritis", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190921", "receivedate": "20190614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16429526, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "CA-009507513-1906CAN002848", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PEMBROLIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125514", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KEYTRUDA" } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune-mediated adverse reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Oligoarthritis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ROBERTS J, SMYLIE M, WALKER J, BASAPPA NS, CHU Q, KOLINSKY M, ET AL.. HYDROXYCHLOROQUINE IS A SAFE AND EFFECTIVE STEROID-SPARING AGENT FOR IMMUNE CHECKPOINT INHIBITOR?INDUCED INFLAMMATORY ARTHRITIS. CLINICAL RHEUMATOLOGY. 2019?38(5):1513-9", "literaturereference_normalized": "hydroxychloroquine is a safe and effective steroid sparing agent for immune checkpoint inhibitor induced inflammatory arthritis", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190924", "receivedate": "20190614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16429459, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "CA-009507513-1906CAN004865", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEMBROLIZUMAB" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "125514", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "KEYTRUDA" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune-mediated enterocolitis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Polyarthritis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Immune-mediated adverse reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ROBERTS J, SMYLIE M, WALKER J, BASAPPA NS, CHU Q, KOLINSKY M, ET AL.. HYDROXYCHLOROQUINE IS A SAFE AND EFFECTIVE STEROID-SPARING AGENT FOR IMMUNE CHECKPOINT INHIBITOR?INDUCED INFLAMMATORY ARTHRITIS. CLINICAL RHEUMATOLOGY. 2019?38(5):1513-9", "literaturereference_normalized": "hydroxychloroquine is a safe and effective steroid sparing agent for immune checkpoint inhibitor induced inflammatory arthritis", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190614", "receivedate": "20190614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16429439, "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": "CA-009507513-1906CAN004863", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PEMBROLIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "125514", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "UNK", "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": "KEYTRUDA" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune-mediated adverse reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Polyarthritis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ROBERTS J, SMYLIE M, WALKER J, BASAPPA NS, CHU Q, KOLINSKY M, ET AL.. HYDROXYCHLOROQUINE IS A SAFE AND EFFECTIVE STEROID-SPARING AGENT FOR IMMUNE CHECKPOINT INHIBITOR?INDUCED INFLAMMATORY ARTHRITIS. CLINICAL RHEUMATOLOGY. 2019?38(5):1513-9", "literaturereference_normalized": "hydroxychloroquine is a safe and effective steroid sparing agent for immune checkpoint inhibitor induced inflammatory arthritis", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190614", "receivedate": "20190614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16429280, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]
{ "abstract": "The efficacy and safety of rituximab against B-cell lymphomas is well established. However, there has been an increased incidence of infectious complications after rituximab treatment, mostly hepatitis B reactivation and progressive multifocal leukoencephalopathy. This is the case of a 67-year-old patient with primary central nervous system lymphoma, who developed cytomegalovirus meningoencephalitis after receiving high-dose chemotherapy and rituximab. As there was no evidence of lymphoma relapse or additional immunosuppression, besides his previous treatment, an association between rituximab and cytomegalovirus meningoencephalitis cannot be ruled out.", "affiliations": "*1st Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School †Immunology and HLA Histocompatibility Laboratory ‡Department of Neurology, Laiko General Hospital §Department of Hematology, Athens Medical Center-Psychikon Branch, Athens, Greece.", "authors": "Siakantaris\|Marina P\|MP\|;Argyropoulos\|Kimon V\|KV\|;Ioannou\|Savvas\|S\|;Papadopoulou\|Vasiliki\|V\|;Tzeletas\|George\|G\|;Tsonis\|John\|J\|;Dimitrakopoulou\|Aglaia\|A\|;Yiannopoulou\|Konstantina G\|KG\|;Pangalis\|Gerassimos A\|GA\|;Vaiopoulos\|George\|G\|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab", "country": "United States", "delete": false, "doi": "10.1097/NRL.0b013e318287fde0", "fulltext": null, "fulltext_license": null, "issn_linking": "1074-7931", "issue": "19(2)", "journal": "The neurologist", "keywords": null, "medline_ta": "Neurologist", "mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D016543:Central Nervous System Neoplasms; D003586:Cytomegalovirus Infections; D006801:Humans; D008223:Lymphoma; D008297:Male; D008590:Meningoencephalitis; D000069283:Rituximab", "nlm_unique_id": "9503763", "other_id": null, "pages": "35-7", "pmc": null, "pmid": "25607329", "pubdate": "2015-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cytomegalovirus meningoencephalitis after rituximab treatment for primary central nervous system lymphoma.", "title_normalized": "cytomegalovirus meningoencephalitis after rituximab treatment for primary central nervous system lymphoma" }	[ { "companynumb": "GR-ACCORD-090633", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGHDOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE/CYTARABINE HYDROCHLORIDE/CYTARABINE OCFOSFATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HD-MTX", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningoencephalitis viral", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SIAKANTARIS MP, ARGYROPOULOS KV, IOANNOU S, PAPADOPOULOU V, TZELETAS G, TSONIS J ET AL. CYTOMEGALOVIRUS MENINGOENCEPHALITIS AFTER RITUXIMAB TREATMENT FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA. NEUROLOGIST. 2015?19(2):35-37. DOI:10.1097/NRL.0B013E318287FDE0.", "literaturereference_normalized": "cytomegalovirus meningoencephalitis after rituximab treatment for primary central nervous system lymphoma", "qualification": "1", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20181103", "receivedate": "20181103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15582998, "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": "GR-PFIZER INC-2018413657", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (2 CYCLES OF HIGH-DOSE METHOTREXATE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CENTRAL NERVOUS SYSTEM LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071868", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (HIGH-DOSE CYTARABINE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CENTRAL NERVOUS SYSTEM LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, WEEKLY (ADDITIONAL 6 CYCLES, WEEKLY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CENTRAL NERVOUS SYSTEM LYMPHOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalitis cytomegalovirus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SIAKANTARIS, M.. CYTOMEGALOVIRUS MENINGOENCEPHALITIS AFTER RITUXIMAB TREATMENT FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA. NEUROLOGIST. 2015?19 (2):35-37", "literaturereference_normalized": "cytomegalovirus meningoencephalitis after rituximab treatment for primary central nervous system lymphoma", "qualification": "1", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20181029", "receivedate": "20181012", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15494469, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "BACKGROUND\nIn our previous study, colorectal cancer (CRC) patients with active Mycobacterium tuberculosis (MTB) tolerated concurrent anti-cancer chemotherapy (anti-CCT) and anti-MTB chemotherapy. In this study, we retrospectively confirmed the efficacy and safety of concurrent chemotherapy in a greater number of patients with different types of malignancies.\n\n\nMETHODS\nWe enrolled 30 patients who were treated concurrently with anti-CCT and anti-MTB regimens between January 2006 and February 2016. Cancer and MTB treatments were administered according to the approved guidelines.\n\n\nRESULTS\nPatient demographics included: men/woman: 24/6; median age: 66.5 years; Eastern Cooperative Oncology Group performance status 0-1/2/3-4: 24/4/2; Stage IIB-IIIC/IV/recurrence: 6/22/2; lung cancer (LC)/CRC/other: 15/10/5; and MTB diagnosis (before or during anti-CCT): 20/10 (LC: 8/7; CRC: 8/2; other: 4/1). For anti-CCT, 23 patients received two cytotoxic agents with or without targeted agents and 7 patients received a single cytotoxic or targeted agent. The overall response rate was 36.7%. Regarding anti-MTB chemotherapy, 22 patients received a daily drug combination containing isoniazid, rifampicin, and ethambutol, plus pyrazinamide in 15 of the 22 patients, followed by daily isoniazid and rifampicin; the remaining 8 patients received other combinations. Hematological adverse events of Grade ≥ 3 were observed in 19 (67.9%) of 28 patients; laboratory data were lost for the remaining 2. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies (P < 0.005). Non-hematological adverse events of Grade ≥ 3 were observed in 5 (16.7%) of 30 patients. One CRC patient experienced Grade 3 hemoptysis and another 2 experienced Grade 3 anaphylaxis. One patient with cholangiocellular carcinoma and gastric cancer experienced Grade 3 pseudomembranous colitis as a result of a Clostridium difficile infection. One patient (3.3%) died of pemetrexed-induced pneumonitis. The success of the anti-MTB chemotherapy was 70.0%. There were no MTB-related treatment failures. The median overall survival (months, 95.0% confidence interval) was 10.5 (8.7-36.7), 8.7 (4.7-10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) for all patients combined, LC, CRC, and Other malignancies, respectively. LC patients experienced delayed MTB diagnosis and shorter overall survival.\n\n\nCONCLUSIONS\nConcurrent chemotherapy is effective and safe for treating cancer patients with active MTB.", "affiliations": "Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan. [email protected].;Departments of Clinical Laboratory, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Infectious Diseases, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Infectious Diseases, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Gynecology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Breast Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Thoracic Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Gastroenterological Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Gastroenterological Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Gastroenterological Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Infectious Diseases, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.", "authors": "Hirashima\|Tomonori\|T\|;Tamura\|Yoshitaka\|Y\|;Han\|Yuki\|Y\|;Hashimoto\|Shoji\|S\|;Tanaka\|Ayako\|A\|;Shiroyama\|Takayuki\|T\|;Morishita\|Naoko\|N\|;Suzuki\|Hidekazu\|H\|;Okamoto\|Norio\|N\|;Akada\|Shinobu\|S\|;Fujishima\|Makoto\|M\|;Kadota\|Yoshihisa\|Y\|;Sakata\|Kazuya\|K\|;Nishitani\|Akiko\|A\|;Miyazaki\|Satoru\|S\|;Nagai\|Takayuki\|T\|", "chemical_list": "D000970:Antineoplastic Agents; D000995:Antitubercular Agents", "country": "England", "delete": false, "doi": "10.1186/s12885-018-4889-1", "fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 488910.1186/s12885-018-4889-1Research ArticleEfficacy and safety of concurrent anti-Cancer and anti-tuberculosis chemotherapy in Cancer patients with active Mycobacterium tuberculosis: a retrospective study Hirashima Tomonori [email protected] 1Tamura Yoshitaka [email protected] 2Han Yuki [email protected] 3Hashimoto Shoji [email protected] 3Tanaka Ayako [email protected] 1Shiroyama Takayuki [email protected] 1Morishita Naoko [email protected] 1Suzuki Hidekazu [email protected] 1Okamoto Norio [email protected] 1Akada Shinobu [email protected] 4Fujishima Makoto [email protected] 5Kadota Yoshihisa [email protected] 6Sakata Kazuya [email protected] 7Nishitani Akiko [email protected] 7Miyazaki Satoru [email protected] 7Nagai Takayuki [email protected] 31 Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 2 Departments of Clinical Laboratory, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 3 Departments of Infectious Diseases, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 4 Departments of Gynecology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 5 Departments of Breast Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 6 Departments of Thoracic Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 7 Departments of Gastroenterological Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 12 10 2018 12 10 2018 2018 18 97519 8 2017 2 10 2018 © The Author(s). 2018Open 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\nIn our previous study, colorectal cancer (CRC) patients with active Mycobacterium tuberculosis (MTB) tolerated concurrent anti-cancer chemotherapy (anti-CCT) and anti-MTB chemotherapy. In this study, we retrospectively confirmed the efficacy and safety of concurrent chemotherapy in a greater number of patients with different types of malignancies.\n\nMethods\nWe enrolled 30 patients who were treated concurrently with anti-CCT and anti-MTB regimens between January 2006 and February 2016. Cancer and MTB treatments were administered according to the approved guidelines.\n\nResults\nPatient demographics included: men/woman: 24/6; median age: 66.5 years; Eastern Cooperative Oncology Group performance status 0–1/2/3–4: 24/4/2; Stage IIB–IIIC/IV/recurrence: 6/22/2; lung cancer (LC)/CRC/other: 15/10/5; and MTB diagnosis (before or during anti-CCT): 20/10 (LC: 8/7; CRC: 8/2; other: 4/1). For anti-CCT, 23 patients received two cytotoxic agents with or without targeted agents and 7 patients received a single cytotoxic or targeted agent. The overall response rate was 36.7%. Regarding anti-MTB chemotherapy, 22 patients received a daily drug combination containing isoniazid, rifampicin, and ethambutol, plus pyrazinamide in 15 of the 22 patients, followed by daily isoniazid and rifampicin; the remaining 8 patients received other combinations. Hematological adverse events of Grade ≥ 3 were observed in 19 (67.9%) of 28 patients; laboratory data were lost for the remaining 2. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies (P < 0.005). Non-hematological adverse events of Grade ≥ 3 were observed in 5 (16.7%) of 30 patients. One CRC patient experienced Grade 3 hemoptysis and another 2 experienced Grade 3 anaphylaxis. One patient with cholangiocellular carcinoma and gastric cancer experienced Grade 3 pseudomembranous colitis as a result of a Clostridium difficile infection. One patient (3.3%) died of pemetrexed-induced pneumonitis. The success of the anti-MTB chemotherapy was 70.0%. There were no MTB-related treatment failures. The median overall survival (months, 95.0% confidence interval) was 10.5 (8.7–36.7), 8.7 (4.7–10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) for all patients combined, LC, CRC, and Other malignancies, respectively. LC patients experienced delayed MTB diagnosis and shorter overall survival.\n\nConclusions\nConcurrent chemotherapy is effective and safe for treating cancer patients with active MTB.\n\nKeywords\nConcurrent chemotherapyTuberculosisBreast cancerColorectal cancerEfficacyGastric cancerLung cancerSafetyissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nMycobacterium tuberculosis (MTB) represents the leading cause of death from an infectious disease worldwide [1], with the majority of cases occurring in Asia (61.0%) and Africa (26.0%). Incidence and mortality rates are noticeably higher in Japan than other developed countries [1].\n\nAlthough active MTB infections may be present in cancer patients, our previous preliminarily report [2] is the only study to discuss the clinical course and chemotherapy outcomes of concurrent anti-cancer chemotherapy (anti-CCT) and anti-MTB chemotherapy, revealing that patients with metastatic colorectal cancer (CRC) and active MTB could safely and effectively continue anti-CCT, and achieve comparable survival to those without the infection, upon receiving appropriate MTB treatment [2].\n\nIn this study, we retrospectively examined the clinical course and chemotherapy outcomes of a larger number of patients treated concurrently with anti-CCT and anti-MTB chemotherapy.\n\nMethods\nStudy approval\nThe present retrospective study was approved by the Institutional Review Board (IRB) of the Osaka Habikino Medical center on 30 January 2017 (approval number: 808–1). The board waived the requirement for informed written consent due to the anonymous nature of the data, and no risk of exposure to subjects.\n\nPatient selection\nWe enrolled 30 cancer patients with active MTB who were treated concurrently with anti-CCT and anti-MTB chemotherapy at our institution between January 1, 2006 and February 29, 2016. The 6 metastatic CRC patients with active MTB from our previous study [2] were also included.\n\nClinical review\nAs described previously, [2] the clinical history of eligible patients was retrospectively reviewed. We collected baseline demographic data and anti-CCT data, which were also collected from clinical records or pharmacy database. Complete history and physical examinations; surgical reports; findings of flexible bronchoscopy, colonoscopy, and esophagogastroduodenoscopy; imaging investigations; pathological reports, and blood test results were available for all patients at the time of anti-MTB chemotherapy.\n\nMTB diagnosis\nAs described previously [2], MTB diagnosis was performed by smears and cultures of various patients’ specimens or chest computed tomography (CT) image in patients without microbiological evaluation. The method of choice for confirming MTB infection was Ziehl-Neelsen staining of sputum smear samples [3]. Polymerase chain reaction (PCR) or loop-mediated isothermal amplification (LAMP) [4] was performed for patients with positive sputum smears to distinguish MTB from other mycobacteria. If the sputum smears were negative or specimens other than sputum were obtained, the diagnosis of MTB was confirmed by culturing mycobacterial organisms. Drug sensitivity was determined for all cases with positive culture. Liquid media with the Mycobacteria Growth Indicator Tube (MGIT) [5] and solid media with the Ogawa-Kudoh method [6] were both used for culturing mycobacteria. Drug sensitivity was determined for all cases. Quantitative drug susceptibility testing for MTB was performed using the MTB-I® (Kyokuto Pharmaceutical Industrial Co., Ltd., Tokyo, Japan) modified Minimum Inhibitory Concentration method [7].\n\nTreatment of MTB infection\nAs described previously [2], in cancer patients with active MTB, appropriate anti-MTB agents were administered for approximately 1.5 months prior to anti-CCT, according to the American Thoracic Society and Infectious Diseases Society of America guidelines [8] A multi-drug resistant MTB, based on the sensitivity test, negated the initiation of anti-CCT. Since MTB patients with severe complications often require longer courses of treatment than those without such complications, patients treated with anti-CCT also received long-term treatment for MTB. Thus, the patients received 2 months of isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z), followed by HR for 7 months, or 6 months of HRE, followed by HR for 6 months as standard anti-MTB chemotherapy. The majority of patients who could not be treated with standard anti-MTB chemotherapy, due to side effects or drug resistance, were treated with a levofloxacin (X)-based regimen.\n\nFollow-up MTB culture\nAfter commencing anti-MTB chemotherapy, sputum specimens were cultured every other week for the first 3 months. Once two consecutive sputum cultures were negative, cultures were done monthly until the course of MTB treatment was completed.\n\nDefinition of MTB treatment outcomes\nMTB treatment outcomes were based on the World Health Organization’s definitions [9]. Treatment success included “cure” and “treatment completed”. A “cured” patient was defined as one who had completed the planned treatment and had two consecutive negative cultures. Patients with treatment failure had positive cultures ≥5 months into MTB treatment.\n\nCancer staging and treatment\nCancer staging and treatment were performed according to the guidelines of the respective lung cancer (LC) [10], CRC [11], gastric cancer (GC) [12], breast cancer, [13], and cholangiocellular carcinoma (CCA) [14] societies.\n\nThe policy of our institution was to commence anti-CCT immediately if patients were sensitive to anti-MTB agents. However, if patients were resistant or had experienced intolerable side effects while awaiting sensitivity test, anti-CCT was suspended until a decision could be reached concerning the appropriate drug combination and duration of anti-MTB chemotherapy. Additionally, when MTB cultures could not be obtained, due to a number of reasons, or the physician could not await the results of the sensitivity test due to rapid tumor progression, anti-CCT was commenced, following informed patient consent.\n\nAssessment of anti-cancer chemotherapy outcomes\nPatients’ best response to chemotherapy was collected from the records of weekly meetings at our institution and clinical summaries. Based on the Response Evaluation Criteria in Solid Tumors [15], the responses of tumors to cytotoxic agents were categorized as complete or partial responses and stable or progressive disease. Tumor responses that could not be assessed were recorded as “not evaluable”. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0 [16].\n\nStatistical analyses\nOverall survival (OS) was measured from the date of commencing concurrent chemotherapy (for both cancer and MTB) to the date of death or last follow-up (February 28, 2017). OS rates were estimated using the Kaplan-Meier method [17]. The duration of concurrent chemotherapy was defined as the time from commencing concurrent chemotherapy to the end date. All statistical analyses were conducted using R statistical software (version 3.2.0). Patient background data were analyzed using chi-square and Fisher’s exact test for categorical variables. A P < 0.05 was considered statistically significant.\n\nResults\nPatient demographics\nIn total, 30 cancer patients with active MTB who were treated concurrently with anti-CCT and anti-MTB chemotherapy between January 1, 2006 and February 29, 2016 at our institution, were enrolled in this study. Fifteen patients were diagnosed with LC (non-small cell LC [NSCLC, n = 10] and small cell LC [SCLC, n = 5]), 10 patients were diagnosed with CRC (rectal cancer [n = 7], sigmoid cancer [n = 2], and transverse colon cancer [n = 1]), and 5 patients were diagnosed with other malignancies (GC [n = 1], Breast Cancer [n = 1], LC with GC [n = 1], CRC with GC [n = 1], and CCA with GC [n = 1]). The patient demographics are summarized in Table 1. No significant differences in patient demographics were observed among LC, CRC, and other malignancy groups. However, LC patients tended to be more frequently diagnosed with active MTB during anti-CCT in comparison to those with CRC or other malignancy.Table 1 Patient Characteristics\n\nCharacteristic\tPatients\t\nAll\tLC\tCRC\tOther\t\n(n = 30)\t(n = 15)\t(n = 10)\t(n = 5)\t\nSex, n (%)\t\n M\t24 (80.0)\t12 (80.0)\t8 (80.0)\t4 (80.0)\t\n F\t6 (20.0)\t3 (20.0)\t2 (20.0)\t1 (20.0)\t\nAge (years), median (range)\t66.5 (39–79)\t68.0 (43–79)\t62.5 (43–75)\t56.0 (39–75)\t\nECOG PS, n (%)\t\n 0–1\t24 (80.0)\t12 (80.0)\t8 (80.0)\t4 (80.0)\t\n 2\t4 (13.3)\t3 (20.0)\t0 (0.0)\t1 (20.0)\t\n 3\t2 (6.7)\t0 (0.0)\t2 (20.0)\t0 (0.0)\t\nStage, n (%)\t\n IIB-IIIA\t3 (10.0)\t2 (13.3)\t0 (0.0)\t1 (20.0)\t\n IIIB-ΙΙΙC\t3 (10.0)\t2 (13.3)\t0 (0.0)\t1 (20.0)\t\n IV\t22 (73.3)\t10 (66.7)\t9 (90.0)\t3 (60.0)\t\nPostoperative recurrence, n (%)\t2 (6.7)\t1 (6.7)\t1 (10.0)\t0 (0.0)\t\nLine of cancer chemotherapy at the commencement of concurrent chemotherapy, n (%)\t\n Adjuvant\t1 (3.3)\t0 (0.0)\t0 (0.0)\t1 (20.0)\t\n First\t21 (70.0)\t9 (60.0)\t8 (80.0)\t4 (80.0)\t\n Second\t3 (10.0)\t3 (20.0)\t0 (0.0)\t0 (0.0)\t\n Third or higher\t5 (16.7)\t3 (20.0)\t2 (20.0)\t0 (0.0)\t\nDiabetes mellitus, n (%)\t\n Y\t7 (20.7)\t3 (20.0)\t2 (20.0)\t2 (40.0)\t\n N\t23 (79.3)\t12 (80.0)\t8 (80.0)\t3 (60.0)\t\nMTB diagnosis, n (%)\t\n Before anti-CCT\t20 (66.7)\t8 (53.3)\t8 (80.0)\t4 (80.0)\t\n During anti-CCT\t10 (33.3)\t7 (46.7)\t2 (20.0)\t1 (20.0)\t\nAbbreviations CCT cancer chemotherapy, CRC colorectal cancer, ECOG Eastern Cooperative Oncology Group, F female, LC lung cancer, M male, MTB Mycobacterium tuberculosis, N no, PS performance status, Y yes\n\n\n\nChest CT imaging\nThoracic CT findings at the time of MTB diagnosis is presented in Fig. 1 (a-d). These CT images present a combination of thick and thin walled lung cavities, infiltration shadows, and multiple nodules. There were no consistent findings on CT imaging based on the type of malignancy.Fig. 1 Thoracic computed tomography findings in 4 cancer patients with active Mycobacterium tuberculosis. a Non-small cell lung cancer patient with a thick wall cavity in the left lung with an infiltration shadow in the right upper lobe. b Colorectal cancer patient with multiple nodules in both lungs. c Breast cancer patient with a small cavity with an infiltration shadow in the right upper lobe. d Non-small cell lung cancer patient with multiple small nodules with partial patty follicular spot in the both lungs and cavity formation in the S6 segment of the right lung and lingular segment of the left lung\n\n\n\nBacteriological examinations\nThe findings of bacteriological examinations are summarized in Table 2. Twenty (66.7%) patients had MTB-positive sputum smears. In 25 (83.3%) cultures were positive for MTB and negative cultures were reported in 5 (16.7%). Cultures were negative for MTB in 3 LC and 2 CRC patients. In the former, active MTB was diagnosed by PCR of sputum in 2 cases and LAMP of sputum in 1, alongside CT results, while in the latter, the diagnosis was confirmed by PCR of sputum in one, and the results of the CT scan and clinical course in the other.Table 2 Bacteriological Examinations\n\nCharacteristic\tPatients\t\nAll\tLC\tCRC\tOther\t\n(n = 30)\t(n = 15)\t(n = 10)\t(n = 5)\t\nSputum smear, n (%)\t\n Negative\t10 (33.3)\t5 (33.3)\t3 (30.0)\t2 (40.0)\t\n Positive\t20 (66.7)\t10 (66.7)\t7 (70.0)\t3 (60.0)\t\nPCR/LAMP, n (%)\t\n Negative\t1 (3.3)\t1 (6.7)\t0 (0.0)\t0 (0.0)\t\n Positive\t15 (50.0)\t10 (66.7)\t3 (30.0)\t2 (40.0)\t\n Unknown\t14 (46.7)\t4 (26.7)\t7 (70.0)\t3 (60.0)\t\nCulture, n (%)\t\n Negative\t5 (16.7)\t3 (20.0)\t2 (20.0)\t0 (0.0)\t\n Positive\t25 (83.3)\t12 (80.0)\t8 (80.0)\t5 (100.0)\t\nSensitivity to anti-MTB agents, n (%)\t\n Sensitive\t22 (88.0)\t12 (100.0)\t6 (75.0)\t4 (80.0)\t\n Resistant\t2 (8.0)a\t0 (0.0)\t2 (25.0)\t0 (0.0)\t\n Unknown\t1 (4.0)b\t0 (0.0)\t0 (0.0)\t1 (20.0)b\t\nTime until the result of Bacteriological Examination come out\t\n\tOverall\tOgawa-Kudoh\tMGIT\t\nTime to MTB-positive culture (days), mean ± SD, n\t20.9 ± 12.4\n(n=23c)\t37.6 ± 8.4\n(n = 5)\t16.2 ± 8.7\n(n = 18)\t\nTime to sensitivity testing (days), mean ± SD, n\t12.6 ± 3.5\n(n=22d)\t\t\t\nAbbreviations CRC colorectal cancer, LAMP loop-mediated isothermal amplification, LC lung cancer, MGIT Mycobacteria Growth Inhibitor Tube, MTB = Mycobacterium tuberculosis, PCR polymerase chain reaction, NTM Nontuberculous Mycobacteriosis\n\nP < 0.0005\n\naOne MTB strain was resistant to isoniazid and streptomycin, another was isoniazid and pyrazinamide\n\nbOne specimen with MTB-positive cultures and concomitant NTM was not used for sensitivity testing\n\ncIn two specimens, measure of the time to MTB-positive cultures were not possible because the culture specimens were obtained in other institutes\n\ndTwenty-two cultures except one which was concomitant NTM and two which was obtained in other institute\n\n\n\nIn the 25 cases positive for MTB, 22 (88.0%) were sensitive, 2 (8.0%) were resistant (one MTB strain was resistant to H and streptomycin, another to H and Z), and 1 (4.0%) was not tested for sensitivity because of concomitant Nontuberculous Mycobacteriosis. In 2 of 25 patients with MTB-positive cultures, the time to MTB-positive culture could not be confirmed because the culture specimens were obtained in other institutes. Therefore, the time to MTB-positive culture in 23 patients was demonstrated by MGIT (n = 18) and Ogawa-Kudoh method (n = 5). The time (days: mean ± SD) to MTB-positive cultures was significantly shorter for MGIT than for the Ogawa-Kudoh method (16.2 ± 8.7 vs 37.6 ± 8.4; P < 0.0005). Furthermore, the time (days: mean ± SD) to sensitivity testing in 22 patients except one with concomitant Nontuberculous Mycobacteriosi was 12.6 ± 3.5.\n\nMTB treatment until concurrent chemotherapy\nOf the 30 patients enrolled in this study, 4 received X-based regimen from the start of MTB treatment due to resistant to INH (n = 2), past history of RFP-induced systemic eruption (n = 1), and preventing the drug interaction between erlotinib and RFP via CYP3A4 (n = 1).\n\nIn 2 of 4 patients the X-based regimen was changed to a different regimen due to renal dysfunction in one and liver dysfunction in the other.\n\nIn 4 patients the planned HREZ or HRE regimen was changed to X-based regimen due to drug eruption (n = 1), drug eruption and liver dysfunction (n = 1), thrombocytopenia (n = 1), and preventing the drug interaction between Paclitaxel and RFP via CYP3A4 and CYP2C8 (n = 1). Subsequently, 8 patients received concurrently X-based regimens and anti-CCT. The remaining 22 patients received concurrent HREZ or HRE and anti-CCT as planned, without many adverse events except in one patient who experienced a paradoxical response on day 23 after starting HREZ and was kept on HREZ while taking prednisolone. Thus, until concurrent chemotherapy, 6 (20.0%) of the 30 patients experienced adverse events with MTB treatment alone, and in 5 the planned MTB treatment was changed to other regimens.\n\nOutcomes of concurrent chemotherapy\nDetails of the initial concurrent anti-CCT regimens are listed in Table 3. Twenty-three patients (76.7%) received intensive anti-CCT regimens with or without targeted agents, 5 patients (16.7%) received a single cytotoxic agent, and 2 patients (6.7%) received a single targeted agent. The overall response rates (ORRs) were 36.7, 33.3 40.0, and 40.0% for all patients combined, LC patients, CRC patients, and patients with other malignancies, respectively. In 15 LC patients, all 5 patients with SCLC received intensive cytotoxic treatment (carboplatin plus etoposide) as first line chemotherapy (Table 3) with a high response rate (80%). Of 10 NSCLC patients, 4 (40%) received platinum doublets as intensive first regimen, and one of them achieved partial response. In the remaining 6 patients (60%), one received platinum doublets, three were administered single cytotoxic agent, and two received erlotinib as re-challenge regimen. They received those regimens as second-line or later anti-CTT and there was no responder.Table 3 Outcomes of Anti-Cancer Chemotherapy (Anti-CCT) and Anti-MTB Chemotherapy\n\nCharacteristic\tPatients\t\nAll\tLC (SCLC/NSCLC)\tCRC\tOther\t\n(n = 30)\t(n = 15, 5/10)\t(n = 10)\t(n = 5)\t\nInitial concurrent anti-CCT regimen, n\t\n Intensive cytotoxic regimen and targeted agenta\t4\t0\t3\t1\t\n Intensive cytotoxic regimenb\t19\t10 (5/5)\t6\t3\t\n Single targeted agentc\t2\t2 (0/2)\t0\t0\t\n Single cytotoxic agentd\t5\t3 (0/3)\t1\t1\t\nBest response on anti-CCT after commencing concurrent chemotherapy, n\t\n CR\t1\t0\t1\t0\t\n PR\t10\t5 (4/1)\t3\t2\t\n SD\t5\t2 (0/2)\t3\t0\t\n PD\t6\t4 (0/4)\t2\t0\t\n NE\t8\t4 (1/3)\t1\t3\t\nORR (%)e\t36.7\t33.3 (80.0/10.0)\t40.0\t40.0\t\nMain anti-MTB chemotherapy, n\t\n 2HREZ/7HRf\t15\t8 (3/5)\t4\t3\t\n 6HRE/6HRg\t7\t2 (0/2)\t4\t1\t\n Levofloxacin-based\t8\t5 (2/3)\t2\t1\t\nDuration of anti-MTB treatment (days), median (range)\t275.0 (72–637)\t274.0 (90–469) [274 (183–469)/255 (90–310)]\t259.0 (72–539)\t368.0 (273–637)\t\nDuration of concurrent chemotherapy (days), median (range)\t157.5 (13–408)\t117.0 (20–245) [93 (20–207)/121 (48–245)]\t168.5 (13–408)\t155.0 (51–376)\t\nMTB treatment outcomes, n (%)\tAll\tLC\tCRC\tOther\t\n Cured\t20 (66.7)\t10 (66.7)\t6 (60.0)\t4 (80.0)\t\n Completed\t1 (3.3)\t0\t1 (10.0)\t0\t\n Died\t9 (30)\t5 (33.3)\t3 (30.0)\t1 (20.0)\t\n Failed\t0\t0\t0\t0\t\n Not evaluated\t0\t0\t0\t0\t\nSuccess (%)h\t70.0\t66.7\t70.0\t80.0\t\nAbbreviations CI confidence interval, CR complete response, CRC colorectal cancer, E ethambutol, EGFR-TKI epidermal growth factor receptor-tyrosine kinase inhibitor, H isoniazid, LC lung cancer, MTB Mycobacterium tuberculosis, NE not evaluable, ORR overall response rate, PD progressive disease, PR partial response, R rifampicin, SD stable disease, Z pyrazinamide\n\naTwo cytotoxic agents combined with targeted therapy (bevacizumab or trastuzumab)\n\nbTwo cytoxic agents\n\ncErlotinib\n\ndSingle cytoxic agent (S-1, vinorelbine, or pemetrexed)\n\neCR + PR\n\nfDaily drug combination containing HREZ for 2 months, followed by daily HR for 7 months\n\ngDaily drug combination containing HRE for 6 months, followed by HR for 6 months\n\nhCured + completed\n\n\n\nThe main anti-MTB regimens were as follows: HREZ/HR (n = 15 patients; LC [n = 8], CRC [n = 4], other [n = 3]); HRE/HR (n = 7 patients; LC [n = 2], CRC [n = 4], other [n = 1]); and X-based (n = 8 patients; LC [n = 5]. and CRC [n = 2], other [n = 1]). The median duration (range) of MTB treatment was 275.0 (72–637), 274.0 (90–469), 259.0 (72–539), and 368.0 (273–637) days for all patients combined, those with LC, CRC, and other malignancies, respectively. The success of anti-MTB chemotherapy in each of the above groups was 70.0, 66.7, 70.0, and 80.0%, respectively. There were no MTB-related treatment failures. The median duration (range) of concurrent chemotherapy was 157.5 (13–408), 117.0 (20–245), 168.5 (13–408), and 155.0 (51–376) days for all patients combined, those with LC, CRC, and other malignancies, respectively.\n\nIn 20 (66.7%) patients MTB was cured, one (3.3%) completed the course for MTB treatment, and 9 (30%) died while receiving MTB treatment. Among the 9 patients who died, one died of pemetrexed-induced pneumonitis and 8 died of cancer.\n\nIn 2 CRC patients with performance status of 3, anti-CCT was started because of patients’ insistence and after the approval of the Cancer Board. In one of these patients, MTB was resistant to H and Z. Hence, X + Streptomycin was administered, alongside Folnic acid, fluorouracil and irinotecan for 1 cycle. The patient died 54 days after treatment withdrawal. Regular MTB cultures performed every other week were negative for six consecutive times. The other patient received modified regimen of Folinic acid, fluorouracil and oxaliplatin for 4 cycles and died 57 days after treatment withdrawal.\n\nEpidermal growth factor receptor sensitive mutation was found in 2 MTB-positive patients with lung adenocarcinoma. They received erlotinib as re-challenge regimen alongside HRE regimen in one patient and X-based regimen without rifampicin in the other. Both died because of cancer progression, 140 and 90 days after the initiation of erlotinib, respectively. Regular MTB cultures were performed for both patients every other week. Cultures were negative in each patient two and three consecutive times, respectively. None of the 30 patients enrolled in this study experienced recurrence of MTB through their clinical course.\n\nAdverse events of concurrent chemotherapy\nHematological adverse events of Grade ≥ 3 were observed in 19 (67.9%) of 28 patients; the laboratory data for 2 patients were lost. Non-hematological adverse events of Grade ≥ 3 were observed in 5 (17.9%) of 28 patients.\n\nNumber of cases in concurrent chemotherapy-related adverse events are shown in Table 4. There were no significant differences in the occurrence of adverse events between different cancer types, except for lymphopenia and neutropenia. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies (P < 0.005). Grade 3 Neutropenia and higher tended to be more frequent in LC compared to other malignancies. In non-hematological adverse events, Grade 1–2 liver dysfunction was frequently observed in each malignancies.Table 4 Concurrent Chemotherapy-Related Adverse Events\n\nNCI-CTCa (Grade)\tPatients\t\nAll\tLC\tCRC\tOther\t\n(n = 28)\t(n = 13b)\t(n = 10)\t(n = 5)\t\nAdverse event\t1–2\t≥3\t1–2\t≥3\t1–2\t≥3\t1–2\t≥3\t\nHematological toxicity, number of cases\t\n Leukocytopenia\t7\t8\t4\t6\t3\t1\t2\t1\t\n Neutropenia\t5\t14\t1\t9\t2\t3\t2\t2\t\n Anemia\t20\t2\t9\t2\t8\t0\t3\t0\t\n Thrombocytopenia\t3\t3\t1\t2\t1\t1\t1\t0\t\n Lymphopenia\t13\t10\t4\t8\t7\t1\t2\t1\t\nNon-hematological toxicity, number of cases\t\n AST/ALT elevation\t12\t0\t4\t0\t6\t0\t2\t0\t\n Interstitial pneumonitis\t0\t1c\t0\t1c\t0\t0\t0\t0\t\n Colitis\t0\t1d\t0\t0\t0\t0\t0\t1d\t\n Anaphylaxis\t0\t2e\t0\t0\t0\t2e\t0\t0\t\n Hemorrhage\t1f\t1g\t1f\t0\t0\t1g\t0\t0\t\nAbbreviations CRC colorectal cancer, LC lung cancer\n\naNCI-CTC: National Cancer Institute Common Toxicity Criteria\n\nbIn two of 15 patients, laboratory data was lost\n\ncDeath caused by pemetrexed-induced pneumonitis\n\ndPseudomembranous colitis due to Clostridium difficile infection\n\neOxaliplatin- and cetuximab-induced anaphylaxis\n\nfNasal bleeding\n\ngHemoptysis\n\n: P < 0.005\n\n\n\nOne CRC patient experienced Grade 3 hemoptysis and another 2 experienced Grade 3 anaphylaxis (oxaliplatin-induced [n = 1] and cetuximab-induced [n = 1]). One patient with CCA and GC experienced Grade 3 pseudomembranous colitis as a result of a Clostridium difficile infection. One LC patient died of pemetrexed-induced pneumonitis (Grade 5).\n\nOverall survival\nThe median OS in all patients was 10.5 (8.7–36.7; 95.0% confidence interval) months (Fig. 2a). The median OS according to the type of malignancy were 8.7 (4.7–10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) months for LC, CRC, and other malignancies, respectively (Fig. 2b).Fig. 2 (a) Kaplan-Meier curve of overall survival for 30 cancer patients with active Mycobacterium tuberculosis who received concurrent chemotherapy between January 1, 2006 and February 29, 2016. The median OS in all patients was 10.5 (8.7–36.7; 95.0% confidence interval) months (b) Kaplan-Meier curves of overall survival according to cancer type. Lung Cancer patients are represented by the thick solid line, Colorectal Cancer patients are represented by the thin solid line, and patients with Other malignancies, are represented by the dashed line. The median OS according to the type of malignancy were 8.7 (4.7–10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) months for Lung Cancer, Colorectal Cancer, and Other malignancies, respectively\n\n\n\nDiscussion\nThis study demonstrates the efficacy and safety of concurrent anti-CCT and anti-MTB chemotherapy for cancer patients with active MTB, confirming the findings of our previous preliminary study [2] in a bigger sample size with a variety of cancer types.\n\nIn Japan, the national rates for success, failed, died, and lost to follow-up of anti-MTB chemotherapy in 2015 were 52.8, 0.4, 17.0, and 5.6%, respectively [18]. In Nagoya which is almost similar to Osaka, where our institution is located, the rates of success, failed, died, and the others were 52.0, 0.7, 20.8, and 26.5%, respectively. [19] The success rate of anti-MTB chemotherapy in this study may have been higher than previous studies [18, 19], possibly because of no loss to follow-up and no unevaluated patient in the present study. However, it is important that there were no MTB-related treatment failures in our study, suggesting that cancer patients with active MTB would be able to tolerate anti-MTB chemotherapy while receiving anti-CCT as well as non-cancer patients with active MTB.\n\nConversely, the ORRs for all patients combined, LC patients, CRC patients, and other malignancy patients were 36.7, 33.3, 40.0, and 40.0%, respectively.\n\nIn 15 LC patients, all 5 patients with SCLC received intensive cytotoxic treatment (carboplatin plus etoposide) as first line chemotherapy (Table 3) with a high response rate (80%), which is similar to the response rate (73%) of similar treatment regimen in the elderly patient or those at poor risk with extensive disease [20]. On the other hand, 10% of response rate in 10 NSCLC patients seems to be low. This may be because 6 (60.0%) of 10 NSCLC patients had received second-line or later anti-CCT after starting anti-MTB chemotherapy.\n\nORR in CRC patients with MTB was 40% which was similar to other 1st line combined chemotherapy regimens without molecular targeted therapy in previous reports [21, 22].\n\nAlthough there were no significant differences in patient characteristics between the LC, CRC, and other malignancy groups, the diagnosis of MTB was more frequently reached during chemotherapy in LC patients when compared to patients with other types of malignancies. If LC and pulmonary MTB coexist in the lungs, a diagnosis of MTB becomes more difficult. Therefore, MTB diagnosis tends to be delayed in these patients.\n\nIn a Japanese retrospective study, [23] 247 (28.7%) of 861 patients who received MTB treatment experienced adverse events. The frequency of adverse events with MTB treatment alone, prior to the initiation of concurrent chemotherapy, in our study was equal to that of the a previous study. [23] Besides, upon starting concurrent chemotherapy in LC and CRC, we did not expect any differences in the prevalence of adverse events between this study and previous studies [20–22] except for liver dysfunction which may be correlated with MTB treatment.\n\nConcurrent chemotherapy-related toxicities were generally acceptable except death caused by pemetrexed-induced pneumonitis. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies. The treatment related lymphopenia may affect poor prognosis in LC patients through decreased immune system shown in previous study [24].\n\nIncreased multi-drug resistance and extensive drug resistance among strains of MTB is becoming a serious problem worldwide. Hattori et al. reported that 171 patients (0.2%) in Japan were diagnosed with multi-drug resistant MTB, and 48 of these (28.1%) were foreigners [25]. Although the number of multi-drug resistant MTB cases in Japan is low, Osaka city and Osaka prefecture have the highest prevalence of tuberculosis in Japan (34.4 and 18.2 per 100,000 individuals in 2015, respectively) [26]. Hence, we are exceedingly cautious of an increase in multi-drug resistant MTB. In our institution, anti-CCT was suspended as far as possible until the results of the sensitivity test were known.\n\nGiven the benefits of a short duration from MTB diagnosis to the turnaround of results from sensitivity test, MGIT [5] is recommended for culturing mycobacterial organisms.\n\nIn this study, 2 (8.0%) of 25 patients had resistant MTB to H and streptomycin and H and Z, respectively, but there was no patient with multi-drug resistant MTB. In National-wide survey in Japan [27], the frequencies of drug-resistant isolates from new cases were as follows 8.5% to any drug which was similar to this study.\n\nPoor PS, extensively drug-resistant MTB (XDR), and severe organ dysfunction were the basic contra-indications for concurrent chemotherapy. However, targeted therapy including EGFR-TKI may be used in selected patients despite a poor PS. Furthermore, concurrent chemotherapy may be initiated in patients with rapidly progressive cancer without waiting the results of MTB sensitivity test, even if the MTB is later categorized as XDR. Therefore, there may be no strict contra-indications for concurrent chemotherapy. However, since 6 (20%) of 30 patients experienced adverse events while receiving MTB treatment alone until concurrent chemotherapy, awaiting the result of sensitivity test will be important not only for excluding XDR but also to evaluate the adverse events of MTB treatment alone.\n\nConcurrent use of R, which induces CYP3A4 and CYP2C8 [28, 29], may weaken the clinical efficacy of some anti-CCT agents. In clinical practice, we attempt to not administer concurrent chemotherapy along with Erlotinib, Irinotecan, or Pclitaxel and HRE regimen as much as possible. Therefore, a better choice would be X-based regimen or other regimens without rifampicin.\n\nThe limitations of this study include its retrospective design and relatively small sample size. It remains unclear whether the findings of this study could be generalized for hematological malignancies or solid malignancies except LC and CRC, or expanded to other institutions. Therefore, a prospective multi-institutional study to evaluate the efficacy and safety of concurrent anti-CCT and anti-MTB chemotherapy in patients with various types of solid tumors and an active MTB infection is warranted.\n\nConclusions\nConcurrent anti-CCT and anti-MTB chemotherapy is effective and safe for treating cancer patients with active MTB.\n\nAbbreviations\nAnti-CCTAnti-cancer chemotherapy\n\nATSAmerican Thoracic Society\n\nCCConcurrent chemotherapy\n\nCCACholangiocellular carcinoma\n\nCCTCancer chemotherapy\n\nCIConfidence interval\n\nCRComplete response\n\nCRCColorectal cancer\n\nCTComputed tomography\n\nEEthambutol\n\nGCGastric cancer\n\nHIsoniazid\n\nIDSAInfectious Diseases Society of America\n\nLAMPLoop-mediated isothermal amplification\n\nLCLung cancer\n\nMDR-TBMulti-drug resistant Mycobacterium Tuberculosis\n\nMGITMycobacteria Growth Indicator Tube\n\nMSTMedian survival time\n\nMTB\nMycobacterium tuberculosis\n\n\nNENot evaluable\n\nNSCLCNon-small cell lung carcinoma\n\nPCRPolymerase chain reaction\n\nPDProgressive disease\n\nPRPartial response\n\nXDRExtensively drug-resistant MTB\n\nZPyrazinamide\n\nAcknowledgements\nThe authors thank Editage (www.editage.jp) for English language editing and a part donation to the Osaka Prefectural Hospital Organization (Osaka, Japan) for writing our manuscript.\n\nFunding\nThis study had no funding source.\n\nAvailability of data and materials\nWe cannot share the detailed data, because the Institutional Review Board of the Osaka Habikino Medical Center has not approved it.\n\nAuthors’ contributions\nTH, HS, NO, YT, and TN planned and designed the study. TH, YT, YH, SH and TN collected data of Bacteriological Examinations, and adverse effects and outcomes of MTB treatment; TH, AT, TS, NM, HS, NO, SA, MF, YK, KS, AN, and SM collected data of adverse effects and outcomes of cancer treatment. TH and HS performed the statistical analyses. All authors have been involved in drafting the manuscript or revising it critically for important intellectual content and approved the final manuscript.\n\nEthics approval and consent to participate\nEthics and publication of this study was approved by the Institutional Review Board of the Osaka Habikino Medical Center (formerly the Osaka Prefectural Medical Center for Respiratory and Allergic Diseases) (Osaka, Japan) on January 30, 2017 (approval no.: 808–1). The board waived the requirement for informed written consent due to the anonymous nature of the data and the fact that this research presented no risk of exposure to the subjects. Research was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nT.H. has received honoraria and research funding from Ono Pharmaceutical Co. Ltd. (Osaka, Japan), Lilly Japan Co. Ltd. (Hyogo, Japan), AstraZeneca Co. Ltd. (Osaka, Japan), Taiho Pharmaceutical Co. Ltd. (Tokyo, Japan), Chugai Pharmaceutical Co. Ltd. (Tokyo, Japan), and MSD Oncology Co. Ltd. (Tokyo, Japan). T.H. received honoraria from Kyowa-Hakko Kirin and Boehringer Ingelheim. T.H. received research funding from Merck Serono Co. Ltd. (Tokyo, Japan). The remaining authors (Y.T., Y.H., S.H., A.T., T.S., N.M., H.S., N.O., S.A., M.F., Y.K., K.S., A.N., S.M., and T.N.) declare 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. WHO: Global tuberculosis report 2017. 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Furuse J Takada T Miyazaki M Miyakawa S Tsukada K Nagino M Guidelines for chemotherapy of biliary tract and ampullary carcinomas J Hepato-Biliary-Pancreat Surg 2008 15 55 62 10.1007/s00534-007-1280-z \n15. Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L New guidelines to evaluate the response to treatment in solid tumors J Natl Cancer Inst 2000 92 205 216 10.1093/jnci/92.3.205 10655437 \n16. Trotti A Colevas AD Setser A Rusch V Jaques D Budach V CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment Semin Radiat Oncol 2003 13 176 181 10.1016/S1053-4296(03)00031-6 12903007 \n17. Kaplan E Meier P Nonparametric estimation from incomplete observations J Am Stat Assoc 1958 53 457 481 10.1080/01621459.1958.10501452 \n18. WHO; Download treatment outcomes [http://www.who.int/tb/country/data/download/en/]. Accessed 1 Aug 2018.\n19. Katsuda N Hirosawa T Reyer JA Hamajima N Roles of public health centers (Hokenjo) in tuberculosis control in Japan Nagoya J Med Sci 2015 77 19 28 25797967 \n20. Okamoto H Watanabe K Kunikane H Yokoyama A Kudoh S Asakawa T Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702 Br J Cancer 2007 97 162 169 10.1038/sj.bjc.6603810 17579629 \n21. Van Cutsem E Kohne CH Hitre E Zaluski J Chang Chien CR Makhson A Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer N Engl J Med 2009 360 1408 1417 10.1056/NEJMoa0805019 19339720 \n22. Douillard JY Siena S Cassidy J Tabernero J Burkes R Barugel M Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study J Clin Oncol 2010 28 4697 4705 10.1200/JCO.2009.27.4860 20921465 \n23. Yamamoto Y Hasegawa Y Ogawa K Retrospective cohort study of risk factors for adverse effects of antituberculous therapy Kekkaku 2011 86 499 507 21735857 \n24. Grossman SA Ellsworth S Campian J Wild AT Herman JM Laheru D Survival in patients with severe lymphopenia following treatment with radiation and chemotherapy for newly diagnosed solid tumors J Natl Compr Cancer Netw 2015 13 1225 1231 10.6004/jnccn.2015.0151 \n25. Hattori T Kobayashi N Nagai H Chagan-Yasutan H Telan E Solante MB Nationwide HIV-, MDR-TB survey in Japan and collaborative study in the Philippines Int J Mycobacteriol 2016 5 Suppl 1 S18 S19 10.1016/j.ijmyco.2016.09.009 28043540 \n26. Statistic of TB 2015 [http://www.jata.or.jp/rit/ekigaku/en/statistics-of-tb/]. Accessed 1 Aug 2018\n27. Tuberculosis Research Committee TJ Nationwide survey of anti-tuberculosis drug resistance in Japan Int J Tuberc Lung Dis 2015 19 157 162 10.5588/ijtld.13.0905 25574913 \n28. Rakhit A Pantze MP Fettner S Jones HM Charoin JE Riek M The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition Eur J Clin Pharmacol 2008 64 31 41 10.1007/s00228-007-0396-z 18000659 \n29. Kajosaari LI Laitila J Neuvonen PJ Backman JT Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin Basic Clin Pharmacol Toxicol 2005 97 249 256 10.1111/j.1742-7843.2005.pto_157.x 16176562\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2407", "issue": "18(1)", "journal": "BMC cancer", "keywords": "Breast cancer; Colorectal cancer; Concurrent chemotherapy; Efficacy; Gastric cancer; Lung cancer; Safety; Tuberculosis", "medline_ta": "BMC Cancer", "mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D015897:Comorbidity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D009369:Neoplasms; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D014376:Tuberculosis", "nlm_unique_id": "100967800", "other_id": null, "pages": "975", "pmc": null, "pmid": "30314434", "pubdate": "2018-10-12", "publication_types": "D016428:Journal Article", "references": "25797967;4218139;10871386;27052720;10655437;25326267;18000659;26483062;12588714;25782566;7494021;17579629;11773109;16176562;18274844;12903007;20921465;16931408;28043540;19339720;21735857;25574913", "title": "Efficacy and safety of concurrent anti-Cancer and anti-tuberculosis chemotherapy in Cancer patients with active Mycobacterium tuberculosis: a retrospective study.", "title_normalized": "efficacy and safety of concurrent anti cancer and anti tuberculosis chemotherapy in cancer patients with active mycobacterium tuberculosis a retrospective study" }	[ { "companynumb": "PHHY2018JP172861", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "64150", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HIRASHIMA T, TAMURA Y, HAN Y, HASHIMOTO S, TANAKA A, SHIROYAMA T ET AL.. EFFICACY AND SAFETY OF CONCURRENT ANTI-CANCER AND ANTI-TUBERCULOSIS CHEMOTHERAPY IN CANCER PATIENTS WITH ACTIVE MYCOBACTERIUM TUBERCULOSIS: A RETROSPECTIVE STUDY. BMC CANCER. 2018?18 (975):1-10", "literaturereference_normalized": "efficacy and safety of concurrent anti cancer and anti tuberculosis chemotherapy in cancer patients with active mycobacterium tuberculosis a retrospective study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181203", "receivedate": "20181203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15682507, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "BACKGROUND\nPatients with pulmonary arterial hypertension (PAH) who develop hyperthyroidism are at risk for acute cardiopulmonary decompensation and death.\nWe present a series of eight idiopathic PAH/heritable PAH pediatric patients who developed hyperthyroidism between 1999 and 2011. Institutional Review Board approval was obtained; informed consent was waived due to the retrospective nature of the series. All eight patients were receiving iv epoprostenol; five of the eight patients presented with acute cardiopulmonary decompensation in the setting of hyperthyroidism. In the remaining three patients, hyperthyroidism was detected during routine screening of thyroid function tests. The one patient who underwent emergency thyroidectomy was the only survivor of those who presented in cardiopulmonary decline.\n\n\nRESULTS\nAggressive treatment of the hyperthyroid state, including emergency total thyroidectomy and escalation of targeted PAH therapy and β-blockade when warranted, may prove lifesaving in these patients. Prompt thyroidectomy or radioactive iodine ablation should be considered for clinically stable PAH patients with early and/or mild hyperthyroidism to avoid potentially life-threatening cardiopulmonary decompensation.\n\n\nCONCLUSIONS\nAlthough the association between hyperthyroidism and PAH remains poorly understood, the potential impact of hyperthyroidism on the cardiopulmonary status of PAH patients must not be ignored. Hyperthyroidism must be identified early in this patient population to optimize intervention before acute decompensation. Thyroid function tests should be checked routinely in patients with PAH, particularly those on iv epoprostenol, and urgently in patients with acute decompensation or symptoms of hyperthyroidism.", "affiliations": "Division of Pediatric Endocrinology, Children’s Hospital of New York Presbyterian, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.", "authors": "Trapp\|Christine M\|CM\|;Elder\|Robert W\|RW\|;Gerken\|Adrienne T\|AT\|;Sopher\|Aviva B\|AB\|;Lerner\|Shulamit\|S\|;Aranoff\|Gaya S\|GS\|;Rosenzweig\|Erika B\|EB\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1210/jc.2012-1109", "fulltext": null, "fulltext_license": null, "issn_linking": "0021-972X", "issue": "97(7)", "journal": "The Journal of clinical endocrinology and metabolism", "keywords": null, "medline_ta": "J Clin Endocrinol Metab", "mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D065627:Familial Primary Pulmonary Hypertension; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D006980:Hyperthyroidism; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "0375362", "other_id": null, "pages": "2217-22", "pmc": null, "pmid": "22622024", "pubdate": "2012-07", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "16507873;15289375;11399743;12426269;19555858;19555857;16889843;19506387;11344172;11999999;20411253;21329849;9814445;17341574;19015610;4622570;21394427;12084741;2493228;19389575;17389704;19289321;21700562;3341864;16373874;164339;19470885;20180281;18811892;20009390;20924158", "title": "Pediatric pulmonary arterial hypertension and hyperthyroidism: a potentially fatal combination.", "title_normalized": "pediatric pulmonary arterial hypertension and hyperthyroidism a potentially fatal combination" }	[ { "companynumb": "US-PFIZER INC-2019396641", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHIMAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "40320", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHIMAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EPOPROSTENOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY ARTERIAL HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPOPROSTENOL." } ], "patientagegroup": null, "patientonsetage": "9", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug eruption", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TRAPP, C.. PEDIATRIC PULMONARY ARTERIAL HYPERTENSION AND HYPERTHYROIDISM: A POTENTIALLY FATAL COMBINATION. JOURNAL OF CLINICAL ENDOCRINOLOGY + METABOLISM. 2012?97 (7):2217-2222", "literaturereference_normalized": "pediatric pulmonary arterial hypertension and hyperthyroidism a potentially fatal combination", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190924", "receivedate": "20190924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16844566, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-PFIZER INC-2019384642", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, 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"drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHIMAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "40320", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHIMAZOLE." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardio-respiratory arrest", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiopulmonary failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Troponin increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2010" } }, "primarysource": { "literaturereference": "TRAPP, C.. PEDIATRIC PULMONARY ARTERIAL HYPERTENSION AND HYPERTHYROIDISM: A POTENTIALLY FATAL COMBINATION. JOURNAL OF CLINICAL ENDOCRINOLOGY + METABOLISM. 2012?97 (7):2217-2222", "literaturereference_normalized": "pediatric pulmonary arterial hypertension and hyperthyroidism a potentially fatal combination", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190923", "receivedate": "20190905", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16776090, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191005" } ]
{ "abstract": "Small cell carcinomas (SCCs) are aggressive neoplasms commonly associated with a pulmonary origin. However, albeit rare, extrapulmonary SCC can occur in a variety of sites with an incidence in North America approximated to be 0.1% to 0.4%. Among these sites, approximately 10% of extrapulmonary SCC cases occur in the prostate and are associated with a poor mortality with a median survival of 10 months. Because of the rarity of the prostatic SCC, there is no formal treatment protocol. In this case report, we present a patient who was diagnosed with SCC in the prostate as primary origin. Adjuvant concurrent chemoradiotherapy was started, which he is tolerating so far. While the management of metastatic disease is well documented with the use of chemotherapy, specific data on nonmetastatic disease is lacking. As some studies suggest, a combined surgical and chemotherapeutic approach is helpful in localized disease. In our case, this approach has led to a good clinical outcome in a disease that does not usually allow such results.", "affiliations": "Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, USA.;Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, USA.;Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, USA.;Department of Hematology/Oncology, Joan C. Edwards School of Medicine, Marshall University, USA.", "authors": "Abusnina\|Waiel\|W\|https://orcid.org/0000-0003-2617-8483;Auyoung\|Eric Yiman\|EY\|;Megri\|Mohammed\|M\|;Pacioles\|Toni\|T\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/2324709618760644", "fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961876064410.1177_2324709618760644Case ReportSmall Cell Carcinoma of Prostate: A Case Report of a Patient With Concomitant Transitional Cell Cancer of the Bladder https://orcid.org/0000-0003-2617-8483Abusnina Waiel MD1Auyoung Eric Yiman MD1Megri Mohammed MD1Pacioles Toni MD21 Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, USA2 Department of Hematology/Oncology, Joan C. Edwards School of Medicine, Marshall University, USAWaiel Abusnina, Internal Medicine, Joan C Edwards School of Medicine at Marshall University, 1600 Medical Center Drive, Huntington, WV 25701-3655, USA. Email: [email protected] 3 2018 Jan-Dec 2018 6 232470961876064423 12 2017 10 1 2018 13 1 2018 © 2018 American Federation for Medical Research2018American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Small cell carcinomas (SCCs) are aggressive neoplasms commonly associated with a pulmonary origin. However, albeit rare, extrapulmonary SCC can occur in a variety of sites with an incidence in North America approximated to be 0.1% to 0.4%. Among these sites, approximately 10% of extrapulmonary SCC cases occur in the prostate and are associated with a poor mortality with a median survival of 10 months. Because of the rarity of the prostatic SCC, there is no formal treatment protocol. In this case report, we present a patient who was diagnosed with SCC in the prostate as primary origin. Adjuvant concurrent chemoradiotherapy was started, which he is tolerating so far. While the management of metastatic disease is well documented with the use of chemotherapy, specific data on nonmetastatic disease is lacking. As some studies suggest, a combined surgical and chemotherapeutic approach is helpful in localized disease. In our case, this approach has led to a good clinical outcome in a disease that does not usually allow such results.\n\nsmall cell cancerprostate cancercover-dateJanuary-December 2018\n==== Body\nIntroduction\nSmall cell carcinomas (SCCs) are aggressive neoplasms commonly associated with a pulmonary origin. However, albeit rare, extrapulmonary SCC (EPSCC) can occur in a variety of sites with an incidence in North America approximated to be 0.1% to 0.4%.1 Among these sites, approximately 10% of EPSCC cases occur in the prostate2,3 and are associated with a poor survival, with a median survival of 10 months.3,4 Because of the rarity of the prostatic SCC, there is no formal treatment protocol. Current treatment is based on studies of pulmonary SCC, using a combined chemoradiotherapeutic approach with radical prostatectomy as an adjunct in only a few selected cases.5-8 With the poor outcome of this aggressive subtype of prostate cancer, further studies can help improve treatment outcomes. Here, we present a case of limited-stage pure SCC of the prostate treated with a total cystoprostatectomy and adjuvant chemoradiotherapy.\n\nCase Report\nA 60-year-old Caucasian male presented with episodes of urinary retention, a normal digital rectal examination, and no other urinary symptoms. His past medical history was significant for a high-grade T1 transitional cell carcinoma of the bladder 1 year prior, as well as another T1 transitional cell carcinoma of the bladder 7 months after the first tumor was diagnosed. For the first tumor, he successfully underwent transurethral resection of the tumor and 6 cycles of intravesical bacillus Calmette-Guerin (BCG) immunotherapy. The same treatment plan was given for his second tumor, but he developed BCG-osis after the fourth cycle. He underwent close follow-up by his urologist with abdominal/pelvic computed tomography (CT) scans and urine cytology. Three months later, around the onset of his urinary retention, imaging showed thickening of his bladder wall, and urine cytology was positive for malignancy. Furthermore, on bimanual examination, a firm, but moveable mass was palpated. With these new findings, the patient was recommended cystoscopy with transurethral resection of the prostate to investigate a suspected recurrence of bladder cancer and to provide relief of his obstructive symptoms. The procedure relieved not only the patient’s urinary retention but also revealed a fleshy mass occupying the right lobe of the prostate and no bladder masses. The pathologist reported the transrectal ultrasound-guided prostate biopsy to be consistent with a small cell neuroendocrine carcinoma. High-power evaluation (400×) demonstrated tumor cells with hyperchromatic nuclei, no nucleoli, scant cytoplasm, and nuclear molding, with numerous mitoses (Figure 1). The tumor has neuroendocrine features as shown by positivity with antibodies to CD5 (Figure 2) and synaptophysin (Figure 3).\n\nFigure 1. The tumor is composed of cells with hyperchromatic nuclei, no nucleoli, scant cytoplasm, and nuclear molding, with numerous mitoses (hematoxylin-eosin, 400×).\n\nFigure 2. The tumor has neuroendocrine features as shown by positivity with antibodies to CD56 (400×).\n\nFigure 3. The tumor has neuroendocrine features as shown by positivity with antibodies to synaptophysin (400×).\n\nImmunohistochemical stains were found to be positive for P53, CK7, and AE1/AE3 (Figures 4-6) but negative for staining with antibodies to chromogranin A, CK20, PSA, uroplakin III, GATA-3, and LCA (data not shown).\n\nFigure 4. p53 mutation is shown by positive nuclear staining with antibody to p53 (400×).\n\nFigure 5. The tumor is a carcinoma as evidenced by positivity with antibodies to CK7 (400×).\n\nFigure 6. The tumor is a carcinoma as evidenced by positivity with antibodies to cytokeratin AE1/AE3 (400×).\n\nThe specimen was also compared with the patient’s previous bladder biopsy and determined to be morphologically dissimilar. Further staging workup was obtained with positron emission tomography (PET)/CT scan and with magnetic resonance imaging of the pelvis–neither of which revealed obvious lymphadenopathy or extraprostatic spread. Considering the localized nature of the tumor, the patient underwent a robotic-assisted total cyst prostatectomy with lymph node sampling of the right and left obturator lymph nodes. Final pathology report confirmed a submucosal small cell neuroendocrine carcinoma in the prostatic base, 3.5 cm at its greatest dimension, with involvement of the bladder neck and trigone area. One of the 2 lymph nodes were positive for metastatic carcinoma, and final pathologic staging was determined to be T3aN1M0. He underwent adjuvant concurrent chemoradiotherapy with cisplatin/etoposide. The patient completed 4 cycles and at last follow-up, 12 months after diagnosis, is tolerating the treatment well with negative CT imaging for recurrence.\n\nDiscussion\nAlthough the prostate is one of the common site for EPSCC, it is a rare prostatic malignancy.2,3,9 Of these cases, only about 35% are pure SCC of the prostate, with the rest having concurrent adenocarcinomatous components,5 but it is currently unknown whether this pathological difference affects the management or prognosis. SCC of the prostate is reported to be more prevalent in the elderly with over 70% of patients being over the age of 65.10 Unlike prostate adenocarcinomas, most patients with SCC of the prostate are symptomatic. The most frequently reported symptoms are obstructive symptoms, pressure-related neurological symptoms, or constitutional symptoms, with 10% of cases present with paraneoplastic symptoms.9,11 Depending on the tumor involvement, other clinical features include bone pain, hydronephrosis, abdominal pain, hematochezia, and hematuria. Imaging of the pelvis is generally nonspecific and serum prostate-specific antigen levels often remain within normal ranges.5 Ultimately, SCC of the prostate is diagnosed by pathological analysis of morphology and immunohistochemistry.3,5,11\n\nMuch of our current treatment approach to prostatic SCC are extrapolated from studies on the management of pulmonary SCC. In the limited studies available on the management of prostatic SCC, the recommended first-line treatment is chemotherapy with a combined use of cisplatin and etoposide because of its comparatively higher efficacy rate.5,6,11 However, most of these cases are patients with metastatic or extensive-stage prostatic SCC, the more common presentation of the tumor. With respect to nonmetastatic or limited-stage prostatic SCC, a couple of studies recommend prostatectomy with adjuvant chemotherapy, but this approach is controversial.2,5,12 Most studies report using chemotherapy as the first-line treatment regardless if the tumor is metastatic or not; hence, it is difficult to properly assess the efficacy of a surgical therapy with adjuvant chemotherapy. Several studies have reported that prostatectomy alone is not effective.5,8,13 In these localized tumors, as in our case, it would be logical to remove the tumor to potentially prevent possible metastases and use adjuvant chemotherapy to treat possible occult metastases.\n\nConclusion\nSCC of the prostate is an aggressive tumor that is associated with a high mortality. While the management of metastatic disease is well documented with the use of chemotherapy, specific data on nonmetastatic disease are lacking. As some studies suggest, a combined surgical and chemotherapeutic approach is helpful in localized disease. In our case, this approach has led to a good clinical outcome in a disease that does not usually allow such results.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.\n\nORCID iD: Waiel Abusnina \nhttps://orcid.org/0000-0003-2617-8483\n==== Refs\nReferences\n1 \nBrennan SM Gregory DL Stillie A Herschtal A Mac Manus M Ball DL. \nShould extrapulmonary small cell cancer be managed like small cell lung cancer? \nCancer . 2010 ;116 :888 -895 .20052730 \n2 \nWhitaker DA JrMiller DH Jagadesh N et al \nSmall cell carcinoma of the prostate in an elderly patient: a case report and review of the literature . Rare Tumors . 2016 ;8 :6657 .28191295 \n3 \nFurtado P Lima MV Nogueira C Frnaco M Tavora F. \nReview of small cell carcinomas of the prostate . Prostate Cancer . 2011 ;2011 :543272 .22110988 \n4 \nCapizzello A Peponi E Simou N et al \nPure small cell carcinoma of the prostate: a case report and literature review . Case Rep Oncol . 2011 ;4 :88 -95 .21475596 \n5 \nGuo A Wen S Ma Y Wei L Liu A. \nClinicopathological analysis on small cell carcinoma of the prostate in Chinese patients . J Cancer . 2014 ;5 :797 -803 .25520757 \n6 \nCohen A Richards KA Patel S Weiner A Eggener SE Szmulewitz RZ. \nMetastatic small cell carcinoma of the prostate: population-based analysis of patient characteristics and treatment paradigms . Urol Oncol . 2015 ;33 :70 .\n7 \nStein ME Bernstein Z Abacioglu U et al \nSmall cell (neuroendocrine) carcinoma of the prostate: etiology, prognosis, and therapeutic implications—a retrospective study of 30 patients from the rare cancer network . Am J Med Sci . 2008 ;336 :478 -488 .19092321 \n8 \nSpiess PE Pettaway CA Vakar-Lopez F et al \nTreatment outcomes of small cell carcinoma of the prostate: a single-center study . Cancer . 2007 ;110 :1729 -1737 .17786954 \n9 \nPalmgren JS Karavadia SS Wakefield MR. \nUnusual and underappreciated: small cell carcinoma of the prostate . Semin Oncol . 2007 ;34 :22 -29 .17270662 \n10 \nWang J Wang FW. \nImpact of age on clinical presentation, treatment, and cancer-specific survival of patients with small-cell carcinoma of the prostate . Clin Interv Aging . 2013 ;8 :871 -877 .23885169 \n11 \nNadal R Schweizer M Kryvenko ON Epstein JI Eisenberger MA. \nSmall cell carcinoma of the prostate . Nat Rev Urol . 2014 ;11 :213 -219 .24535589 \n12 \nWeiner AB Patel SG Richards KA Szmulewitz RZ Eggener SE. \nPopulation-based analysis of treatment modalities and survival for clinically localized small-cell carcinoma of the prostate . Prostate Cancer Prostatic Dis . 2014 ;17 :286 -291 .25027862 \n13 \nBolton DM Chiu ST Clarke S Angus D. \nPrimary small cell carcinoma of the prostate: unusual modes of presentation . Aust N Z J Surg . 1994 ;64 :91 -94 .7507315\n\n", "fulltext_license": "CC BY", "issn_linking": "2324-7096", "issue": "6()", "journal": "Journal of investigative medicine high impact case reports", "keywords": "prostate cancer; small cell cancer", "medline_ta": "J Investig Med High Impact Case Rep", "mesh_terms": null, "nlm_unique_id": "101624758", "other_id": null, "pages": "2324709618760644", "pmc": null, "pmid": "29536021", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": "25044254;17786954;28191295;25027862;17270662;23885169;21475596;24535589;25520757;22110988;19092321;20052730;7507315", "title": "Small Cell Carcinoma of Prostate: A Case Report of a Patient With Concomitant Transitional Cell Cancer of the Bladder.", "title_normalized": "small cell carcinoma of prostate a case report of a patient with concomitant transitional cell cancer of the bladder" }	[ { "companynumb": "US-009507513-1810USA013511", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN" }, "drugadditional": "3", "drugadministrationroute": "043", "drugauthorizationnumb": "102821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INSTILLATION FLUID", "drugdosagetext": "6 DOSAGE FORM, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLADDER CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICE BCG" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN" }, "drugadditional": "3", "drugadministrationroute": "043", "drugauthorizationnumb": "102821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INSTILLATION FLUID", "drugdosagetext": "4 DOSAGE FORM, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICE BCG" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disseminated Bacillus Calmette-Guerin infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ABUSNINA W, AUYOUNG EY, MEGRI M, PACIOLES T. 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{ "abstract": "Nontuberculous mycobacterial (NTM) genitourinary (GU) infections are relatively rare, and there is frequently a delay in diagnosis. Mycobacterium avium-intracellulare complex (MAC) cases seem to be less frequent than other NTM as a cause of these infections. In addition, there are no set treatment guidelines for these organisms in the GU tract. Given the limitations of data this review summarizes a case presentation of this infection and the literature available on the topic. Many different antimicrobial regimens and durations have been used in the published literature. While the infrequency of these infections suggests that there will not be randomized controlled trials to determine optimal therapy, our case suggests that a brief course of amikacin may play a useful role in those who cannot tolerate other antibiotics.", "affiliations": "School of Medicine, Creighton University, Omaha, NE 68124, USA.;College of Pharmacy, Creighton University, Omaha, NE 68124, USA.;School of Medicine, Creighton University, Omaha, NE 68124, USA.", "authors": "Rajendraprasad\|Sanu\|S\|;Destache\|Christopher\|C\|;Quimby\|David\|D\|0000-0003-3976-9522", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/idr13020045", "fulltext": "\n==== Front\nInfect Dis Rep\nInfect Dis Rep\nidr\nInfectious Disease Reports\n2036-7430\n2036-7449\nMDPI\n\n10.3390/idr13020045\nidr-13-00045\nCase Report\nMycobacterium Avium Complex Genitourinary Infections: Case Report and Literature Review\nRajendraprasad Sanu 1\nDestache Christopher 2\nhttps://orcid.org/0000-0003-3976-9522\nQuimby David 1\nPetrosillo Nicola Academic Editor\n1 School of Medicine, Creighton University, Omaha, NE 68124, USA; [email protected]\n2 College of Pharmacy, Creighton University, Omaha, NE 68124, USA; [email protected]\n Correspondence: [email protected]\n24 5 2021\n6 2021\n13 2 454464\n06 5 2021\n20 5 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nNontuberculous mycobacterial (NTM) genitourinary (GU) infections are relatively rare, and there is frequently a delay in diagnosis. Mycobacterium avium-intracellulare complex (MAC) cases seem to be less frequent than other NTM as a cause of these infections. In addition, there are no set treatment guidelines for these organisms in the GU tract. Given the limitations of data this review summarizes a case presentation of this infection and the literature available on the topic. Many different antimicrobial regimens and durations have been used in the published literature. While the infrequency of these infections suggests that there will not be randomized controlled trials to determine optimal therapy, our case suggests that a brief course of amikacin may play a useful role in those who cannot tolerate other antibiotics.\n\nnontuberculous mycobacteria\nmycobacterium avium-intracellulare complex\nurinary tract infections\ngenitourinary infections\n==== Body\n1. Introduction\n\nIn recent decades, the incidence and prevalence of nontuberculous mycobacteria (NTM) causing extrapulmonary infections have greatly increased, becoming a major worldwide public health problem [1,2]. Among numerous NTM species, the Mycobacterium avium complex (MAC) is the most common cause of infection in humans. MAC is recognized as a ubiquitous microorganism, with contaminated water and soil as established sources of infection [3]. MAC consists of multiple species, of which two of the most common are M.avium and M.intracellulare [4,5,6]. There are four main manifestations of MAC infection: (1.) HIV with disseminated disease; (2.) focal lymphadenitis also in predominantly HIV patients; (3.) pulmonary infection in those with structural lung disease; and (4.) skin and soft tissue infections [7,8,9,10]. Genitourinary tract infections secondary to MAC appear to be rare with questionable clinical relevance and no standardized treatment. Here we present a case of MAC-associated urinary tract infection in a woman with an extensive urological history and recurrent urinary tract infections.\n\n2. Case Presentation\n\nPatient is a 79-year-old woman with a complicated urologic history. Three years prior to her presentation in the infectious disease clinic, she had issues with urinary retention and frequent urinary tract infections, for which she would receive antibiotics. She required an indwelling urinary catheter for several months due to urinary retention, but voiding trials after initiation of tamsulosin were effective, and she was catheter-free for over 2 years prior to infectious disease clinic presentation. Recurrent infections were treated with methenamine and she had no symptoms of infection between November 2016 and June 2017. Starting in June 2017, she had more issues with urinary tract infection (UTI) symptoms, which improved with thrice-weekly vaginal estrogen cream and intermittent antibiotics.\n\nBeginning in January 2019, however, her symptoms became near-constant. Repeated urine cultures were positive for methicillin-sensitive Staphylococcus aureus (Table 1); she was found to have some kidney stones, which were removed in February of 2019. Unfortunately, despite this intervention, she remained with constant symptoms, significantly affecting her quality of life. She underwent cystoscopy in August 2019 showing inflammation but no mass lesions; biopsies were not performed. Urine cytology showed no malignancy, abundant inflammation, and significant Candida. CT imaging of the abdomen and pelvis was significant only for a thickened bladder wall, consistent with cystitis. Given the persistent symptoms, pyuria, and relatively negative urine cultures (Table 1), she was treated with antifungal medication for the possibility of a true candida cystitis and had a urine sample sent for AFB culture. Given no improvement, she was started on silver nitrate bladder instillations by urology for symptomatic relief. The first treatment of silver nitrate bladder instillation led to an improvement in discomfort which was regrettably short-lived.\n\nPrior to the second planned instillation of silver nitrate, her urine AFB culture was positive for Mycobacterium avium complex via the nucleic acid DNA probe (AccuProbe Mycobacterium avium complex culture identification test, Hologic). In October 2019, she was started on an antimicrobial regimen of clarithromycin 500 mg BID, rifampin (RIF) 600 mg/day, and ethambutol 1200 mg/day based on susceptibilities (Table 2) and continued with the silver nitrate instillations for about a month given a little improvement after starting them. The instillations were discontinued due to intolerable bladder spasms. Unfortunately, despite antimicrobial therapy, she remained quite symptomatic and was having increasing nausea from the medications.\n\nIn January 2020, due to gastrointestinal symptoms from medications, lack of improvement in pyuria, and lack of improvement in her dysuria, the antimicrobial regimen was changed to rifampin 600 mg/day, linezolid 600 mg/day, and three-times-weekly amikacin. After the first week of this regimen, she had significant improvement in her urinary symptoms. By the end of the second week, she was completely asymptomatic. She completed three weeks of the amikacin and was then maintained on linezolid and rifampin alone. Follow-up urinalysis showed marked improvement in pyuria, and she remained asymptomatic. For the next ten months, she remained symptom-free from a urinary standpoint and tolerated the linezolid/rifampin combination with no ill effects. She completed twelve months of therapy from initiation of the amikacin with a follow-up urine analysis demonstrating no pyuria. A second urine analysis a few weeks the first was also negative. Interestingly, a second urinary AFB culture obtained prior to any antimycobacterial therapy (but after the first silver nitrate instillation) was ultimately negative.\n\n3. Nontuberculous Mycobacteria: An Overview\n\nAmong numerous NTM species, MAC is the most predominant group causing disease in humans. Originally not recognized as pathogenic, in the 1950s, the isolation of acid-fast bacilli with atypical cultural characteristics was noted at Battey State hospital, Rome, Georgia USA. At this time there developed evidence of direct causation of disease [11,12]. In 1959, Runyon proposed the first classification of NTM into four groups, the first three comprising “Slowly Growing Mycobacteria” (SGM) and the fourth of “Rapidly Growing Mycobacteria” [5]. MAC is part of group III or Battey type NTM in the Runyon classification [13]. With advances in the systematic analysis we are able to identify and classify new (sub) species within MAC at the molecular level. The most common SGM is the species belonging to the Mycobacterium avium complex (MAC), comprising especially Mycobacterium avium and Mycobacterium intracellulare.\n\nThe incidence of MAC infections is increasing in most industrialized countries, possibly because of the increase in immunocompromised and/or older patients [1,2]. In addition, improvement in testing methods to culture and identify have spurred increases in MAC have likely led to increased diagnoses. The use of fluorescent stain and fluorescent microscope appears to be superior to Ziehl-Neelson stain for AFB smear [14]. AFB culture in liquid Mycobacteria Growth Indicator Tube (MGIT) has replaced the Lowenstein-Jensen slant in isolating NTM and DNA probes and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) allows for precise identification in hours compared to the traditional biochemical and phenotypic methods that can take weeks [15,16].\n\n4. Mycobacterial Genitourinary (GU) Infections: Clinical Presentation\n\nMycobacterial genitourinary (GU) tract infections are a not-uncommon event, and genitourinary tract tuberculosis is a common manifestation of extrapulmonary TB. In genitourinary tuberculosis, men are more frequently infected than women, and HIV-infected men are at the highest risk [17]. Initial presentation is not always associated with specific symptoms; pyuria and/or microscopic hematuria may be observed as incidental findings. Involvement of the bladder may cause symptoms of frequency, dysuria, urgency, and nocturia in approximately half of the cases; gross hematuria and low back pain develop in 1/3 of cases. Systemic symptoms (fever, weight loss) are relatively rare [18]. While there are good data on prevalence and therapeutic options for tubercular GU infections, non-tubercular (NTM) infections of the GU tract are much less common, and there is currently no standard approach to therapy.\n\nMost cases that have been documented of genitourinary NTM showed increased prevalence in women. Infections are more common in the elderly population, although a case of genitourinary MAC associated with disseminated infection has been reported in a child as young as 14 years [19]. Genitourinary infection does not appear to be isolated to the immunocompromised, as only one infection in a transplant recipient has been documented [20]. Most patients appear immunocompetent. It is unclear if race is a factor; of the published cases, most patients are Caucasian, but lack of diagnosis and publication bias could play a role in this.\n\nPrimary complaints of UTI appear to be present in all those that have been diagnosed with MAC as the etiology of their symptoms. Duration of symptoms varies from 1 week to 3 years. Several patients appear to have been treated with antibiotics for suspected bacterial urinary tract infections in the past. Sterile pyuria in routine urine culture with dysuria appears to be a common presenting sign. Of interest is the duration of symptoms and persistence of symptoms after routine treatment with antibiotics. In our patient, she has grown multiple bacterial organisms in the urine cultures over the years including Candida species with some improvement in symptoms until the next recurrence. Other NTM (M. abscessus, M. fortuitum, M. gordonae) causing genitourinary infection do not have a similar presentation [21,22,23,24,25,26,27].\n\nThe most common species of rapidly growing mycobacteria of clinical relevance are M.fortuitum, M.abscessus, M.marinum, and M.chelonae. While predominantly known to cause skin and soft tissue infections, these pathogens can cause disease in other parts of the body, including the GU tract, and there are increasing published reports of these organisms leading to infection in this organ system. M. fortuitum has been associated with prolonged urinary tract elimination in patients with AIDS as well as hemodialysis patients [23,25]. While it is not always clear that the presence of these pathogens in a urine culture is necessarily reflective of true infection, in several cases there has been clinical evidence of true disease, and antimicrobial treatment led to culture sterilization and clinical improvement (Table 3) [20,28,29,30,31,32].\n\nUrinary involvement with disseminated spread has been associated with underlining cell-mediated immune deficiencies or serum interferon-Y-neutralizing autoantibodies [19,28]. None of the patients appear to have any history of HIV which has been associated with disseminated MAC. One of the patients that completed treatment and had sterilization of urine was found to have a recurrence after undergoing orthotopic liver and kidney transplant and being placed on immunosuppression. It is unclear if immunosuppression definitively increases the risk of isolated GU infection secondary to MAC as noted in Obeid et al. [20].\n\nStudies question the clinical significance of MAC in the urine as some patients are not treated with antibiotics and managed conservatively [33,34,35]. Like other potential pathogens isolated on cultures, the presence of a positive culture does not necessarily mean true infection: in one large New York hospital over a 3-year period, there were 422 HIV-negative patients with cultures positive for MAC from various body sites. Of these, 375 had clinical data available to determine true mycobacterial infection or not, of which only 119 felt to have a true infection. One patient had repeated positive urine cultures for MAC but was not categorized as having NTM disease since the patient was asymptomatic [36]. Additionally, it has been suggested that about 43% (12/28 tested) of HIV+ individuals with disseminated MAC infection will have positive urine cultures for this organism [37]. Two reported patients continued to be symptomatic, despite achieving urine sterilization, which raises the question if treatment was beneficial or necessary [31,32]. Two patients had renal involvement requiring surgical management in addition to antibiotic therapy which led to symptomatic improvement and urine sterilization [29,30]. Thus, proper source control may have provided a similar effect. Given the lack of susceptibility information or standardization of care with antibiotics and duration of treatment, it is difficult to form a firm conclusion.\n\n5. Mycobacterial GU Infections: Diagnosis\n\nGeneral practice for patients with ongoing culture-negative urinary symptoms often involves cultures for atypical organisms (such as Chlamydia, Gonorrhoea, Mycoplasma, Ureaplasma, and mycobacterial organisms). Molecular techniques have been explored, and one study used nucleic acid probes of tissue from bladder wall biopsy of patients with interstitial cystitis to look for missed mycobacterial pathogens; of the eight tested, none were positive suggesting that this may not be a common cause of ongoing culture-negative urinary symptoms in this small study [38]. However, there are clear cases where MAC has been implicated in true GU tract infections (Table 3) with consistent symptoms, positive cultures, and clinical benefit from antimicrobial therapy. However, the optimal treatment of medications and duration is not clear at this time.\n\nOur patient exemplifies the difficulty in making a diagnosis of NTM GU tract infection. She had ongoing symptoms for years, constant pyuria on cultures, and was treated repeatedly for small-quantity colonizing bacteria with no clinical improvement. In addition, like many patients with recurrent GU issues, she had more than one problem along the way: initially she had urinary retention, and later developed colonized/infected kidney stones. AFB culture was sent after evaluation by infectious diseases clinic and returned positive after four weeks of incubation. Prior to starting therapy, the culture was repeated, but ultimately reported as negative perhaps as a result of the intermittent intravesicular silver nitrate installations for symptomatic relief. Studies have shown silver nanoparticles (AgNPs) demonstrate antimycobacterial effect in bacterial cultures and within macrophages [39]. The use of monthly silver nitrate installations in conjunction with antibiotic management may have been the key to the eradication of the infection in this patient.\n\n6. Mycobacterial GU Infections: Treatment\n\nTreatment for genitourinary mycobacterial infection has not been standardized. Initial regimens appeared to favor isoniazid (INH), ethambutol (EMB), RIF, and streptomycin [29,30,31,32]. All except Faber et al. used three drug regimens to initiate treatment with modifications as needed for each patient, despite which urine sterilization was achieved. Recent case reports show a shift to macrolide (azithromycin or clarithromycin) based treatment with the use of Clinical and Laboratory Standards Institute (CLSI) published guidelines for drug susceptibility testing (DST) of NTM in 2011 and updated in 2018. Along with macrolides, RIF, EMB, fluoroquinolones, and aminoglycosides have been used as additional medications for three drug antibiotic therapy [20,28].\n\nTreatment for genitourinary MAC does appear to be extrapolating from pulmonary MAC treatment which is based on macrolides combined with a rifamycin (rifampin or rifabutin) and ethambutol. The use of amikacin can be parenteral or inhaled in for severe cases of pulmonary MAC [7,40], although older case reports show streptomycin (600 mg-1g) as the most common addition in 5 out of 7 cases [28,29,30,31,32]. Moxifloxacin, bedaquiline, linezolid, and clofazimine are alternative drugs proposed mainly for the treatment of infections caused by macrolide-resistant pulmonary MAC [41].\n\nIn NTM lung disease, CLSI and the British Thoracic Society (BTS) recommend testing the isolate for clarithromycin and amikacin susceptibility prior to the initiation of therapy. It is reasonable to assume that genitourinary infections would benefit from similar testing. In cases of resistance to clarithromycin, CLSI recommends DST of moxifloxacin and linezolid, whereas BTS recommends testing a wider panel of antibiotics to guide treatment regimens [42,43,44]. Ethambutol and rifamycins, unfortunately, have no clinical breakpoints defined for treatment of MAC infections [41].\n\nThe use of these antimicrobials does require further evaluation regarding pharmacokinetics with special consideration of urine concentration achieved by each. Linezolid, clarithromycin, clofazimine, and aminoglycosides (streptomycin and amikacin) achieve the highest levels in urine as noted in Table 4. It is not certain how relevant urine antimicrobial concentrations are, as the use of oral medications with lower urinary concentration often leads to urinary sterilization.\n\nBased on the minimal amount of published data on Mycobacterium avium complex genitourinary infections, optimal therapy and duration are unclear at this time. Patients have been treated with several regimens with varying duration of treatment ranging from 6 weeks to 18 months. While likely rare enough to make randomized trials of different therapeutic options impossible, this case suggests that relatively brief therapy with amikacin may be of benefit. The practice of confirming pathogen clearance with repeat sputum culture in pulmonary MAC could be transitioned to genitourinary MAC infection with the determination of duration of treatment after urine sterilization. While the ideal duration of both aminoglycoside therapy and total therapy is unclear, patient symptoms and degree of pyuria may be of benefit in measuring disease activity even in the face of negative follow-up cultures.\n\n7. Conclusions\n\nGenitourinary Mycobacterium avium complex infection appears to be rare. Patients commonly have symptoms with dysuria and sterile pyuria for prolonged periods prior to proper diagnosis. Concern of clinical relevance despite urine culture positivity is present although our case in addition to prior reports of similar patients confirms the need for aggressive and prolonged management to provide symptomatic relief when true infection, and not just colonization, is present. Based on data from the more-common pulmonary infections, beginning with three-drug therapy and evaluation of sensitivity to macrolides and aminoglycosides is recommended. A short course of aminoglycoside for genitourinary MAC may be beneficial in some patients. Overall duration of therapy is unclear, as literature review shows a wide range of therapy, ranging from six weeks to 18 months. Optimal medication choice and antibiotic duration may require tailoring to each individual patient.\n\nAuthor Contributions\n\nWriting manuscript, original draft: S.R., D.Q. Writing manuscript, revisions: S.R., C.D., D.Q. Literature search: S.R., D.Q. Table preparation: S.R., C.D. Manuscript submission: D.Q. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nWritten consent has been obtained from the patient to publish this paper.\n\nData Availability Statement\n\nNot applicable.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nAbbreviations\n\nAFB\tAcid-fast bacillus\t\nAgNPs\tsilver nanoparticles\t\nAIDS\tAcquired immunodeficiency syndrome\t\nBTS\tBritish Thoracic Society\t\nCLSI\tClinical and Laboratory Standards Institute\t\nDST\tDrug susceptibility testing\t\nEMB\tethambutol\t\nGU\tGenitourinary\t\nHIV\tHuman immunodeficiency virus\t\nINH\tisoniazid\t\nMAC\tMycobacterium avium complex\t\nMAI\tMycobacterium Avium-Intracellulare\t\nMALDI-TOF\tmatrix-assisted laser desorption ionization-time of flight mass spectrometry\t\nMGIT\tMycobacteria growth indicator tube\t\nNTM\tNontuberculous mycobacteria\t\nRIF\tRifampin\t\nSGM\tSlowly growing mycobacteria\t\nUTI\tUrinary tract infection\t\n\nidr-13-00045-t001_Table 1 Table 1 Urine culture results 2016 to present.\n\nDate\tLeucocyte Esterase\tWBC/HPF\tCulture\t\n1/9/16\tLarge\t>100\t>100K Pseudomonas aeruginosa, 20K MSSA\t\n2/15/16\tSmall\t10–20\t50K MSSA\t\n5/6/16\tLarge\t>100\t>100K MSSA\t\n5/10/16\tLarge\t\t60K MSSA\t\n5/21/16\tLarge\t>100\t50K Candida albicans\t\n6/18/16\tLarge\t>100\t>100K Citrobacter freundii, >100K Enterococcus faecalis, 10K mixed gram-positive flora\t\n6/19/16\tLarge\t50–100\t>100K Candida albicans\t\n6/28/16\t\t\t40K Candida albicans\t\n8/31/16\tSmall\t10–20\t>100K Proteus mirabilis\t\n9/4/16\tLarge\tPacked field\t>100K Candida albicans\t\n6/19/17\t\t\t>100K MSSA\t\n9/1/17\tLarge\t\t>100K MSSA\t\n9/15/17\tLarge\t\t50K MSSA\t\n9/20/17\tLarge\t>100\t40K MSSA\t\n2/6/18\tLarge\t\t5K mixed Gram-positive flora\t\n7/16/18\tLarge\t\t40K MSSA\t\n8/21/18\tLarge\t\t30K MSSA, 6K mixed Gram-positive flora\t\n11/16/18\tModerate\t\t>100K MSSA\t\n1/7/19\tModerate\t\t20K MSSA\t\n1/19/19\tSmall\t20–50\t400 CFU yeast\t\n3/9/19\tModerate\t>100\t2K yeast\t\n8/19/19\tModerate\tPacked field\t4K yeast\t\n9/5/19\t\t\tMycobacterium avium complex\t\n10/15/19\tLarge\t\tAFB culture negative\t\n11/5/19\tModerate\t\t30K Enterococcus faecalis, 20K yeast\t\n12/8/19\tModerate\t>100\t20K normal urogenital flora\t\n12/23/19\tLarge\t\t20K yeast, 10K Enterococcus faecalis\t\n1/3/20\tLarge\tPacked field\t50K yeast\t\n9/20/20\tNegative\t<5\tNo growth\t\n2/25/2021\tNegative\t<5\tNo growth\t\nWBC/HPF—white blood cells/high power field, MSSA—methicillin-susceptible Staphylococcus aureus, AFB—acid-fast bacillus, CFU—colony forming unit.\n\nidr-13-00045-t002_Table 2 Table 2 Mycobacterium avium complex susceptibility.\n\nAntimicrobial\tMIC\tInterpretation\t\nAmikacin IV\t2\tSensitive\t\nAmikacin—Liposomal, Inhaled\t2\tSensitive\t\nClarithromycin\t0.25\tSensitive\t\nLinezolid\t≤1\tSensitive\t\nMoxifloxacin\t0.25\tSensitive\t\nAbbreviation: MIC, minimum inhibitory concentration.\n\nidr-13-00045-t003_Table 3 Table 3 MAC case reports.\n\nYear\tReference\tAge/Sex\tRace\tClinical Findings\tDuration of Symptoms\tOrganism in Urine\tSusceptibility\tTreatment\tOutcome\t\n1963\tFaber et al. [29]\t27/F\tJapanese—American\tGross hematuria. Left renal mass\t1 week\tAtypical AFB (Battey type)\tN/A\tEmpirically started Streptomycin 1 g/day, INH 250 mg/day. One month in decrease streptomycin to twice a week. Total duration 4 months\tRemoval of left renal mass (pathology showed no AFB) after surgery pt was asymptomatic\t\n1966\tNewman, H. [30]\t52/F\tCaucasian\tPyuria and dysuria\t10 days, Intermittent dysuria since teenager, similar symptoms after 2 years\t2 cultures grew 3 atypical mycobacteria and one group 4 rapid growers\tN/A\tStreptomycin 1 g twice a week, INH 300 mg/day + PAS 12 g daily for 12 months, after which INH and PAS were continued for another 6 months\tSymptomatic improvement. Had left nephroureterectomy which showed granulomatosis changes consistent with tuberculosis. Urine sterilization after procedure.\t\n1973\tPergament et al. [31]\t62/F\tPresumed Caucasian\tFrequency, urgency, nocturia, suprapubic pain and right lower quadrant pain with gross hematuria\t6 months\tBattey-avian complex\tSensitive: INH, RIF, EMB\tINH 300 mg/day, RIF 600 mg/day, EMB 15 mg/kg/day and Streptomycin 1 g 3 times a week for total of 6 weeks\tPatient continued to have symptoms but achieved urine sterilization\t\n1986\tMikolich et al. [32]\t75/M\tPresumed Caucasian\tGranulomatous Prostatitis, Difficulty urinating with hematuria and pyuria\t1 year\tMAC\tInitial culture: Sensitive: PZA; Resistant: INH, EMB, streptomycin and RIF. CDC sensitivities to initial culture: Sensitive: ansamycin Resistant: Capreomycin, streptomycin, INH, PAS, RIF, EMB, kanamycin, PZA, cycloserine and ethionamide\tINH 300 mg/day, RIF 600 mg/day × 4 months, EMB 1 g/day + PZA 1.5 g/day. No change, 6 weeks of ansamycin 300 mg/day, INH 300 mg/day, EMB 1 g/day + 1 g of streptomycin IM 3 times a week for 1 week then twice weekly for total of 6 weeks\tNo improvement with treatment. Some improvement with NSAIDs\t\n2015\tObeid et al. [20]\t61/F\tSomali born\tLiver cirrhosis with chronic dysuria, s/p transplant with recurrence\tUnclear duration\tMAI\tSensitive to Clarithromycin, Moxifloxacin, Linezolid\tAzithromycin 250 mg/day, EMB 1200 mg/day, RIF 600 mg/day (substituted rifabutin), Moxifloxacin 400 mg/day—17 months total\tUrine sterilization in 5 months and completed 17 months of treatment. With 1 year of therapy after first negative mycobacterial urine culture. Recurrence after 8 months of orthotopic liver and kidney transplant. Refused treatment and pt died unrelated to MAI\t\n2018\tMiyashita et al. [28]\t63/F\tPresumed Japanese\tDisseminated MAC initially presented with fever, eruption and sterile pyuria\tUnclear duration\tMAC\tN/A\tClarithromycin 800 mg/day, RIF 450 mg/day, EMB 750 mg/day, (streptomycin 600 mg/day × 3 days—2 months)\t1 month after treatment afebrile, resolution of urinary incontinence—Regression of multiple organ involvement except splenic lesions—Over 20 months of therapy\t\n2019\tPresent case\t79/F\tCaucasian\tRecurrent symptomatic UTI\t3 years\tMAC\tSensitive: Amikacin, Clarithromycin, Linezolid and Moxifloxacin\tClarithromycin 500 mg po BID, RIF 600 mg po daily and EMB 1200 mg po daily changed treatment after 4 months to continue RIF 600 mg/day, linezolid 600 mg/day, and three-times-weekly amikacin for 3 weeks.\tAsymptomatic after 12 months of treatment. Urine sterilization.\t\nAFB—acid-fast Bacillus, N/A—not available, INH—isoniazid, PAS—para-aminosalicylic acid, RIF—rifampin, EMB—ethambutol, PZA—pyrazinamide, MAI—Mycobacterium Avium-Intracellulare, MAC—Mycobacterium avium complex, UTI—urinary tract infection, NSAIDs—nonsteroidal anti-inflammatory drugs.\n\nidr-13-00045-t004_Table 4 Table 4 Pharmacokinetics of antimycobacterial drugs with urine concentration.\n\nDrug\tDose\tUrinary Drug Level (μg/mL)\t\nClarithromycin [45]\t500 mg BID\t~1.24\t\nAzithromycin [46]\t500 mg qd\t~148\t\nRifampin [47]\t600 mg qd\t400–600\t\nEthambutol [48]\t25 mg/kg/d\t7–9\t\nStreptomycin [49]\t600 mg IM qd\t174–534\t\nAmikacin [50]\t500 mg IM qd\t600–832\t\nLinezolid [51]\t600 mg BID po\t192–61\t\nMoxifloxacin [52]\t400 mg qd po\t~137.6\t\nBedaquiline [53]\t400 mg po qd\t~4\t\nClofazimine [54]\t100 mg 3 times/wk\t156–456\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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"CLARITHROMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SILVER NITRATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2019", "drugenddateformat": "602", "drugindication": "Candida infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2019", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SILVER NITRATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SILVER NITRATE" }, "drugadditional": null, "drugadministrationroute": null, 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"drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Genitourinary tract infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SILVER NITRATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SILVER NITRATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Cystitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SILVER NITRATE" } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20190101" } }, "primarysource": { "literaturereference": "Rajendraprasad S, Destache C, Quimby D. Mycobacterium avium complex genitourinary infections: Case report and literature review. Infectious Disease Reports. 2021;13(2):454-464", "literaturereference_normalized": "mycobacterium avium complex genitourinary infections case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211124", "receivedate": "20210921", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19865323, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]
{ "abstract": "BACKGROUND\nPost-transplant lymphoproliferative disease (PTLD), a lymphoid proliferation observed after the solid organ transplantation or allogeneic stem cell transplant, is an important and mortal complication that can occur during the post-transplant period. Classical Hodgkin lymphoma-like PTLD is the least form of PTLD. We are presenting an adult case of classical Hodgkin lymphoma-like PTLD which was successfully treated with nivolumab.\n\n\nMETHODS\nA 31-year-old female was diagnosed with primary myelofibrosis and we performed allogeneic stem cell transplantation from her HLA fully matched brother in 2015. Two years after transplant, classical Hodgkin lymphoma-like PTLD was diagnosed. The patient was resistant to six cycles of ABVD chemotherapy and four cycles of brentuximab vedotin.\nAfter the failure of ABVD and brentuximab vedotin, we started nivolumab therapy at a dose of 3 mg/kg every 2 weeks. After six cycles, we achieved a PET negative complete remission. After 10 cycles of nivolumab, the patient is still followed with a complete remission. Still, there is no evidence of acute or chronic GvHD, and therefore no need for immunosuppressive treatment. No auto-immune complication was observed. It is planned to give nivolumab treatment to the patient until the progression.\n\n\nCONCLUSIONS\nOur case has depicted that the classical Hodgkin lymphoma type PTLD may be resistant to the conventional treatments and anti-CD30 brentuximab vedotine. In such cases, nivolumab may be an effective and worth assessing agent in terms of both activity and safety profile.", "affiliations": "Department of Hematology, Ankara City Hospital, Ankara, Turkey.;Department of Internal Medicine, Gaziantep University School of Medicine, Gaziantep, Turkey.;Department of Hematology, Gaziantep University School of Medicine, Gaziantep, Turkey.", "authors": "Gunes\|Ahmet K\|AK\|https://orcid.org/0000-0001-5522-8342;Demir\|Ilknur\|I\|;Pehlivan\|Mustafa\|M\|", "chemical_list": "D000074322:Antineoplastic Agents, Immunological; D001761:Bleomycin; D000077594:Nivolumab; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin", "country": "England", "delete": false, "doi": "10.1177/1078155220946462", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "27(2)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Nivolumab; allogeneic stem cell transplant; classical Hodgkin lymphoma-Like PTLD; post-transplant lymphoproliferative disease", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003606:Dacarbazine; D004317:Doxorubicin; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008232:Lymphoproliferative Disorders; D000077594:Nivolumab; D049268:Positron-Emission Tomography; D055728:Primary Myelofibrosis; D033581:Stem Cell Transplantation; D016896:Treatment Outcome; D014747:Vinblastine", "nlm_unique_id": "9511372", "other_id": null, "pages": "509-512", "pmc": null, "pmid": "32762294", "pubdate": "2021-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Classical Hodgkin lymphoma-like post-transplant lymphoproliferative disease after allogeneic stem cell transplantation for primary myelofibrosis is successfully treated with nivolumab: A case report.", "title_normalized": "classical hodgkin lymphoma like post transplant lymphoproliferative disease after allogeneic stem cell transplantation for primary myelofibrosis is successfully treated with nivolumab a case report" }	[ { "companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-298046", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91418", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (6 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": 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"drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (4 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BRENTUXIMAB VEDOTIN" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GUNES AK, DEMIR I, PEHLIVAN M. CLASSICAL HODGKIN LYMPHOMA?LIKE POST?TRANSPLANT LYMPHOPROLIFERATIVE DISEASE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION FOR PRIMARY MYELOFIBROSIS IS SUCCESSFULLY TREATED WITH NIVOLUMAB: A CASE REPORT. J ONCOL PHARM PRACT. 2021?27:(2):509?512", "literaturereference_normalized": "classical hodgkin lymphoma like post transplant lymphoproliferative disease after allogeneic stem cell transplantation for primary myelofibrosis is successfully treated with nivolumab a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20210527", "receivedate": "20210527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19313334, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "BACKGROUND\nSusac syndrome (SuS) is a rare condition characterized by a clinical triad of sensorineural hearing loss, branch artery occlusion and encephalopathy. This study reports an increased incidence of SuS in Israel. We describe the clinical characteristics of these patients, diagnostic procedures and the use and subsequent outcomes of newly published treatment guidelines.\n\n\nMETHODS\nThis is a single center retrospective study. Patients who were diagnosed with SuS between July 2017 and August 2018 were enrolled in this study.\n\n\nRESULTS\nSeven patients were diagnosed with SuS according to the diagnostic criteria in a time period of 13 months. The annual incidence was recently evaluated in Austria to be 0.024/100000, therefore, our case series represent at least a 5.4- fold increase in the annual incidence of SuS expected in Israel and a 7-fold increase in the annual incidence expected in our medical center. Mean time from the onset of the symptoms to diagnosis was three weeks and follow-up time was twenty four months. Recent exposure to cytomegalovirus was serologically evident in three patients and one patient had high titer of anti-streptolysin antibody. All patients underwent brain MRI, fluorescein angiography and audiometry. All patients were treated according to the newly recommended guidelines. All patients achieved clinical and radiological stability.\n\n\nCONCLUSIONS\nWe report of an increased incidence of SuS in Israel. Infectious serological findings may imply a post infectious mechanism. The use of the recommended diagnostic procedures reduced the time to diagnosis. Newly published treatment guidelines led to favorable clinical outcomes.", "affiliations": "Neuro-Immunology Service and Department of Neurology Rabin Medical Center, 4941492, Petach Tikva, Israel. [email protected].;Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Neuroradiology unit, Department of Radiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Department of ENT, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Neuroimmunology and Multiple Sclerosis Unit of the Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Neuroimmunology and Multiple Sclerosis Unit of the Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.", "authors": "Wilf-Yarkoni\|A\|A\|http://orcid.org/0000-0002-2584-5793;Elkayam\|O\|O\|;Aizenstein\|O\|O\|;Oron\|Y\|Y\|;Furer\|V\|V\|;Zur\|D\|D\|;Goldstein\|M\|M\|;Barequet\|D\|D\|;Hallevi\|H\|H\|;Karni\|A\|A\|;Habot-Wilner\|Z\|Z\|;Regev\|K\|K\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12883-020-01892-0", "fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377 BioMed Central London \n\n1892\n10.1186/s12883-020-01892-0\nResearch Article\nIncreased incidence of Susac syndrome: a case series study\nhttp://orcid.org/0000-0002-2584-5793Wilf-Yarkoni A. [email protected] 1 Elkayam O. 23 Aizenstein O. 4 Oron Y. 5 Furer V. 23 Zur D. 36 Goldstein M. 36 Barequet D. 36 Hallevi H. 7 Karni A. 378 Habot-Wilner Z. 36 Regev K. 7 1 grid.413156.40000 0004 0575 344XNeuro-Immunology Service and Department of Neurology Rabin Medical Center, 4941492 Petach Tikva, Israel \n2 grid.413449.f0000 0001 0518 6922Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel \n3 grid.12136.370000 0004 1937 0546Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel \n4 grid.413449.f0000 0001 0518 6922Neuroradiology unit, Department of Radiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel \n5 grid.413449.f0000 0001 0518 6922Department of ENT, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel \n6 grid.413449.f0000 0001 0518 6922Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel \n7 grid.413449.f0000 0001 0518 6922Neuroimmunology and Multiple Sclerosis Unit of the Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel \n8 grid.12136.370000 0004 1937 0546Sagol School of Neuroscience Tel Aviv University, Tel Aviv, Israel \n2 9 2020 \n2 9 2020 \n2020 \n20 33225 5 2020 18 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nSusac syndrome (SuS) is a rare condition characterized by a clinical triad of sensorineural hearing loss, branch artery occlusion and encephalopathy. This study reports an increased incidence of SuS in Israel. We describe the clinical characteristics of these patients, diagnostic procedures and the use and subsequent outcomes of newly published treatment guidelines.\n\nMethods\nThis is a single center retrospective study. Patients who were diagnosed with SuS between July 2017 and August 2018 were enrolled in this study.\n\nResults\nSeven patients were diagnosed with SuS according to the diagnostic criteria in a time period of 13 months. The annual incidence was recently evaluated in Austria to be 0.024/100000, therefore, our case series represent at least a 5.4- fold increase in the annual incidence of SuS expected in Israel and a 7-fold increase in the annual incidence expected in our medical center. Mean time from the onset of the symptoms to diagnosis was three weeks and follow-up time was twenty four months.\n\nRecent exposure to cytomegalovirus was serologically evident in three patients and one patient had high titer of anti-streptolysin antibody. All patients underwent brain MRI, fluorescein angiography and audiometry.\n\nAll patients were treated according to the newly recommended guidelines. All patients achieved clinical and radiological stability.\n\nConclusions\nWe report of an increased incidence of SuS in Israel. Infectious serological findings may imply a post infectious mechanism. The use of the recommended diagnostic procedures reduced the time to diagnosis. Newly published treatment guidelines led to favorable clinical outcomes.\n\nKeywords\nSusac syndromeTreatmentcmv post infectiousBranch retinal artery occlusionissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nSusac syndrome (SuS) is a rare immune-mediated occlusive microvascular disease. It is characterized by a typical clinical triad of encephalopathy, visual disturbances and hearing loss [1–5]. However, there is a great variability in clinical manifestations and the complete triad is present in less than 20% of patients at disease onset [4–9]. Treatment of SuS is particularly challenging, owning to its rarity, and the great variability in presentation, there are no randomized control trials to evaluate treatment strategies. Optimal outcome requires rapid and aggressive treatment, and acute treatments limited to glucocorticoids and/or IVIg appears to be insufficient to halt the progression of disease [10–15]. Recent treatment guidelines have been published based on disease severity [10].\n\nThe available data regarding the prevalence and incidence of SuS is limited. The annual incidence was recently evaluated in Austria to be 0.024/100000 [16]. The largest case series from Israel comprises 10 patients who were diagnosed over a period of 26 years [17].\n\nIn this retrospective case series, we report seven newly diagnosed cases of SuS in a single referral center over a time period of thirteen months. For a reference, from 2013 to 2016 only two patients were diagnosed with SuS in our institute. We hereby describe the clinical features, diagnostic procedures employed, treatment approach and outcome of this cohort.\n\nMethods\nStudy design and data collection\nThis is a retrospective case series of patients treated at a single tertiary medical center. The study was approved by the Tel Aviv Sourasky Medical Center Institutional Review Board (Helsinki Committee). (0435-15-TLV).\n\nAll patients diagnosed with SuS, between July 2017 and August 2018 were included. The European Susac consortium criteria were used for diagnosis. According to these criteria, patients with involvement of all three main organs (brain, eye and ear) who fulfill the typical clinical triad were defined as definite SuS and patients with involvement of two main organs were defined as probable SuS (Supplementary Table 1) [18].\n\nAll patients were hospitalized in the neurological department in Tel Aviv Sourasky Medical Center and were examined by ophthalmologist and ear, nose and throat specialist. Data regarding the following parameters were collected: patient demographics, medical history, and medications. Clinical presentation including history, neurological assessment, treatment protocol, evidence of relapse and response to treatment were recorded. Detailed personal and occupational history was obtained together with possible environmental, toxic, chemical exposures according to the exposure survey.\n\nAll patients underwent extensive medical investigations to establish the diagnosis of SuS: blood tests and screening tests for infectious diseases; cerebrospinal fluid (CSF) analysis and diagnostic procedures including brain MRI, auditory evaluation, and Fluorescein angiogram (FA). Spectral-domain optical coherence tomography (OCT) was done in all cases since it is an emerging diagnostic tool in SuS [19, 20]. Macular OCT scans were evaluated for (1) areas of hyperreflective thickening of retinal nerve fiber layer to the outer plexiform layer which is indicative for tissue swelling due to acute branch retinal artery occlusion (BRAO), and (2) areas of thinning of these layers indicative for previous ischemic damage. Cerebral angiography was performed in two patients and brain biopsy was performed in one patient.\n\nCNS involvement was characterized by both clinical and radiological evidence. Clinical symptoms included new cognitive impairment and/or behavioral changes and/or new focal neurological symptoms and/or new headache. MRI findings included typical findings on cranial MRI—hyperintense, multifocal, small round lesions; at least one of them in the corpus callosum (‘snowball’) in T2 (or FLAIR) weighted sequences [18]. Cervical spine MRI was done in one patient.\n\nIn order to evaluate treatment response, a special follow-up clinic was created with a multi-disciplinary team including a neurologist, rheumatologist and an ophthalmologist as well as continuing monitoring by MRI scans and FA. New or worsening of neurological, ocular or auditory symptoms and/or new lesions on brain MRI and/or evidence of new BRAO’s on FA determined a relapse. Clinical stability was defined as no evidence of clinical relapse, no new lesion on brain MRI and no evidence of BRAOs on FA study. Outcome measures included adverse events and clinical and para-clinical evidence of disease sequelae.\n\nResults\nClinical characteristics\nTable 1 summarizes the demographic data, signs and symptoms upon presentation. Seven patients (4 females, 3 males) were diagnosed with SuS. There is no available data on the incidence of SuS in Israel. Two patients were diagnosed with SuS in Tel-Aviv Medical Center from 2013 to 2016 (Supplementary figure 1). We calculated the expected number of patients per year in Israel, based on annual incidence evaluation in Austria of 0.024/100000 (age over 19), to be 1.3. Therefore, our case series represent at least a 5.4-fold increase in the annual incidence of SuS compared to a published registry and a 7-fold increase in the annual incidence expected in our medical center.\nTable 1 Demographic and clinical presentation\n\n\tTime to diagnosis\tDisease severity\tLumber Puncture\tCNS involvment\tEye involvment\tEar involvment\tComplete triad**\tSerology\tNon-neurological symptoms\t\n\t\t\tOpening Pressure (mm H2o)\tWBC (cells/μl)\tProtein (mg/dl)\tCognitive/ Psychiatric\tFocal signs\tHeadache\tS\tA-S*\tS\tA-S*\t\t\t\t\n1.M/20\tTwo weeks\tSevere\t260\t1\t110\tCognitive + psychiatric\tAphasia and sensory disturbance\t+\t\tBL\tBL\t\t+\tCMV IgM\tGI symptoms\t\n2.F/34\tTwo weeks\tModerate\t80\t14\t125\tModerate encephalopathy\t–\t–\t\tBL\tUL+\n\nVertigo\n\n\t\t+\t\t\t\n3.F/20\tThree weeks\tMild\t–\t–\t–\tCognitive + psychiatric\t–\t+\tUL\t\t\t\t–\t\tGI symptoms\t\n4.F/38\tTwo weeks\tModerate\t165\t3\t61\tCognitive + psychiatric\t–\t–\tBL\t\t\tBL\t+\tCMV IgM\tGI symptoms\t\n5.M/35\tNine weeks\tSevere\tN/A\t9\t140\tCognitive impairment\t–\t+\tBL\t\tUL\t\t+\t\t\t\n6.M/33\tThree weeks\textremely severe\t205\t3\t109\tSevere encephalopathy\tLeft hemiparesis\t+\t\tBL\t\tBL\t+\tCMV IgM\t\t\n7.F/30\tTwo weeks\tModerate\t220\t4\t99\tCognitive impairment\tLeft hemihypoesthesia\t+\tBL\t\t–\t–\t–\tAnti Streptolysin\t\t\nNote: S – symptomatic, A-S – A-symptomatic. * complete triad – evidence for CNS, retinal and Vestibulocochlear involvement; UN – unilateral, bilateral, Abbreviations: CMV – cytomegalovirus, GI – gastrointestinal, WBC –white blood cells\n\n\n\nFive patients fulfilled the criteria for definite SuS and two patients for probable SuS. Their mean age at presentation was 30 years (range 20-38 years). All cases were diagnosed during the summer-autumn seasons (July-October). One women was pregnant in her 7th gestational week. The mean duration from the onset of the symptoms to diagnosis was three weeks (2-9 weeks). Mean duration of follow-up was 24 months and one patient was lost to follow after 2 months. No patient had previous neurological disease. Based on the detailed personal history, no common demographic characteristics were found among patients. Toxic environmental exposure was not reported.\n\nAt clinical onset, the most common manifestations were CNS symptoms. Disease severity was determined according to the extent of CNS involvement; one patient was defined as extremely severe SuS, two patients as severe SuS, three patients as moderate SuS and one as mild SuS. All patients suffered from different severity of encephalopathy characterized by cognitive impairment (mainly deficits in executive function, language and memory) or confusion. Three patients had a psychiatric manifestation of depression and anxiety. Three patients presented with focal neurological signs; sensory disturbance (two patients) and severe hemiparesis (one patient). Five patients had severe migrainous or oppressive headache. Visual disturbances were described as flashing lights in one patient, and visual field defects in three patients. Vestibulocochlear involvement was the least common presentation; three patients suffered from acute sensorineural hearing loss, one of these patients also suffered from vertigo. Gastrointestinal (GI) symptoms, i.e. abdominal pain and diarrhea were reported in three patients.\n\nDiagnostic procedures\nCharacteristic brain MRI findings included: 1. All patients presented with Flair/T2 hyperintense lesions located in the supratentorial white and gray matter areas. Three patients had additional infratentorial lesions. 2. Typical corpus callosum “snow ball” lesions that are considered a characteristic sign of SuS (Fig. 1a1) [21–23] were detected in all of our patients although was not evident on the initial imaging upon presentation in one patient. 3. Punctuate DWI hyperintense lesions with corresponding ADC hypointensity (restricted diffusion) were associated with disease activity in all of our patients (Fig. 1a) [9]. 4. Leptomeningeal enhancement was demonstrated in four patients (Fig. 1a6), three of these patients suffered from severe headache. 5. Corpus callosum hypointense T1 lesions were found in all our patients and corpus callosum atrophy was evident in five patients [24]. One of our patients (patient number 6) had a cervical spinal cord MRI done at disease onset. No evidence of cervical spine involvement was detected.\nFig. 1 Typical diagnostic procedures findings. a Brain MRI. Sagittal and axial T2 FLAIR sequence, showing hyperintense lesions in the corpus callosum (“snow balls”). A1. Periventricular and subcortical areas. A2-3. Sagittal T1 sequence corpus callosum (“black holes”). A4. Axial DWI sequence which show restricted diffusion A5. Leptomeningeal enhancement with gadolinium A6. b Wide field Fluorescein angiogram demonstrating right eye peripheral (superior, temporal and inferior) branch artery occlusions and focal arterial leakage in an inferior branch artery. c. A bilateral low-tone and middle-tone sensorineural hearing loss is seen, with abnormal low scores in speech audiometry\n\n\n\nFA was pathological in all our patients, even though three patients had no ocular symptoms. Abnormalities included BRAOs and arterial wall hyperfluorescence (AWH) (Fig. 1b) [21, 22, 25]. One case had both arterial and venous occlusions. Audiometry showed low-frequency sensorineural hearing loss in five cases (Fig. 1c) [1, 6, 9, 18, 26], three were bilateral and two were unilateral. Of note, two patients had SNHL on audiometry with no auditory symptoms. All our patients performed OCT. Three patients showed signs of acute retinal hypoxia indicating an acute macular BRAO. Additionally, five patients showed signs of macular retinal thinning, compatible with previous events of macular ischemia. Two patients had normal OCT.\n\nSerology for cytomegalovirus (CMV) was available in four patients. Three patients had IgM antibodies for CMV. CMV serology was retested in two patients; in one patient (Patient number one) there was sero-conversion from IgM to IgG and in the second patient (Patient number four) both IgG and IgM levels remained high during follow-up, this patient showed clinical and laboratory evidence of CMV reactivation. CMV PCR in the serum was done in two patients; patient number one had 543 IU/ml and patient number four had 70,635 IU/ml. CMV IgM antibody in the CSF were not measured. CMV immune-stain was done on tissue obtained from brain biopsy. One patient had high titer of anti-streptolysin antibodies. Anti-streptolysin titer in the CSF was not measured.\n\nCSF analysis was performed in six patients (Table 1). Elevated protein levels were observed in all these patients (mean levels 107 mg/dl; 61- 140 mg/dl) and mean CSF cell count was 6 cells/μl (1-14 cells/μl). The presence of oligoclonal bands (OCB) in the CSF was examined in four patients and were all negative providing no evidence of intrathecal synthesis of OCB. Brain angiography was performed in two patients and was unremarkable. One of our patients (patient number 6) who presented with severe encephalopathy underwent stereotactic brain biopsy from an active lesion on his right parietal lobe. The samples include fragments of cortex, white matter and some vessels from subarachnoid space. There was no evidence of vasculitis or inflammatory reaction. CMV immune-stain was negative.\n\nFigure 1 demonstrates typical diagnostic findings.\n\nTreatment regimen and clinical outcomes\nTable 2 summarizes treatment regimens, major side effects and patient outcomes. Patients were treated according to disease course and the severity of CNS involvement based on the recently published treatment guidelines (Supplementary Table 2) [10]. IV Methyprednisolone (IVMP), intravenous immune globulin (IVIG) and mycophenolate mofetil were used for mild cases. An addition of Cyclophosphamide (CPM) and Rituximab (RTX) is optional for the treatment of moderate cases and is recommended to use in severe CNS involvement. All seven patients were treated with IV Methyprednisolone (IVMP) within the first month following the onset of symptoms and during relapses, followed by very slow tapering of prednisone. In addition, all patients received mycophenolate mofetil (MMF) or azathioprine. Six patients were treated with intravenous immune globulin (IVIG) 2 g/kg every 3-4 weeks or 1 g/mg every 2 weeks until clinical stability achieved. Cyclophosphamide (CPM; after fertility preservation) was administered in one patient with moderate SuS and in four patients with severe or extremely severe SuS. Three patients were treated with rituximab. Anti- aggregation is not included in the treatment guidelines and evidence for its efficiency in SuS in lacking [14, 15, 27], nevertheless, all seven patients were treated with an anti- aggregation agent.\nTable 2 Treatment regimens, major side effects and patient outcomes\n\n\t\t\tTreatment\toutcome\tSide effects\tMaintenece treatment\t\nPatient\tDisease Severity\tFollwup time (months)\tAnti aggregation drugs\tIVMP\tIVIG\tCPM\tMMF\tRTX\tAuditory\tVision\tCNS\t\t\t\n1\tSevere\t33\tAcetylsalicylic acid (+Clopidogrel)\t+\t+\t+\t+\t+\tSevere bilateral SNHL\t\tNo evidence for neurological residual\tCMV reactivation\tAspirin, Prednisone, IVIG (1 g/kg), Rituximab,MMF\t\n2\tModerate\t33\tAcetylsalicylic acid\t+\t–\t+\t+\t–\tSNHL\tBilateral VF deficient\tNo evidence for neurological residual\t\tAspirin,MMF\t\n3\tMild\t2\tAcetylsalicylic acid\t+\t+\t–\t+\t–\tN/A\tN/A\tN/A\tN/A\tN/A\t\n4\tModerate\t30\tAcetylsalicylic acid\t+\t+\t–\t+\t+\t\tMild VF deficient\tFatigue\tCMV reactivation\tAspirin, IVIG (1 g/kg), Rituximab\t\n5\tSevere\t30\tAcetylsalicylic acid\t+\t+\t+\tAzathioprine\t+\tSNHL\tbilateral VF deficient\tNo evidence for neurological residual\tPathological fracture\tPrednisone, Rituximab\t\n6\textremely severe\t21\tAcetylsalicylic acid(+Enoxaparin)\t+\t+\t+\t+\t\t\t\tHemiparesis,ataxia and severe cognitive decline\t\tAspirin, Prednisone, IVIG (1 g/kg),MMF\t\n7\tModerate\t20\tAcetylsalicylic acid\t+\t+\t+\t+\t–\t\t\tMild cognitive decline\t\tAspirin, prednisone and IVIG (1 g/kg)\t\nNote: N/A – not available; Abbreviations: CMV – cytomegalovirus, CPM – cyclophosphamid, IVMP – intravenous methylprednisolone, IVIG – intravenous immune globulin, MMF – mycophenolate mofetil, RTX - rituximab, SNHL - sensorineural hearing loss, VF – visual field\n\n\n\nPatients were clinically monitored with frequent clinical assessments in addition to routine brain MRI, FA and audiometry to evaluate treatment response and outcome. Treatment led to clinical and radiological stability in all patients. One patient who presented with severe encephalopathy and hemiparesis was stable under this regimen but suffered from a residual mild hemiparesis, ataxia, memory impairment, attention deficit and behavioral disinhibition. Another patient experienced a relapse after discontinuation of medication due to adherence problem. This patient has a residual mild cognitive decline. Three patients had no residual neurological deficits. Brain MRI lesions remained unchanged in five patients however, in one patient some lesions disappeared on follow-up MRI. Follow up MRI revealed global brain atrophy and corpus callosum atrophy in four patients.\n\nTwo patients had residual visual field defects. OCT at final visit was performed in patients and showed bilateral thinning of retinal layers in five patients. Three patients who presented with SNHL did not improve on follow up auditory testing. Major side effects of the treatment included pathological fracture in one patient and reactivation of CMV infection in two patients that caused GI symptoms and was diagnosed by testing CMV PCR in serum. Patient number 4 suffered from severe diarrhea and serum CMV PCR reached a maximum level of 70,635 IU/ml and return to negative after treatment with valcyclovir.\n\nThe maintenance treatment included aspirin, mycophenolate mofetil (MMF) 1000 mg BID, prednisone with very slowly tapering down, decreasing doses of IVIG and Rituximab every 6 months.\n\nDiscussion\nIn this case series, we describe seven patients diagnosed with SuS over a time period of thirteen months, representing at least a 5.4 - fold increase in the annual incidence of SuS expected in comparison to a published registry and a 7-fold increase in the annual incidence expected in our medical center. The clinical presentation and phenotype of our cohort was consistent with previously reported cases of SuS [4, 6, 7, 16–18]. We didn’t find any common environmental or toxic exposure preceding the disease onset.\n\nThe etiology of SuS remains unknown. An autoimmune process leading to occlusion of micro vessels have been postulated [2]. Elevated serum levels of anti-endothelial cells antibodies are found in approximately 25% of the patients, suggestive of an antibody-mediated immunity process [28, 29]. Recently a CD8+ T-cell-mediated endotheliopathy has been shown to play a key role in SuS [5]. What triggers this immune response is currently unknown.\n\nBased on review of the literature, an infectious trigger does not seem to play a major role since it was detected only in 19 out of 304, of published cases [6]. Given a predisposition of the disease onset to the summer-autumn months and the absence of a clear disease trigger in our cohort, we searched for a possible infectious trigger. Interestingly, at presentation three quarters of our patients, who were tested for CMV, had positive IgM antibodies in the sera, while PCR for CMV in CSF was negative. Two of these patients suffered from CMV reactivation that caused GI symptoms following immunosuppressive treatment. In another patient, there was evidence of a recent streptococcal infection with a high serum anti-streptolysin titer. The fact that despite strong immunosuppressive therapy there was marked improvement and no eruption of symptoms supports an inflammatory post or para-infectious pathophysiology. Accordantly, the use of anti-viral treatment does not seem to be indicated. One hypothesis regarding disease pathophysiology that supports a para-infectious mechanism is the presentation of viral antigen on the endothelium following viral infection [5].\n\nTwo conclusions might be derived from our observation: the importance of searching for an infectious trigger, which might shed some light on disease mechanism and risk factors. Additionally, we believe that it is highly recommended to screen for possible latent infections due to robust immune suppression used to effectively treat these patients.\n\nThere is a great variability in the clinical presentation of SuS and the complete triad is present in less than 20% of patients at presentation. As a result, misdiagnosis or delay in diagnosis and treatment are common [5–7]. Diagnostic procedures such as MRI, FA, OCT [19, 20] and audiometry are crucial to enable early and accurate diagnosis since, as mentioned above, subclinical pathology may occur without clinical manifestation [5, 7, 18]. Of note, only one patient in this cohort presented with the complete triad of neurological, auditory and visual symptoms. Using these diagnostic tools, we were able to establish the diagnosis of definite SuS at presentation in five patients and to reduce time to diagnosis from twenty-one weeks to three weeks [6]. Moreover, close monitoring using these tools may allow the detection of silent disease activity. Anti-endothelial cell antibodies were not checked. Although high levels of anti-endothelial cell antibodies have been reported, titers > 1:100 were found in only 25% of patients with SuS and therefore, are not included in the diagnosis criteria of SuS [12].\n\nGI symptoms reported by three of our patients may reflect the systemic nature of the disease as had already been proposed [30]. This could also be a result of preceding infection with CMV as two of these patients were CMV IgM positive.\n\nTreatment of SuS is particularly challenging [10, 11, 22]. Importantly, Multiple sclerosis treatments may cause exacerbation of SuS [31]. Due to the rarity of the disease, no randomized controlled trials have been done. Rennebohm et al. published treatment guidelines based on large cohort of patients [10]. Treatment regimen is based on disease manifestation and severity. This is the first case series published using these treatment guidelines and it demonstrates that in order to achieve optimal outcomes, rapid and sometimes aggressive immunosuppressive combination therapy is required.\n\nThis study has several limitations. This is a retrospective case series that relies on medical records. There was some missing data, such as CMV status in three patients, serology follow-up of CMV levels, CMV serology in the CSF and antibody detection rate of IgM CMV antibodies in a control group. The small sample size makes it difficult to establish causal interference between infections and SuS, so that we cannot rule out the possibility of co-incidence or false positivity. It is important to recognize that potentially rise in awareness due recently published diagnostic criteria and suggested therapeutic guidelines [10, 18] led to earlier and more frequent detection of the syndrome. However, this publications did not cause a shift in diagnosis as criteria have not been revised.\n\nMoreover, the mean follow-up time was less than two years, so that long-term outcomes cannot be drawn from this study. As this is a tertiary referral center, our case series probably includes more severe forms of SuS.\n\nConclusion\nOur case series adds to the present knowledge regarding this rare disorder. It emphasizes the variability in clinical presentation and highlights the importance of diagnostic procedures such as FA, audiometry and MRI in order to establish early diagnosis and avoid irreversible neurological damage. Further research on the pathophysiology of SuS and randomized controlled clinical trials are warranted to enable the development of evidence-based management strategies for these patients.\n\nSupplementary information\n\nAdditional file 1 Supplementary figure 1. PPT. Incidence of Susac syndrome between the years 2013-2018 in Tel-Aviv Medical Center. Each line represents a new diagnosis of Susac syndrome.\n\n Additional file 2 Supplementary Table 1. DOC. Diagnostic criteria for Susac syndrome. Adopted from Kleffner et al. J Neurol Neurosurg Psychiatry 2016. Abbreviations: AWH = arterial wall hyperfluorescence; BRAO = branch retinal artery occlusion; FLAIR = fluid-attenuated inversion recovery; SD-OCT = spectral domain optical coherence tomography; SuS = Susac syndrome; SNHL = sensorineural hearing loss.\n\n Additional file 3 Supplementary Table 2. DOC. Treatment guidelines according to severity of CNS involvement. Adopted from Rennebohm et al. International journal of stroke 2017. Abbreviations: BID twice a day; CPM-cyclophosphamid; IVIG – intravenous immune globulin; IVMP – intravenous methylprednisolone; MMF – mycophenolate mofetil; TAC-tacrolimus.\n\n \n\nAbbreviations\nAWHArterial wall hyperfluorescence\n\nBRAOBranch retinal artery occlusion\n\nCSFCerebrospinal fluid\n\nCMVCytomegalovirus\n\nCPMCyclophosphamide\n\nCCCorpus Callosum\n\nFAFluorescein angiography\n\nGIGastrointestinal\n\nIVIGIntravenous immune globulin\n\nIVMPIV Methyprednisolone\n\nMMFMycophenolate mofetil\n\nOBCOligoclonal bands\n\nOCTOptical coherence tomography\n\nSuSSusac syndrome\n\nSNHLSensorineural hearing loss\n\nRTXRituximab\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s12883-020-01892-0.\n\nAcknowledgements\nNo acknowledgements.\n\nAuthors’ contributions\nAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by AWY, OE, OA, YO, VF, DZ, MG, DB, HH, AK, ZHW, KR. The first draft of the manuscript was written by AWY and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or nonprofit sectors.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThe study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. The study was approved by the Tel Aviv Sourasky Medical Center Institutional Review Board (Helsinki Committee). (0435-15-TLV). The need for consent was waived by the IRB due to the retrospective nature of the study.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interest. None of the authors reports conflicts of interest related to this work. Dr. Karni Arnon received research support from Stem Cell Medicine Ltd., Medison Pharma Ltd. and from Novartis Pharmaceutical Ltd.\n==== Refs\nReferences\n1. Kleffner I A brief review of Susac syndrome J Neurol Sci 2012 322 1-2 35 40 10.1016/j.jns.2012.05.021 22640902 \n2. Susac JO Susac's syndrome: 1975-2005 microangiopathy/autoimmune endotheliopathy J Neurol Sci 2007 257 1-2 270 272 10.1016/j.jns.2007.01.036 17331544 \n3. Susac JO Hardman JM Selhorst JB Microangiopathy of the brain and retina Neurology 1979 29 3 313 316 10.1212/WNL.29.3.313 571975 \n4. Susac JO Susac's syndrome: the triad of microangiopathy of the brain and retina with hearing loss in young women Neurology 1994 44 4 591 593 10.1212/WNL.44.4.591 8164809 \n5. Gross CC CD8(+) T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome Nat Commun 2019 10 1 5779 10.1038/s41467-019-13593-5 31852955 \n6. Dorr J Characteristics of Susac syndrome: a review of all reported cases Nat Rev Neurol 2013 9 6 307 316 10.1038/nrneurol.2013.82 23628737 \n7. Zengin Karahan S Susac syndrome: clinical characteristics, diagnostic findings and treatment in 19 cases Mult Scler Relat Disord 2019 33 94 99 10.1016/j.msard.2019.05.018 31176296 \n8. Garcia-Carrasco M Susac's syndrome: an update Autoimmun Rev 2011 10 9 548 552 10.1016/j.autrev.2011.04.006 21515413 \n9. Garcia-Carrasco M Mendoza-Pinto C Cervera R Diagnosis and classification of Susac syndrome Autoimmun Rev 2014 13 4-5 347 350 10.1016/j.autrev.2014.01.038 24424186 \n10. Rennebohm RM, et al. 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Seifert-Held T Susac's syndrome: clinical course and epidemiology in a central European population Int J Neurosci 2017 127 9 776 780 10.1080/00207454.2016.1254631 27788613 \n17. Vishnevskia-Dai V Susac syndrome: clinical characteristics, clinical classification, and long-term prognosis Medicine (Baltimore) 2016 95 43 e5223 10.1097/MD.0000000000005223 27787385 \n18. Kleffner I Diagnostic criteria for Susac syndrome J Neurol Neurosurg Psychiatry 2016 87 12 1287 1295 10.1136/jnnp-2016-314295 28103199 \n19. Brandt AU RETINAL LESION EVOLUTION IN SUSAC SYNDROME Retina 2016 36 2 366 374 10.1097/IAE.0000000000000700 26200513 \n20. Ringelstein M Retinal pathology in Susac syndrome detected by spectral-domain optical coherence tomography Neurology 2015 85 7 610 618 10.1212/WNL.0000000000001852 26203089 \n21. Saw VP Susac syndrome: microangiopathy of the retina, cochlea and brain Clin Exp Ophthalmol 2000 28 5 373 381 10.1046/j.1442-9071.2000.00345.x 11097286 \n22. Lubow M Fluorescein and indocyanine green angiographies in Susac syndrome Retina 2008 28 8 1174 10.1097/IAE.0b013e31817bf052 18779724 \n23. Susac JO MRI findings in Susac's syndrome Neurology 2003 61 12 1783 1787 10.1212/01.WNL.0000103880.29693.48 14694047 \n24. Wuerfel J Lesion morphology at 7 tesla MRI differentiates Susac syndrome from multiple sclerosis Mult Scler 2012 18 11 1592 1599 10.1177/1352458512441270 22711711 \n25. Egan RA Hills WL Susac JO Gass plaques and fluorescein leakage in Susac syndrome J Neurol Sci 2010 299 1-2 97 100 10.1016/j.jns.2010.08.043 20880549 \n26. Egan RA Diagnostic criteria and treatment algorithm for Susac syndrome J Neuroophthalmol 2019 39 1 60 67 10.1097/WNO.0000000000000677 29933288 \n27. Gordon DL Hayreh SS Adams HP Jr Microangiopathy of the brain, retina, and ear: improvement without immunosuppressive therapy Stroke 1991 22 7 933 7 10.1161/01.STR.22.7.933 1853414 \n28. Jarius S Anti-endothelial serum antibodies in a patient with Susac's syndrome J Neurol Sci 2009 285 1-2 259 261 10.1016/j.jns.2009.07.002 19643446 \n29. Magro CM Susac syndrome: an organ-specific autoimmune endotheliopathy syndrome associated with anti-endothelial cell antibodies Am J Clin Pathol 2011 136 6 903 912 10.1309/AJCPERI7LC4VNFYK 22095376 \n30. Marrodan M Gastrointestinal compromise in Susac syndrome J Neurol Sci 2017 379 318 320 10.1016/j.jns.2017.06.040 28716271 \n31. Zhovtis Ryerson L Incomplete Susac syndrome exacerbated after natalizumab Neurol Neuroimmunol Neuroinflamm 2015 2 5 e151 10.1212/NXI.0000000000000151 26445727\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2377", "issue": "20(1)", "journal": "BMC neurology", "keywords": "Branch retinal artery occlusion; Susac syndrome; Treatment; cmv post infectious", "medline_ta": "BMC Neurol", "mesh_terms": "D000328:Adult; D001927:Brain Diseases; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D015994:Incidence; D008279:Magnetic Resonance Imaging; D008297:Male; D011859:Radiography; D012189:Retrospective Studies; D055955:Susac Syndrome; D055815:Young Adult", "nlm_unique_id": "100968555", "other_id": null, "pages": "332", "pmc": null, "pmid": "32878610", "pubdate": "2020-09-02", "publication_types": "D016428:Journal Article", "references": "19643446;24424186;8164809;22640902;29933288;1853414;26200513;22095376;21515413;14694047;27787385;22221557;27788613;23628737;24606999;20880549;31176296;28103199;17331544;26445727;29971525;26203089;18779724;571975;24662104;31852955;11097286;22711711;26715396;28716271", "title": "Increased incidence of Susac syndrome: a case series study.", "title_normalized": "increased incidence of susac syndrome a case series study" }	[ { "companynumb": "IL-BEH-2020123524", "fulfillexpeditecriteria": "1", "occurcountry": "IL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "NOT REPORTED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUSAC^S SYNDROME", 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"reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection reactivation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILF-YARKONI A., ELKAYAM O., AIZENSTEIN O., ORON Y., FURER V., ZUR D. ET AL. INCREASED INCIDENCE OF SUSAC SYNDROME: A CASE SERIES STUDY. 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUSAC^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": "ACETYLSALICYLIC ACID" } ], "patientagegroup": "5", "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection reactivation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WILF-YARKONI A., ELKAYAM O., AIZENSTEIN O., ORON Y., FURER V., ZUR D. 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SYNDROME: A CASE SERIES STUDY? WILF-YARKONI? 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WILF-YARKONI, A ET AL? BMC NEUROLOGY (2020) 20:332 HTTPS://DOI.ORG/10.1186/S12883-020- 01892-0", "literaturereference_normalized": "increased incidence of susac syndrome a case series study", "qualification": null, "reportercountry": "IL" }, "primarysourcecountry": "IL", "receiptdate": "20201001", "receivedate": "20200923", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18302551, "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": "Current management of osteosarcoma at the authors' institution involves intraarterial induction chemotherapy using intermittent cycles of cisplatin and doxorubicin (Adriamycin), surgical resection with limb-sparing wherever possible, and adjuvant systemic chemotherapy (high-dose methotrexate with retrieval and doxorubicin). Twenty cases treated in this way between May 1983 and May 1989 are reviewed. There were 18 Stage IIB osteosarcomas and two Stage IIB malignant fibrous histiocytomas. Chemotherapeutic effect was evaluated in the resected tumors. There was little correlation between the clinical response to the induction chemotherapy and cell necrosis present in the resected tumor mass. Wide resection margins were achieved in 17 cases, a minimal margin in two, and a contaminated margin in one. Radiotherapy was used in these three cases where resection margin was in doubt. There were two local recurrences in these three cases. Four patients have died of their disease, and there was one treatment-related death. Overall probability of survival in this group of 20 patients has been expressed by the Kaplan-Meier method as 58%.", "affiliations": "Department of Orthopaedics, Royal Prince Alfred Hospital, Sydney, Australia.", "authors": "Marsden\|F W\|FW\|;Stephens\|F O\|FO\|;McCarthy\|S W\|SW\|;Ferrari\|A M\|AM\|", "chemical_list": "D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0009-921X", "issue": null, "journal": "Clinical orthopaedics and related research", "keywords": null, "medline_ta": "Clin Orthop Relat Res", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000671:Amputation; D000971:Antineoplastic Combined Chemotherapy Protocols; D001315:Australia; D001859:Bone Neoplasms; D002648:Child; D002945:Cisplatin; D003131:Combined Modality Therapy; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007269:Injections, Intra-Arterial; D015993:Life Tables; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009336:Necrosis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D012516:Osteosarcoma; D010027:Osteotomy; D011183:Postoperative Complications; D011878:Radiotherapy; D012074:Remission Induction; D015996:Survival Rate", "nlm_unique_id": "0075674", "other_id": null, "pages": "113-9", "pmc": null, "pmid": "1884529", "pubdate": "1991-09", "publication_types": "D016428:Journal Article", "references": null, "title": "IIB osteosarcoma. Current management, local control, and survival statistics--the Australian experience.", "title_normalized": "iib osteosarcoma current management local control and survival statistics the australian experience" }	[ { "companynumb": "AU-PFIZER INC-202101654004", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "013", "drugauthorizationnumb": "50467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT THREE-WEEK INTERVALS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Osteosarcoma", "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": "6", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "4", "drugadministrationroute": "013", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT THREE-WEEK INTERVALS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Osteosarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FIRST POSTOPERATIVE CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "Osteosarcoma", "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": "19", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Marsden, F.. IIB osteosarcoma: Current management, local control, and survival statistics - The Australian experience. Clinical Orthopaedics and Related Research. 1991;270:113-119", "literaturereference_normalized": "iib osteosarcoma current management local control and survival statistics the australian experience", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20211130", "receivedate": "20211130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20130959, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220304" } ]
{ "abstract": "Aromatase inhibitors are sometimes chosen for adjuvant therapy in post-menopausal breast cancer patients with a history of venous thromboembolism over an antiestrogen due to the lower risk of venous thromboembolism associated with aromatase inhibitors compared to antiestrogens. We report two cases where patients on warfarin therapy had an increase in their international normalized ratio with the initiation of exemestane therapy. Initially, the patients also showed international normalized ratio variability possibly due to variable absorption of exemestane. We suggest patients being treated with warfarin and exemestane concomitantly need close monitoring and education in order to decrease the risk of adverse events that could be associated with this possible interaction. To our knowledge, there are no similar reported cases in the literature.", "affiliations": "Department of Pharmacy, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, USA [email protected].;Department of Pharmacy, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, USA.;Department of Pharmacy, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, USA.;School of Pharmacy, The Ohio State University, Columbus, USA.", "authors": "Dush\|Aaron\|A\|;Williams\|Abby\|A\|;Mangini\|Neha\|N\|;Klaczak\|Kendra\|K\|", "chemical_list": "D000730:Androstadienes; D000925:Anticoagulants; D047072:Aromatase Inhibitors; D014859:Warfarin; C056516:exemestane", "country": "England", "delete": false, "doi": "10.1177/1078155214568583", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "22(2)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "INR; Warfarin; exemestane; interaction", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000730:Androstadienes; D000925:Anticoagulants; D047072:Aromatase Inhibitors; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008875:Middle Aged; D014859:Warfarin", "nlm_unique_id": "9511372", "other_id": null, "pages": "371-3", "pmc": null, "pmid": "25596194", "pubdate": "2016-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Initiation of exemestane in two warfarin-treated patients leading to elevation and variability of INR.", "title_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr" }	[ { "companynumb": "US-ACTAVIS-2016-06392", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "25 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE (ACTAVIS)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOUR CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ENOXAPARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOUR CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "AVERAGE TOTAL WEEKLY DOSE : 23 MG/WEEK", "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": "WARFARIN (UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TAMOXIFEN CITRATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076179", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMOXIFEN CITRATE (ACTAVIS LABORATORIES FL)" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "37 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN (UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOUR CYCLES", "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": "BEVACIZUMAB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. J ONCOL PHARM PRACT. 2016;22(2):371-3.", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160407", "receivedate": "20160324", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12207194, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "PHHY2016US053988", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40196", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "23 MG, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "23", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40196", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37 MG, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. JOURNAL OF ONCOLOGY PHARMACY PRACTICE (USA). 2016;22(2):371-73", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160426", "receivedate": "20160426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12308387, "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": "US-MYLANLABS-2016M1016973", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED TO 12 MG/WEEK AFTER EXEMESTANE INITIATION", "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": "WARFARIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "21 MG/WEEK AND THEN DECREASED TO 12 MG/WEEK AFTER EXEMESTANE INITIATION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRADUCTAL PROLIFERATIVE BREAST LESION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "International normalised ratio fluctuation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. J-ONCOL-PHARM-PRACT 2016;22(2):371-373.", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160623", "receivedate": "20160623", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12493607, "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": "US-TEVA-646805USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TAMOXIFEN" }, "drugadditional": null, 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null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOUR CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, 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null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. JOURNAL OF ONCOLOGY PHARMACY PRACTICE. 2016; 22(2): 371-373", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160429", "receivedate": "20160325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12211612, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "PHHY2016US055947", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40196", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "21 MG, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "21", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40196", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 MG, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. JOURNAL OF ONCOLOGY PHARMACY PRACTICE (USA). 2016;22(2):371-73", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160426", "receivedate": "20160426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12308392, "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": "US-MYLANLABS-2016M1017038", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37 MG/WEEK AND THEN DECREASED TO 23 MG/WEEK AFTER EXEMESTANE INITIATION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED TO 23 MG/WEEK AFTER EXEMESTANE INITIATION", "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": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "International normalised ratio fluctuation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. J-ONCOL-PHARM-PRACT 2016;22(2):371-373.", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160622", "receivedate": "20160622", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12489661, "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": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-01370", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AVERAGE TOTAL WEEKLY DOSE 21 MG/WEEK", "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": "WARFARIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AVERAGE TOTAL WEEKLY DOSE 21 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077431", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A,WILLIAMS A,MANGINI N,KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. JOURNAL OF ONCOLOGY PHARMACY PRACTICE 2016;22(2):371-373.", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160726", "receivedate": "20160726", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12594191, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "US-TEVA-646806USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AVERAGE TOTAL WEEKLY DOSE OF WARFARIN WAS 12 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AVERAGE TOTAL WEEKLY DOSE 21 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRADUCTAL PROLIFERATIVE BREAST LESION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "International normalised ratio fluctuation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. JOURNAL OF ONCOLOGY PHARMACY PRACTICE. 2016; 22(2): 371-373", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160621", "receivedate": "20160325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12211453, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]
{ "abstract": "Implantable cardioverter-defibrillator (ICD) is the gold standard therapy for the prevention of sudden cardiac death. Nevertheless, ICD placement in the paediatric population is still limited because of several technical difficulties. Several implantation techniques have been proposed but experience in infants with very low weight and less than 6 months is very limited. We herein describe a case of a minimally invasive ICD epicardial implantation in a 4-month-old infant weighing 5 kg. A diagnosis of arrhythmic cardiomyopathy with left ventricular non-compaction disease with ventricular tachycardia storms, QT prolongation and Wolff-Parkinson-White pattern was made. Antiarrhythmic drugs, radiofrequency ablation and sympathetic denervation were not effective. ICD implantation was successful allowing the infant to survive and bridging to heart transplantation.", "affiliations": "Pediatric Cardiology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Pediatric Cardiology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Pediatric Cardiology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Pediatric Cardiology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.", "authors": "Carro\|Cristina\|C\|;Cereda\|Alberto Francesco\|AF\|;Annoni\|Giuseppe\|G\|;Marianeschi\|Stefano Maria\|SM\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/icvts/ivx129", "fulltext": null, "fulltext_license": null, "issn_linking": "1569-9285", "issue": "25(5)", "journal": "Interactive cardiovascular and thoracic surgery", "keywords": "Congenital heart disease; Electrical storms; Heart transplantation; Implantable cardioverter–defibrillator (ICD); Paediatric cardiomyopathy", "medline_ta": "Interact Cardiovasc Thorac Surg", "mesh_terms": "D016757:Death, Sudden, Cardiac; D017147:Defibrillators, Implantable; D006330:Heart Defects, Congenital; D016027:Heart Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D017180:Tachycardia, Ventricular", "nlm_unique_id": "101158399", "other_id": null, "pages": "832-833", "pmc": null, "pmid": "28510647", "pubdate": "2017-11-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Epicardial cardioverter-defibrillator implantation in a 4-month-old infant bridged to heart transplantation.", "title_normalized": "epicardial cardioverter defibrillator implantation in a 4 month old infant bridged to heart transplantation" }	[ { "companynumb": "IT-GLENMARK PHARMACEUTICALS-2017GMK030184", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "206498", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ELECTROCARDIOGRAM QT PROLONGED", "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": "4", "patientonsetageunit": "802", "patientsex": null, "patientweight": "5", "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CARRO C, CEREDA AF, ANNONI G, MARIANESCHI SM.. EPICARDIAL CARDIOVERTER-DEFIBRILLATOR IMPLANTATION IN A 4-MONTH-OLD INFANT BRIDGED TO HEART TRANSPLANTATION. INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY. 2017;25(5):832-833", "literaturereference_normalized": "epicardial cardioverter defibrillator implantation in a 4 month old infant bridged to heart transplantation", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20171228", "receivedate": "20171228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14331534, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180321" } ]
{ "abstract": "To determine the risk and pertinent features of non-Hodgkin's lymphoma (NHL) as a second malignancy, medical records were searched of 5484 consecutive children treated for various malignancies at a single institution during a 27 year period. Of these, three have developed secondary NHL. The probability of secondary NHL in this cohort at 5 and 10 years after the diagnosis of the first malignancy was 0.05% (95% confidence interval, 0.01%, 0.2%) and at 15 years 0.16% (0.04%, 0.63%). With 30710 person-years observed, the risk in this cohort was 9.8 per 100,000 person-years. A literature search disclosed variously detailed descriptions of 21 cases of secondary NHL in patients whose primary malignancy had been diagnosed when they were less than 20 years old. Of 18 cases with documented secondary NHL histology, the most common subtypes were large cell (n = 7) and small non-cleaved cell (n = 6); mixed histology was found in three and lymphoblastic in two cases. Twenty-three of 24 children with secondary NHL had initial lymphohematopoietic neoplasms: Hodgkin's disease (n = 18), acute lymphoblastic leukemia (n = 4) and acute myelogenous leukemia (n = 1); the remaining child had astrocytoma. Of 18 patients (including three cases from this institution) with known outcome, only four were reported to be alive at 5+, 6+, 12+ and 96+ months, respectively. Secondary NHL occurs most often after therapy for Hodgkin's disease and confers a dismal prognosis.", "affiliations": "Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38101.", "authors": "Eguiguren\|J M\|JM\|;Ribeiro\|R C\|RC\|;Pui\|C H\|CH\|;Hancock\|M L\|ML\|;Pratt\|C B\|CB\|;Head\|D R\|DR\|;Crist\|W M\|WM\|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0887-6924", "issue": "5(10)", "journal": "Leukemia", "keywords": null, "medline_ta": "Leukemia", "mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D016609:Neoplasms, Second Primary; D012307:Risk Factors", "nlm_unique_id": "8704895", "other_id": null, "pages": "908-11", "pmc": null, "pmid": "1961025", "pubdate": "1991-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.; D016454:Review", "references": null, "title": "Secondary non-Hodgkin's lymphoma after treatment for childhood cancer.", "title_normalized": "secondary non hodgkin s lymphoma after treatment for childhood cancer" }	[ { "companynumb": "US-PFIZER INC-2019099626", "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, CYCLIC (SYSTEMIC CHEMOTHERAPY)", "drugenddate": "1981", "drugenddateformat": "602", "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (SYSTEMIC CHEMOTHERAPY)", "drugenddate": "1981", "drugenddateformat": "602", "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": 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{ "abstract": "BACKGROUND\nIsolated splenic metastasis from colorectal cancer is very rare, as metastatic colorectal cancer involving the spleen is usually a manifestation of widely disseminated disease. Splenectomy is the best therapeutic option for this entity and probably the only chance for radical cure.\nA 73-year-old male presented with abdominal distension and dark red bloody stool of 6-month duration.\nSynchronous isolated splenic metastasis from colorectal cancer.\n\n\nMETHODS\nBased on multidisciplinary team (MDT) mode, the patient underwent the primary hepatic flexure tumor resection due to his poor general condition. One month after surgery the patient began treatment with Xelox (capecitabine 1000 mg/m, oxaliplatin 130 mg/m) every 3 weeks. The patient underwent isolated splenic metastasis resection successfully by laparoscopic after four courses of chemotherapy.\n\n\nRESULTS\nThe patient's postoperative course was uneventful and he completed four courses of postoperative chemotherapy using the original chemotherapy regimen Xelox (capecitabine 1000 mg/m, oxaliplatin 130 mg/m). The patient was subsequently followed up every 3 months and no signs of recurrence were noted in a recent examination.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first case report of isolated splenic metastasis from colorectal cancer in China. It is also the first case in which treatment was overseen by an MDT. The possibility of splenic metastasis should be considered in cases in which colorectal cancer is associated with a splenic lesion, despite its rarity. Splenectomy and adjuvant chemotherapy are the optimal therapeutic approaches, as such an approach prolongs survival and palliates the disease.", "affiliations": "Department of Colorectal Surgery.;Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.;Department of Colorectal Surgery.;Department of Colorectal Surgery.", "authors": "Zhao\|Huiying\|H\|;Zhong\|Weixiang\|W\|;Chen\|Dong\|D\|;Cheng\|Xiaofei\|X\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000015016", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30946331MD-D-18-0801710.1097/MD.0000000000015016150164500Research ArticleClinical Case ReportSynchronous isolated splenic metastasis from cancer of hepatic flexure of colon A case reportZhao Huiying MDaZhong Weixiang MDbChen Dong MDaCheng Xiaofei MDa∗NA. a Department of Colorectal Surgeryb Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.∗ Correspondence: Xiaofei Cheng, Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou 310003, Zhejiang Province, China (e-mail: [email protected]).6 2019 05 4 2019 98 14 e1501630 10 2018 20 2 2019 6 3 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nIsolated splenic metastasis from colorectal cancer is very rare, as metastatic colorectal cancer involving the spleen is usually a manifestation of widely disseminated disease. Splenectomy is the best therapeutic option for this entity and probably the only chance for radical cure.\n\nPatient Concerns:\nA 73-year-old male presented with abdominal distension and dark red bloody stool of 6-month duration.\n\nDiagnoses:\nSynchronous isolated splenic metastasis from colorectal cancer.\n\nInterventions:\nBased on multidisciplinary team (MDT) mode, the patient underwent the primary hepatic flexure tumor resection due to his poor general condition. One month after surgery the patient began treatment with Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2) every 3 weeks. The patient underwent isolated splenic metastasis resection successfully by laparoscopic after four courses of chemotherapy.\n\nOutcomes:\nThe patient's postoperative course was uneventful and he completed four courses of postoperative chemotherapy using the original chemotherapy regimen Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2). The patient was subsequently followed up every 3 months and no signs of recurrence were noted in a recent examination.\n\nLessons:\nTo the best of our knowledge, this is the first case report of isolated splenic metastasis from colorectal cancer in China. It is also the first case in which treatment was overseen by an MDT. The possibility of splenic metastasis should be considered in cases in which colorectal cancer is associated with a splenic lesion, despite its rarity. Splenectomy and adjuvant chemotherapy are the optimal therapeutic approaches, as such an approach prolongs survival and palliates the disease.\n\nKeywords\ncolorectal cancerisolated splenic metastasesmultidisciplinary teamsplenectomyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nIsolated splenic metastasis from colorectal cancer is very rare, as metastatic colorectal cancer involving the spleen is usually a manifestation of widely disseminated disease.[1] In a cadaver study, the incidence of splenic metastases from colorectal cancer was 2% of 1019 cases, but the incidence of isolated splenic metastasis was not reported.[2] To the best of our knowledge, only 32 cases (5 synchronous and 27 metachronous cases) of isolated splenic metastasis from colorectal cancer have been reported in the English-language literature.[3] Because synchronous splenic metastasis is very rare, preoperative diagnosis is difficult. Splenectomy is the best therapeutic option for isolated splenic metastasis and probably the only chance for radical cure. Some authors suggest that splenectomy may lead to long-term survival in patients with isolated splenic metastasis.[4,5] Herein, we report the first case of isolated splenic metastasis from colorectal cancer in China. We diagnosed this rare clinical entity and resected the primary tumor and isolated splenic metastasis using a multidisciplinary team (MDT) approach. MDT approach is important for advanced colorectal cancer, especially for patients with synchronous metastasis.[6,7]\n\n2 Case report\nIn October 2017, a 73-year-old male presented with abdominal distension and dark-red bloody stool of 6-month duration. He also complained of general fatigue and weight loss of 15 kg. He had no familial history of cancer, no prior pathological conditions, and no concomitant medication use. The patient's carcinoembryonic antigen (CEA) and hemoglobin levels were 6.9 ng/mL (0–5 ng/mL) and 101 g/L (131–175 g/L), respectively. The results of all other laboratory tests were normal, including cancer antigen 19 to 9 (CA 19–9), biochemical, and hematologic tests. Endoscopic examination revealed an obstructing neoplasm in the hepatic flexure, about 4.5 cm in diameter, with surface depression, erosion, and a propensity for bleeding. A biopsy of the lesion established a diagnosis of moderately differentiated adenocarcinoma. Whole-abdomen computed tomography (CT) revealed wall thickening of the hepatic flexure with proximal incomplete intestinal obstruction (Fig. 1A). The CT scan also revealed a single low-density lesion of about 5.7 cm diameter in the spleen (Fig. 1B). Genetic testing of the biopsy material indicated non-mutated KRAS, NRAS, and BRAF genes. After the first MDT discussion, due to the poor general condition of the patient, we decided to remove the primary lesion and biopsy the splenic mass during the operation. The biopsy indicated the presence of splenic metastasis from adenocarcinoma. The patient underwent a laparoscopic right hemicolectomy due to the histopathological finding of a moderately and poorly differentiated adenocarcinoma invading the serosa. Twenty-two lymph nodes were removed and 7 showed metastases (pT3N2M1, stage IV). One month later, the patient's CEA level had decreased to 3 ng/mL. The patient's postoperative recovery was uneventful, and 1 month after surgery he began treatment with Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2) every 3 weeks for 3 months. After 4 courses of Xelox therapy, the patient's clinical response was excellent, with II degree vomiting and no obvious bone marrow suppression or neurotoxicity. The diameter of the splenic lesion had decreased from 5.7 to 2.5 cm (Fig. 1C), and a partial response had been achieved after 4 courses of chemotherapy. In April 2018, based on a second MDT discussion, the patient underwent laparoscopic splenectomy. The histological findings showed that the splenic tumor was a moderately and poorly differentiated adenocarcinoma, similar to the tumor of the hepatic flexure (Fig. 2A). Negative staining for cytokeratin 7 and positive staining for cytokeratin 20 was consistent with splenic metastasis of an adenocarcinoma of the hepatic flexure (Fig. 2B and C). The patient's postoperative course was uneventful and he completed 4 courses of postoperative chemotherapy using the original chemotherapy regimen Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2). The patient's clinical response was good, with II degree vomiting, II degree bone marrow suppression, and II degree neurotoxicity. The patient was subsequently followed up every 3 months and no signs of recurrence were noted in a recent examination on January, 2019.\n\nFigure 1 Whole abdominal computed tomography (CT). (A) a heterogeneous enhanced tumor in hepatic flexure; (B) a single low-density lesion of the spleen about 5.7 cm in diameter before primary treatment; (C) the spleen mass about 2.5 cm in diameter after 4 courses chemotherapy with Xelox (capecitabine, oxaliplatin).\n\nFigure 2 Histological findings of the tumor of the spleen. (A) Moderately-poorly differentiated adenocarcinoma (HE, ×100); (B) immunostaining for cytokeratin 7 showing a negative reaction (×100); (C) immunostaining for cytokeratin 20 showing a positive reaction (×100).\n\n3 Discussion\nApproximately 1 in 4 patients with colorectal cancer have metastases at the time of initial diagnosis.[8] Metastases to the spleen from colorectal cancer in the absence of liver or lung involvement are extremely rare,[9,10] possibly due to the anatomical and immunological characteristics of the tumor. The anatomical factors that restrict metastasis include the rhythmic contraction of the sinusoidal splenic architecture and the sharp angle of the splenic artery with the celiac axis.[11] Moreover, immune surveillance in the spleen inhibits tumor cell proliferation.[12] A PubMed search yielded only 32 cases of isolated solitary splenic metastasis from colorectal cancer (synchronous, 5 cases summarized in Table 1;[13–16] metachronous, 27 cases) in the English language literature. We report here the sixth case in which an isolated splenic lesion was synchronous with colorectal cancer. A particularly interesting aspect of this case is its diagnosis and treatment by an MDT. The MDT is defined as “a group of people of different health-care disciplines, which meets together at a given time to discuss a given patient and who are each able to contribute independently to the diagnostic and treatment decisions about the patients.” The colorectal cancer MDT in our hospital includes colorectal surgeons, hepatobiliary surgeons, urological surgeons, thoracic surgeons, gynecologists, radiologists, radiation therapist, histopathologists, medical oncologists, and nurse specialist. An MDT approach may not only reduce the risk for perioperative morbidity and mortality but also improves long-term survival.[17,18] Because of the poor general condition of the patient, the staging and resection of the primary and metastatic lesions were overseen by an MDT.\n\nTable 1 Summary of reported cases of synchronous isolated splenic metastasis from colorectal cancer.\n\nBecause the majority of patients with isolated splenic metastasis from colorectal cancer are asymptomatic, the condition is typically diagnosed through imaging tests and evaluation of CEA levels. CEA levels are elevated in more than 80% of such cases, to 4.6 to 223 ng/mL3; the level in our patient was 6.0 ng/mL. In addition, careful examination of an abdominal CT scan can facilitate early diagnosis of synchronous and metachronous splenic metastasis; therefore, this should be a priority.[19] None of the cases reported to date were misdiagnosed. Overall, isolated splenic metastasis is relatively easy to diagnose.\n\nSplenectomy is necessary in the presence of isolated metastases from colorectal cancer.[16] Splenectomy was performed in all reported cases of isolated splenic metastasis from colorectal cancer, but only two cases were treated using a laparoscopic approach, as in our patient. Due to the risk for peritoneal dissemination, use of laparoscopy for splenic malignancies is controversial. However, laparoscopic splenectomy for splenic metastasis reportedly does not increase the rate of surgical complications, and survival ranges from 2 months to 11 years.[5] Moreover, laparoscopic surgery for other abdominal tumors is not associated with a greater risk of surgical complications compared to conventional techniques.[20,21] Thus, laparoscopic splenectomy for splenic metastasis is safe and reproducible, and yields outcomes superior to those of open surgery. The survival duration after splenectomy ranges from 3 to 84 months (mean, 22.5 months).[3] Only 2 of 27 reported cases of metachronous splenic metastasis relapsed between 9 and 11 months, compared to 3 of 5 cases of synchronous splenic metastases.[3,22] Chemotherapy is the appropriate treatment for isolated splenic metastases from colorectal cancer, particularly synchronous splenic metastases.[23] Chemotherapy regimens for metastatic colorectal cancer include CapeOX/Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2), mFOLFOX6 (5-fluorouracil 2400 mg/m2, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2), and FOLFIRI (5-fluorouracil 2400 mg/m2, leucovorin 400 mg/m2, and irinotecan 180 mg/m2).[18,24,25] Our patient underwent the primary hepatic flexure tumor and isolated splenic metastasis resection in stages due to his poor general condition. The interval between the 2 operations is about 3 to 4 months. Since this entity was advanced colorectal cancer (pT3N2M1, stage IV), our MDT team recommended that the patient underwent adjuvant chemotherapy first during the waiting period. Our patient completed perioperative chemotherapy using the regimen Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2).\n\nIn conclusion, we report the first case of isolated splenic metastasis from colorectal cancer in China; it is also the first case in which treatment was overseen by an MDT. Despite its rarity, the possibility of splenic metastasis should be considered in cases in which colorectal cancer is associated with a splenic lesion. Splenectomy and adjuvant chemotherapy is the optimal therapeutic approach; such an approach prolongs survival and palliates the disease. We report this rare clinical entity for the purpose of improving the management and survival of patients with isolated splenic metastases from colorectal cancer.\n\nAcknowledgments\nWe gratefully acknowledge the contributions made by the clinical nurse specialists, surgeons, radiologists, pathologists, and oncologists to the Colorectal MDT. In particular, we would like to thank: Jianjiang Lin, Wenbin Chen, and Yingsheng Wu.\n\nAuthor contributions\nData curation: Huiying Zhao, Weixiang Zhong.\n\nInvestigation: Dong Chen.\n\nVisualization: Weixiang Zhong.\n\nWriting – Original Draft: Huiying Zhao.\n\nWriting – Review & Editing: Xiaofei Cheng.\n\nAbbreviations: CA 19–9 = cancer antigen 19–9, CEA = carcinoembryonic antigen, CT = computed tomography, MDT = multidisciplinary team.\n\nThis study was supported by the Zhejiang Province Natural Science Foundation of China (LGF18H030001; LY19H160040), Chinese traditional medicine Foundation of Zhejiang Province (2017ZA077), and Zhejiang education department scientific research project (Y201636334).\n\nAll data generated or analyzed during this study are included in this published article.\n\nWritten informed consent was obtained from the patient and the present study (Ethics approval number; 2018-604) was approved by the Ethics Board of the First Affiliated Hospital Zhejiang University School of Medicine.\n\nWritten informed consent was obtained from the patient for the publication of their data.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Abi Saad GS Hussein M El-Saghir NS \nIsolated splenic metastasis from colorectal cancer . Int J Clin Oncol \n2011 ;16 :306–13 .21258837 \n[2] Berge T \nSplenic metastases. Frequencies and patterns . Acta Pathol Microbiol Scand A \n1974 ;82 :499–506 .4854372 \n[3] Abdou J Omor Y Boutayeb S \nIsolated splenic metastasis from colon cancer: case report . World J Gastroenterol \n2016 ;22 :4610–4 .27182171 \n[4] Takada T Takami H \nSolitary splenic metastasis of a carcinoid tumor of the lung eight years postoperatively . J Surg Oncol \n1998 ;67 :47–8 .9457257 \n[5] Lopez Monclova J Targarona Soler E Peraza Solis Y \nLaparoscopic approach for isolated splenic metastasis: comprehensive literature review and report of 6 cases . Surg Laparosc Endosc Percutan Tech \n2013 ;23 :21–4 .23386144 \n[6] Lamb BW Sevdalis N Taylor C \nMultidisciplinary team working across different tumour types: analysis of a national survey . Ann Oncology \n2012 ;23 :1293–300 .\n[7] Lowes M Kleiss M Lueck R \nThe utilization of multidisciplinary tumor boards (MDT) in clinical routine: results of a health care research study focusing on patients with metastasized colorectal cancer . Int J Colorectal Dis \n2017 ;32 :1463–9 .28779354 \n[8] Simmonds PC Primrose JN Colquitt JL \nSurgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies . Br J Cancer \n2006 ;94 :982–99 .16538219 \n[9] Klein B Stein M Kuten A \nSplenomegaly and solitary spleen metastasis in solid tumors . Cancer \n1987 ;60 :100–2 .3581023 \n[10] Place RJ \nIsolated colon cancer metastasis to the spleen . Am Surg \n2001 ;67 :454–7 .11379648 \n[11] Kim JC Jeong CS Kim HC \nIsolated splenic metastasis from colorectal carcinoma: a case report . J Korean Med Sci \n2000 ;15 :355–8 .10895982 \n[12] Gabizon A Small M Trainin N \nKinetics of the response of spleen cells from tumor-bearing animals in an in vivo tumor neutralization assay . Int J Cancer \n1976 ;18 :813–9 .992909 \n[13] Ishida H Konno K Ishida J \nIsolated splenic metastases . J Ultrasound Med \n1997 ;16 :743–9 .9360238 \n[14] Avesani EC Cioffi U De Simone M \nSynchronous isolated splenic metastasis from colon carcinoma . Am J Clin Oncol \n2001 ;24 :311–2 .11404507 \n[15] Hiraiwa K Morozumi K Miyazaki H \nIsolated splenic vein thrombosis secondary to splenic metastasis: a case report . World J Gastroenterol \n2006 ;12 :6561–3 .17072993 \n[16] Pisanu A Ravarino A Nieddu R \nSynchronous isolated splenic metastasis from colon carcinoma and concomitant splenic abscess: a case report and review of the literature . World J Gastroenterol \n2007 ;13 :5516–20 .17907299 \n[17] Lordan JT Karanjia ND Quiney N \nA 10-year study of outcome following hepatic resection for colorectal liver metastases: the effect of evaluation in a multidisciplinary team setting . Eur J Surg Oncol \n2009 ;35 :302–6 .18328668 \n[18] Van Cutsem E Cervantes A Adam R \nESMO consensus guidelines for the management of patients with metastatic colorectal cancer . Ann Oncol \n2016 ;27 :1386–422 .27380959 \n[19] Gilardi L Vadrucci M \nIsolated metachronous splenic metastasis from colon cancer found by 18F-FDG PET/CT . Clin Nucl Med \n2017 ;42 :79–80 .27775944 \n[20] Jingli C Rong C Rubai X \nInfluence of colorectal laparoscopic surgery on dissemination and seeding of tumor cells . Surg Endosc \n2006 ;20 :1759–61 .17024537 \n[21] Zanghi A Cavallaro A Piccolo G \nDissemination metastasis after laparoscopic colorectal surgery versus conventional open surgery for colorectal cancer: a metanalysis . Eur Rev Med Pharmacol Sci \n2013 ;17 :1174–84 .23690186 \n[22] Pavlovic M Separovic R Vukelic-Markovic M \nIsolated splenic metastasis from colorectal carcinoma in a high risk patient: a case report . Coll Antropol \n2011 ;35 :1307–10 .22397278 \n[23] Cavallaro A Modugno P Specchia M \nIsolated splenic metastasis from colon cancer . J Exp Clin Cancer Res \n2004 ;23 :143–6 .15149163 \n[24] Glynne-Jones R Wyrwicz L Tiret E \nRectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol \n2017 ;28 suppl_4 :iv22–40 .28881920 \n[25] Messersmith WA \nSystemic management of colorectal cancer . J Natl Compr Canc Netw \n2017 ;15 (5S) :699–702 .28515248\n\n", "fulltext_license": "CC BY", "issn_linking": "0025-7974", "issue": "98(14)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000368:Aged; D044682:Colon, Ascending; D003110:Colonic Neoplasms; D006801:Humans; D008297:Male; D013154:Spleen; D013160:Splenic Neoplasms", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e15016", "pmc": null, "pmid": "30946331", "pubdate": "2019-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Synchronous isolated splenic metastasis from cancer of hepatic flexure of colon: A case report.", "title_normalized": "synchronous isolated splenic metastasis from cancer of hepatic flexure of colon a case report" }	[ { "companynumb": "CN-ACCORD-121696", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "202593", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "EVERY 3 WEEKS FOR 3 MONTHS,ALSO RECEIVED ON APR-2018", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2017", "drugstartdateformat": "602", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "207474", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "EVERY 3 WEEKS FOR 3 MONTHS,ALSO RECEIVED ON APR-2018", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2017", "drugstartdateformat": "602", "drugstructuredosagenumb": "130", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZHAO H, ZHONG W, CHEN D, CHENG X. SYNCHRONOUS ISOLATED SPLENIC METASTASIS FROM CANCER OF HEPATIC FLEXURE OF COLON: A CASE REPORT. MEDICINE (BALTIMORE). 2019 APR?98(14):E15016.", "literaturereference_normalized": "synchronous isolated splenic metastasis from cancer of hepatic flexure of colon a case report", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20190503", "receivedate": "20190417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16205451, "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": "OBJECTIVE\nTo report a case of aplastic anemia in a patient treated with cyanamide, an alcohol-aversive drug. A 67-year-old man was admitted to hospital because of fever and pancytopenia. He had taken cyanamide for 6 months as an alcohol deterrent. No other risk factors for aplastic anemia were identified by interviewing the patient using a structured validated questionnaire. The results of bone-marrow biopsy showed severe aplastic anemia. Cyanamide was discontinued and the patient was treated according to a prespecified treatment protocol. One year after hospital admission, the patient was completely recovered with no need of immunosuppressive therapy. An objective causality assessment revealed that an adverse drug reaction was probable.\n\n\nCONCLUSIONS\nAs the efficacy of cyanamide has been questioned, due to the failure of various trials to show any benefit over placebo, its overall benefit/risk ratio should be reconsidered. The complete and rapid hematological recovery after discontinuation of the drug, and the absence of other factors that could explain the condition support the association of the present case of aplastic anemia with cyanamide. The mechanism remains unknown. Aplastic anemia is a rare but potentially serious adverse drug effect of cyanamide treatment.\n\n\nCONCLUSIONS\nGiven the poor evidence on the efficacy of cyanamide and the associated risk of aplastic anemia, its use in reducing alcohol consumption should be reconsidered.", "affiliations": "Fundació Institut Català de Farmacologia Servei de Farmacologia Clínica, Hospital Universitari Vall d'Hebron Universitat Autònoma de Barcelona, P Vall d'Hebron 129-139, 08035, Barcelona, Spain. [email protected]", "authors": "Ballarín\|Elena\|E\|;Ibáñez\|Luisa\|L\|;Hernández\|José-Angel\|JA\|;Force\|Lluís\|L\|;Laporte\|Joan-Ramon\|JR\|", "chemical_list": "D003484:Cyanamide", "country": "Germany", "delete": false, "doi": "10.1007/s00228-005-0954-1", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-6970", "issue": "61(5-6)", "journal": "European journal of clinical pharmacology", "keywords": null, "medline_ta": "Eur J Clin Pharmacol", "mesh_terms": "D000368:Aged; D000437:Alcoholism; D000741:Anemia, Aplastic; D003484:Cyanamide; D006801:Humans; D008297:Male; D013997:Time Factors", "nlm_unique_id": "1256165", "other_id": null, "pages": "467-9", "pmc": null, "pmid": "15991038", "pubdate": "2005-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "2291154;6112345;10320388;11168499;12554608;5334883;8044121;58177;1543940;1559576;9746025;2673441;7249508;10803790;9313109;6101808;6346921", "title": "Cyanamide-induced aplastic anemia.", "title_normalized": "cyanamide induced aplastic anemia" }	[ { "companynumb": "JP-DSJP-DSJ-2018-152837", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLMESARTAN MEDOXOMIL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021286", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORODISPERSIBLE TABLET", "drugdosagetext": "40MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLMETEC OD" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYANAMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ABSTAINS FROM ALCOHOL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYANAMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MIGLITOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50MG/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": "MIGLITOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EPALRESTAT" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50MG/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": "EPALRESTAT" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750MG/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": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TENELIGLIPTIN HYDROBROMIDE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20MG/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": "TENELIGLIPTIN HYDROBROMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aplastic anaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YOHEI OSAKI, YUKIE TERASAKI, SHUHEI KANAYA, KENICHI TAHARA, HIROAKI SHIMIZU, KUNIO YANAGISAWA, ET AL.. CYANAMIDE INDUCED APLASTIC ANEMIA. THE KITAKANTO MEDICAL JOURNAL. 2018?68 (4):261-265", "literaturereference_normalized": "cyanamide induced aplastic anemia", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181220", "receivedate": "20181220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15747295, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "BACKGROUND\nVerrucous carcinoma is an uncommon variant of low-grade squamous cell malignancy with a low malignant potential but a high risk of recurrence.\n\n\nMETHODS\nWe report a case of a Human Papilloma Virus negative local verrucous carcinoma in the perianal area of a 45-year old otherwise healthy female. The tumor presented clinically as a persistent genital wart not responding to usual dermatologic local therapy. The patient was referred to the Department of Plastic Surgery and Breast Surgery after primary excision in a private practice setting of a general surgeon. Three months later, further excision revealed local lichen sclerosus inflammatory changes in close proximity to the excision scar.\n\n\nCONCLUSIONS\nDue to the low occurrence of verrucous carcinoma in the perianal area, no guidelines are available for the management of this disease. Conflicting reports on the ethiology and the nomenclature and classifications of verrucous carcinomas exist.\n\n\nCONCLUSIONS\nAvoid pitfalls in the diagnosis of a rare variant of squamous cell cancer with a high recurrence ratio: Common genital warts not responding to ordinary local antimitotic Podophyllotoxin treatment require biopsy to exclude verrucous carcinoma. Follow-up is recommended at a 3-6 months interval due to the relative high risk of relapse.", "affiliations": "Department of Plastic Surgery and Breast Surgery, Zealand University Hospital, Roskilde, Denmark. Electronic address: [email protected].;Department of Plastic Surgery and Breast Surgery, Zealand University Hospital, Roskilde, Denmark.", "authors": "Trøstrup\|Hannah\|H\|;Matzen\|Steen H\|SH\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.ijscr.2018.11.017", "fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(18)30524-810.1016/j.ijscr.2018.11.017ArticleAnogenital Verrucous Carcinoma—A case report Trøstrup Hannah [email protected]@regionsjaelland.dk⁎Matzen Steen H. Department of Plastic Surgery and Breast Surgery, Zealand University Hospital, Roskilde, Denmark⁎ Corresponding author at: Department of Plastic Surgery and Breast Surgery, Zealand University Hospital, 4000, Roskilde, Denmark. [email protected]@regionsjaelland.dk27 11 2018 2019 27 11 2018 54 7 9 27 9 2018 23 10 2018 10 11 2018 © 2018 The Authors2018This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Verrucous carcinoma (VC) is a variant of squamous cell carcinoma.\n\n• Anogenital VC is a rare condition, which clinically presents as common genital warts.\n\n• Early recognition of VC and radical excision is crucial due to local destruction of tissue.\n\n• Recurrence of VC is not uncommon.\n\n\n\nIntroduction\nVerrucous carcinoma is an uncommon variant of low-grade squamous cell malignancy with a low malignant potential but a high risk of recurrence.\n\nPresentation of case\nWe report a case of a Human Papilloma Virus negative local verrucous carcinoma in the perianal area of a 45-year old otherwise healthy female. The tumor presented clinically as a persistent genital wart not responding to usual dermatologic local therapy. The patient was referred to the Department of Plastic Surgery and Breast Surgery after primary excision in a private practice setting of a general surgeon. Three months later, further excision revealed local lichen sclerosus inflammatory changes in close proximity to the excision scar.\n\nDiscussion\nDue to the low occurrence of verrucous carcinoma in the perianal area, no guidelines are available for the management of this disease. Conflicting reports on the ethiology and the nomenclature and classifications of verrucous carcinomas exist.\n\nConclusion\nAvoid pitfalls in the diagnosis of a rare variant of squamous cell cancer with a high recurrence ratio: Common genital warts not responding to ordinary local antimitotic Podophyllotoxin treatment require biopsy to exclude verrucous carcinoma. Follow-up is recommended at a 3–6 months interval due to the relative high risk of relapse.\n\nKeywords\nAnogenital verrucous carcinomaSquamous cell cancer variantCase report\n==== Body\n1 Introduction\nVerrucous carcinomas are rare, low-grade warty exophytic squamous cell carcinomas (SCC). Verrucous carcinomas were first described by Ackermann in 1948 in the oral pharynx. However, the lesions can also be located to the larynx or plantar surface of the foot (epithelioma cuniculatum or carcinoma cuniculatum). In the anogenital region, the tumor may present as condyloma accuminatum, common genital warts. Dawson et al. described for the first time anorectal giant condyloma accuminatum in 1965 [1]. A morfologically alike tumour in the anogenital area is the rare sexually transmitted disease Giant Condylomata of Buschke and Lowenstein tumour (BLT), which was first described in 1925 [2]. It is believed to account for 5–16% of all penile carcinomas [3]. It is not clear whether VC and BLT belong to the same entity of tumours or not.\n\nDue to the low incidence, no estimates of cutaneous presentations of verrucous carcinomas of the anogenital area exists. It is more common in middle-aged white individuals, predominantly males [4] or in immunocompromised patients. In females, it is more often localised to the vulva, whereas perianal verrucous tumours are more seldom. Lichen sclerosis (LS) may predispose to verrucous carcinomas [5,6].\n\nHistopathologically, the tumor grows locally in a papillary manner, destructing surrounding tissue, but distant metastases are uncommon. Pushing tumour margins as opposed to infiltrating margins as seen in SCC is described histopathologically. Early, radical excision is crucial.\n\n2 Case\nA 45- year old unmarried heterosexual, otherwise healthy and non-smoking female with no previous history of cancer, diabetes or lichen sclerosus was referred to the Department of Breast and Plastic Surgery for reexcision of a histopathologically verified 20 mm x 10 mm perianal verrucous carcinoma. The resection base margin was not free, so the patient was referred to Dep. of Plastic Surgery for further surgical intervention and follow-up. Histopathologically, there was some discussion whether the tumor excised prior to admission should be described as a verrucous carcinoma or a Buschke Loewenstein tumour. However, since no Human Papilloma Virus (HPV) could be found in the tissue by immunohistochemical staining, the final conclusion was verrucous carcinoma of the anogenital area (Fig. 1).Fig. 1 The postoperative appearance of the excised verrucous carcinoma: A mobile 20 × 18 mm scar, located at 7–9 o-clock in the perianal area is observed.\n\nFig. 1\n\nThe tumour had been present and growing for 3 months. As local treatment by Podophyllotoxin failed to treat the lesion, the patient was referred to a general surgeon in a private clinic, who had excised the tumor. Resection borders were not reported.\n\nNo bleeding, itching, painful sensations or previous history of lichen sclerosus were reported. The patient had no risk factors for HIV or symptoms from the gastrointestinal tract. The only medicine prescribed was peroral Imigrane for intermittent migraine. No lymphadenopathy was found.\n\nThe clinical presentation was a scar (a) of 20 × 18 mm located in close proximity to the anus remained from the primary excision (Fig. 1). A stalked, soft mobile tumor of 5 × 4 mm (b) was also observed in the perianal region at 4 o’clock (Fig. 2). Histopathologic evaluation of a 4 mm punch biopsy from lesion b determined that is was a benign fibroepithelial tumor. The patient was referred to the department of surgical gastroenterology, Herlev, Denmark, for endoscopy and further surgical intervention on the suspicion of involvement of the anal canal. PET-CT scan determined no signs of dissemination. A transrectal ultrasound examination revealed a tumour observed at 4 o’clock. This tumour involved the internal muscular sphincter of the anus and it was excised in toto. Histologic diagnosis was lichenoid inflammation.Fig. 2 a) H&E stained slide (magnification ×2.5) of the verrucous carcinoma (primary excision). Epidermis is seen to the upper left. Explicit dyskeratotic changes are observed. b) H&E stained slide (magnification ×25) of the verrucous carcinoma (primary excision). Note the several mitosis in proximity to the basal membrane.\n\nFig. 2\n\nFollow-up was set for 6 months in which the patient did not display any signs of relapse (Table 1).Table 1 Clinical conclusions.\n\nTable 1Management of verrucous carcinomas in the anogenital area:\t\nVerrucous carcinomas of the anogenital area are rare, low-grade squamous cell cancers clinically resembling common genital warts\nMeticulous surgery including subcutaneous tissue should ensure free surgical margins\nLong term follow-up due to the propensity for recurrence\nLong term prognosis is good\nClinicians should consider verrucous carcinoma in case of failure of local antimitotic Podophyllotoxin treatment of genital warts\t\n\n\n3 Discussion\nVerrucous carcinomas of the anogenital area are rare. They are low-grade variants of squamous cell cancer presenting as common genital warts [7]. Pathophysiological ethiologies for anogenital verrucous carcinomas suspected are Human Papilloma Virus (HPV) type 6 and 11 [4]. Immunohistochemical staining showed no HPV in the excised tissue. The final histopathological diagnosis was VC. Tumour staging was …\n\nDifferentiation between VC and BLT is clinically and histopathologically challenging. Zidar and collegues recently suggested that anal verrucous carcinoma should be distinguished from BLT due to the lack of HPV [8]. This might also explain the lack of effect of local treatment by Podyphyllotoxin to treat VC/BLT [8]. Some pathologists equate BLT to verrucous carcinoma of the anogenital region [9], however, other authors classify VC as an intermediary lesion between condyloma acuminata and squamous cell carcinoma [10,11].\n\nIn this case, excision was done before admission to our department, which also sets limitations to the study. However, it is our belief that early recognition of VC is crucial in order to prevent late effects of such tumours. In larger VCs, endoscopy, Computed Tomography (CT) or Magnetic Resonance\n\nImaging (MRI) may locate extent of the lesion prior to surgical intervention. Rigorous excision with standard surgical margins and excision of subcutaneous fat is required as recurrence of verrucous carcinomas has a poor prognosis. Recurrence is not uncommon. Long term follow is thus suggested at 3–6 months interval due to the frequent transformation to usual type squamous carcinoma.\n\n4 Conclusions\nClinicians should be aware of genital warts not responding to ordinary gold standard treatment and should consider tissue biopsies in these cases.\n\nThis work is reported in line with the SCARE criteria [12] and as well the PROCESS criteria [13].\n\nConflicts of interest\nNone declared.\n\nFunding\nNo funding was received.\n\nEthical approval\nThe institution (Zealand University Hospital) exempts the case report from ethical approval.\n\nConsent\nWritten consent from the patient was given prior to the data collection.\n\nAuthor contribution\nHannah Trøstrup: study consent, design, data collection, interpretation, writing of the paper.\n\nSteen H. Matzen: design, interpretation, writing of the paper.\n\nRegistration of research studies\nNot applicable.\n\nGuarantor\nSteen H. Matzen.\n\nProvenance and peer review\nNot commissioned, externally peer reviewed.\n\nAcknowledgement\nThe Department of Pathology, Zealand University Hospital, Roskilde, Denmark, who provided the H&E slides.\n==== Refs\nReferences\n1 Dawson D.F. Duckworth J.K. Bernhard H. Giant condyloma and verrucous carcinoma of the genital area Arch. Pathol. 79 1965 225 231 14246201 \n2 Lowenstein L.W. Carcinoma-like condylomata acuminata of the penis Med. Clin. North Am. 23 1939 789 795 \n3 Nomikos M. Barmpoutis P. Papakonstantinou E. Chousiantis Z. Ouzounoglou P. Efstathiadou P. Katsifotis C. A giant verrucous carcinoma of the penis presenting with a urinary sepsis and angina Case Rep. Med. 2014 2014 207026 25477967 \n4 Schwartz R.A. Verrucous carcinoma of the skin and mucosa J. Am. Acad. Dermatol. 32 January (1) 1995 1 21 7822496 \n5 Nasca M.R. Innocenzi D. Micali G. Penile cancer among patients with genital lichen sclerosus J. Am. Acad. Dermatol. 41 December (6) 1999 911 914 10570372 \n6 Wang S.H. Chi C.C. Wong Y.W. Salim A. Manek S. Wojnarowska F. J. Eur. Acad. Dermatol. Venereol. 24 July (7) 2010 815 819 20015174 \n7 Vandeweyer E. Sales F. Deraemacker R. Cutaneous verrucous carcinoma Br. J. Plast. Surg. 54 March (2) 2001 168 170 11207133 \n8 Zidar N. Langner C. Odar K. Hosniak L. Kamaradova K. Daum O. Pollheimer M.J. Koserok P. Poljak M. Anal verrucous carcinoma is not related to infection with human papillomaviruses and should be distinguished from giant condyloma (Buschke-Löwenstein tumour) Histopathology 70 May (6) 2017 938 945 28012208 \n9 Lévy Lebbe C. Buschke-Löwenstein tumour: diagnosis and treatment Ann. Urol. 40 3 2006 175 178 \n10 Creasman Malignant transformation of anorectal giant condyloma acuminatum (Buschke-Loewenstein tumor) Diseases of the Colon & Rectum 1989 \n11 Bogomoletz W.V. Potet F. Molas G. Condylomata acuminata, giant condyloma acuminatum (Buschke‐Loewenstein tumour) and verrucous squamous carcinoma of the perianal and anorectal region: a continuous precancerous spectrum? Histopathology 9 November (11) 1985 1155 1169 4085991 \n12 Agha R.A. Fowler A.J. Saetta A. Barai I. Rajmohan S. Orgill D.P. for the SCARE Group The SCARE statement: consensus-based surgical case report guidelines Int. J. Surg. 34 2016 180 186 27613565 \n13 Agha Riaz A. Fowler Alexander J. Rajmohan Shivanchan Barai Ishani Orgill Dennis P. for the PROCESS Group Preferred reporting of case series in surgery; the PROCESS guidelines Int. J. Surg. 36 Pt A 2016 319 323 27770639\n\n", "fulltext_license": "CC BY", "issn_linking": "2210-2612", "issue": "54()", "journal": "International journal of surgery case reports", "keywords": "Anogenital verrucous carcinoma; Case report; Squamous cell cancer variant", "medline_ta": "Int J Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101529872", "other_id": null, "pages": "7-9", "pmc": null, "pmid": "30508696", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": "16869538;28012208;27770639;25477967;14246201;27613565;7822496;4085991;11207133;2791784;10570372;20015174", "title": "Anogenital Verrucous Carcinoma-A case report.", "title_normalized": "anogenital verrucous carcinoma a case report" }	[ { "companynumb": "DK-BAUSCH-BL-2018-036141", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PODOFILOX" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90184", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANOGENITAL WARTS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PODOPHYLLOTOXIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SUMATRIPTAN SUCCINATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMIGRANE" } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TROSTRUP H, MATZEN S. ANOGENITAL VERRUCOUS CARCINOMA-A CASE REPORT. INTERNATIONAL JOURNAL OF SURGERY CASE REPORTS. 2018?54:7-9.", "literaturereference_normalized": "anogenital verrucous carcinoma a case report", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20190103", "receivedate": "20190103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15786824, "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": "Presently described is a case of disseminated adenovirus infection in a heart-kidney transplant recipient that was successfully treated with cidofovir. There are several reports of adenovirus infections in adult solid organ transplant recipients and the prognosis is usually poor, with mortality rates of 40% to 60%. Severe disseminated adenovirus infections have been associated with increased risk of adverse transplant events, such as rejection, ventricular dysfunction, allograft vasculopathy, graft loss, and the need for re-transplantation. The patient's lack of clinical improvement, the onset of hemorrhagic cystitis and acute kidney injury were factors in our decision to temporarily discontinue administration of immunosuppressive agents and start an antiviral agent. It is important to suspect adenovirus in transplant patients when they do not respond to antibiotics and cultures are negative. Early diagnosis and treatment are critical to improving outcomes in immunocompromised patients.", "affiliations": "Department of Internal Medicine, Rutgers Robert Wood Johnson University Hospital, New Brunswick, NJ, USA. [email protected].", "authors": "Xu\|Jack\|J\|;Patel\|Keval V\|KV\|;Dsouza\|Melroy\|M\|;Almendral\|Jesus\|J\|;Mody\|Kanika\|K\|;Iyer\|Deepa\|D\|", "chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D007166:Immunosuppressive Agents", "country": "Turkey", "delete": false, "doi": "10.5543/tkda.2017.74957", "fulltext": null, "fulltext_license": null, "issn_linking": "1016-5169", "issue": "46(3)", "journal": "Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir", "keywords": null, "medline_ta": "Turk Kardiyol Dern Ars", "mesh_terms": "D000256:Adenoviridae; D000257:Adenoviridae Infections; D000368:Aged; D000998:Antiviral Agents; D004279:DNA, Viral; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D019562:Viral Load", "nlm_unique_id": "9426239", "other_id": null, "pages": "231-233", "pmc": null, "pmid": "29664432", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Disseminated adenovirus infection in heart and kidney transplant.", "title_normalized": "disseminated adenovirus infection in heart and kidney transplant" }	[ { "companynumb": "PHHY2018US073520", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "80336", "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": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SIROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEART TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEART TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "1", "activesubstance": { "activesubstancename": "SIROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEART TRANSPLANT", "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": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cystitis haemorrhagic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adenovirus infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary incontinence", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "XU J, PATEL KV, DSOUZA M, ALMENDRAL J, MODY K, IYER D. DISSEMINATED ADENOVIRUS INFECTION IN HEART AND KIDNEY TRANSPLANT. TURK KARDIYOLOJI DERNEGI ARSIVI. 2018?46(3):231-3", "literaturereference_normalized": "disseminated adenovirus infection in heart and kidney transplant", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180502", "receivedate": "20180502", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14839578, "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": "Full- or lower-dose anticoagulant therapy or aspirin can be used for extended therapy in patients with venous thromboembolism (VTE), but information on their relative benefit-risk profiles is limited.\n\n\n\nData from the EINSTEIN-CHOICE trial were used to compare the benefit-risk profiles of extended treatment with rivaroxaban (20 or 10 mg once daily) and aspirin (100 mg once daily) in VTE patients who had completed 6 to 12 months of anticoagulation therapy. One-year cumulative incidences of recurrent VTE and major bleeding were estimated and benefits and risks were calculated by determining the between group differences in a hypothetical population of 10,000 VTE patients treated for 1 year.\n\n\n\nA total of 1107 patients were treated with 20 mg of rivaroxaban, 1127 with 10 mg of rivaroxaban, and 1131 with aspirin. The cumulative incidences of recurrent VTE in the rivaroxaban 20-mg, rivaroxaban 10-mg and aspirin groups were 1.9%, 1.6%, and 5.0%, respectively, whereas the cumulative incidences of major bleeding were 0.7%, 0.4% and 0.5%, respectively. The incidences of the combined outcome of recurrent VTE and major bleeding were 2.8% and 3.4% lower in the rivaroxaban 20-mg and 10-mg groups than in the aspirin group. For 10,000 patients treated for 1 year, there would be 284 (95% confidence interval [CI] 106 to 462) and 339 (95% CI 165 to 512) fewer events with rivaroxaban 20 mg or 10 mg than with aspirin.\n\n\n\nCompared with aspirin, extended anticoagulation with once daily rivaroxaban reduces recurrent VTE with a favourable benefit-risk profile.\n\n\n\nBayer AG.", "affiliations": "Department of Cardiothoracic & Vascular Sciences, Vascular Medicine Unit, University of Padua, Italy.;Bayer AG, Leverkusen, Germany.;Department of Epidemiology and Technology Assessment, University of Maastricht, Maastricht, The Netherlands.;Bayer AG, Leverkusen, Germany.;Bayer AG, Leverkusen, Germany.;Bayer AG, Leverkusen, Germany.;Department of Vascular Medicine, Klinikum Darmstadt GmbH, Germany.;Department of Hematology, Medical Clinic I, University Hospital \"Carl Gustav Carus\" Dresden, Germany; Department of Haematology, Oncology Kings College London, UK.;Division of Angiology and Hemostasis, University Hospitals of Geneva, Faculty of Medicine, Geneva, Switzerland.;Department of Haematological Medicine, Guys and St Thomas' Hospitals, King's College Hospital, London, UK.;University of Washington School of Medicine, Seattle, WA, USA.;Hospital Beneficência Portuguesa, São Paulo, Brazil.;Vascular Medicine and Hemostasis, University of Leuven, Belgium.;Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ontario, Canada.;Janssen Research & Development, Raritan, NJ, USA.;Janssen Research & Development, Raritan, NJ, USA.;Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada. Electronic address: [email protected].", "authors": "Prandoni\|Paolo\|P\|;Lensing\|Anthonie W A\|AWA\|;Prins\|Martin H\|MH\|;Gebel\|Martin\|M\|;Pap\|Akos F\|AF\|;Homering\|Martin\|M\|;Bauersachs\|Rupert\|R\|;Beyer-Westendorf\|Jan\|J\|;Bounameaux\|Henri\|H\|;Cohen\|Alexander T\|AT\|;Davidson\|Bruce L\|BL\|;van Bellen\|Bonno\|B\|;Verhamme\|Peter\|P\|;Wells\|Philip S\|PS\|;Yuan\|Zhong\|Z\|;Levitan\|Bennett\|B\|;Weitz\|Jeffrey I\|JI\|", "chemical_list": "D065427:Factor Xa Inhibitors; D010975:Platelet Aggregation Inhibitors; D000069552:Rivaroxaban; D001241:Aspirin", "country": "United States", "delete": false, "doi": "10.1016/j.thromres.2018.06.009", "fulltext": null, "fulltext_license": null, "issn_linking": "0049-3848", "issue": "168()", "journal": "Thrombosis research", "keywords": null, "medline_ta": "Thromb Res", "mesh_terms": "D001241:Aspirin; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D012307:Risk Factors; D000069552:Rivaroxaban; D054556:Venous Thromboembolism", "nlm_unique_id": "0326377", "other_id": null, "pages": "121-129", "pmc": null, "pmid": "30064683", "pubdate": "2018-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin.", "title_normalized": "benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin" }	[ { "companynumb": "CA-INGENUS PHARMACEUTICALS NJ, LLC-ING201807-000740", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN\\CARISOPRODOL\\CODEINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "040860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARISOPRODOL, ASPIRIN AND CODEINE PHOSPHATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WEITZ J, PRANDONI P, LENSING A, PRINS M, GEBEL M, PAP A. BENEFITS AND RISKS OF EXTENDED TREATMENT OF VENOUS THROMBOEMBOLISM WITH RIVAROXABAN OR WITH ASPIRIN. THROMBOSIS RESEARCH (2018). 2018?168:121?9.", "literaturereference_normalized": "benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20180731", "receivedate": "20180731", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15221254, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "CA-INGENUS PHARMACEUTICALS NJ, LLC-ING201807-000741", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN\\CARISOPRODOL\\CODEINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARISOPRODOL, ASPIRIN AND CODEINE PHOSPHATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEITZ J, PRANDONI P, LENSING A, PRINS M, GEBEL M, PAP A. BENEFITS AND RISKS OF EXTENDED TREATMENT OF VENOUS THROMBOEMBOLISM WITH RIVAROXABAN OR WITH ASPIRIN. THROMBOSIS RESEARCH (2018). 2018?168:121?9.", "literaturereference_normalized": "benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20180731", "receivedate": "20180731", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15221255, "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": "Drug induced myocardial infarction is a known entity with different forms of steroids linked to coronary artery disease (CAD) either through promoting its traditional risk factors, inducing coronary spasm, or by other unidentified mechanisms. Dexamethasone is known to promote an atherogenic and hypercoagulable state. We report a case of a 75-year-old woman who had ST elevation myocardial infarction (STEMI) associated with dexamethasone use just 4 days following an angiogram showing minor luminal irregularities.", "affiliations": "Internal Medicine Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA.;Cardiology Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA.;Cardiology Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA.;Cardiology Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA.", "authors": "Shokr\|Mohamed\|M\|0000-0002-8227-0463;Rashed\|Ahmed\|A\|;Lata\|Kusum\|K\|;Kondur\|Ashok\|A\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2016/4970858", "fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2016/4970858Case ReportDexamethasone Associated ST Elevation Myocardial Infarction Four Days after an Unremarkable Coronary Angiogram—Another Reason for Cautious Use of Steroids: A Case Report and Review of the Literature http://orcid.org/0000-0002-8227-0463Shokr Mohamed \n1\n\n\nRashed Ahmed \n2\nLata Kusum \n2\nKondur Ashok \n2\n1Internal Medicine Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA2Cardiology Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USAMohamed Shokr: [email protected] Editor: Antonio de Padua Mansur\n\n2016 18 7 2016 2016 49708583 5 2016 20 6 2016 Copyright © 2016 Mohamed Shokr et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug induced myocardial infarction is a known entity with different forms of steroids linked to coronary artery disease (CAD) either through promoting its traditional risk factors, inducing coronary spasm, or by other unidentified mechanisms. Dexamethasone is known to promote an atherogenic and hypercoagulable state. We report a case of a 75-year-old woman who had ST elevation myocardial infarction (STEMI) associated with dexamethasone use just 4 days following an angiogram showing minor luminal irregularities.\n==== Body\n1. Introduction\nST elevation myocardial infarction is a substantial health problem with estimated 30-day mortality between 2.5 and 10% [1]. Nontraditional risk factors play a significant role in more than 50% of CAD cases [2]. More than 150 drugs were reported as possible causes of acute MI. Betamethasone, methylprednisolone, and dexamethasone were among 39 drugs highlighted as prime suspects that can cause acute MI [3]. We report a case of STEMI associated with dexamethasone use 4 days following a coronary angiogram with only minor luminal irregularities.\n\n2. Case Presentation\nOur patient is a 75-year-old African-American woman with a history of diabetes mellitus, hypertension, hyperlipidemia, and four prior cerebrovascular accidents with mild right sided residual weakness and ventral hernia status after surgical repair. She has no prior history of smoking, alcohol use, illicit drug use, or family history of premature coronary artery disease. She initially presented with shortness of breath, rhinorrhea, and cough productive of yellowish sputum and tested positive for influenza A for which she was started on oseltamivir. On her second day of hospitalization she reported mild retrosternal chest pain accompanied with a Troponin I elevation up to 0.3 ng/mL with an unchanged EKG showing right bundle branch block (RBBB) (Figure 1(a)). She received Aspirin, Clopidogrel, and Heparin drip in addition to Diltiazem and Atorvastatin as treatment for a NSTEMI.\n\nOn the following day, she underwent a coronary angiogram revealing only minor luminal irregularities and no significant CAD (Figure 2(a)). Two days later, she underwent nasopharyngolaryngoscopy for progressive dysphonia that showed inflammatory changes of true and false vocal folds, mild granulation changes of the subglottis, and pachydermia. This was deemed secondary to her upper respiratory tract infection and the resulting acute tracheobronchitis. Subsequently, she was started on intramuscular dexamethasone 10 mg Q8 hours.\n\nOne day later, she complained of severe retrosternal chest pain with a blood pressure of 90/65 mmHg, heart rate of 95 bpm, and oxygen saturation of 95% on room air. Cardiovascular exam was unremarkable revealing regular heart rate and normal S1 and S2 with no appreciated murmurs, rubs, or gallop. She had no JVD and clear lungs on auscultation. Distal pulses were well felt without appreciated lower extremity edema. The EKG however showed ST elevation in the anterior leads, V2 to V5 (Figure 1(b)). Bedside echocardiogram revealed a left ventricular ejection fraction (EF) of 30–35% and regional wall motion in the form of apical dyskinesis and severe hypokinesis in the mid to apical anteroseptal, anterior, apical inferior, inferoseptal, and lateral segments. Of note, the pre-MI echocardiogram showed a normal EF with no appreciated regional wall motion abnormalities. The Troponin I level was 0.1 ng/mL (cutoff value of 0.2 ng/mL). She was immediately transferred to the catheterization lab where the angiogram surprisingly revealed a filling defect, likely a thrombus, occluding the midsegment of the LAD (Figure 2(b)). Subsequently, a 2.5 × 18 mm drug eluting stent was deployed with pre- and postballoon dilation resulting in TIMI III flow (Figure 2(c)). Eptifibatide was started in addition to Ticagrelor, Aspirin, Deltiazem, and Atorvastatin. The chest pain resolved shortly after the intervention and the EKG returned to baseline (Figure 1(c)).\n\nBlood work revealed a platelet count of 461 k/cumm, hemoglobin of 10.5 mg/dL, and white blood cell count of 9 k/cumm. Homocysteine level was mildly elevated (15.5 micromoles/L, normal range 3.2–10.7). High sensitivity CRP was elevated at 40.9 mg/L. Factor VIII activity (325%, normal range: 63–150), factor XI activity (211%, normal range: 71–124), and thrombin antithrombin complex (13.7 ng/mL, normal range: 0.7–3.2) were all increased while factor VII activity was normal. Fibrinogen level and protein C and S activity were normal. Cardiolipin antibody, JAK2 V617F mutation, and Factor V Leiden were all negative.\n\n3. Discussion\nBesides impacting traditional risk factors for CAD such as hypertension (HTN), glucose intolerance, obesity, and hyperlipidemia (HLD), glucocorticoids influence vascular functions, atherogenesis, and remodeling following ischemia or intravascular injury. This influence is mediated by both glucocorticoids and mineralocorticoid receptors and is modified by 11b-hydroxysteroid dehydrogenase enzyme local metabolism of glucocorticoids [4].\n\nDexamethasone was shown to promote an atherogenic and hypercoagulable state through different mechanisms. In high doses, it increases Von Willebrand Factor (VWF) which is a prothrombotic marker and increases the platelet activator P-selectin. Moreover, short term use of dexamethasone is associated with increased levels of Fibrinogen, VII, VIII, and XI [5, 6].\n\nIn 2014 Okumura et al. reported 3 cases of steroid induced coronary spasm [7]. This might be explained by the fact that, in a dose dependent manner, cortisol treatment decreases ATP-induced intracellular calcium mobilization, which in turn decreases nitrate, nitrite, and nitric oxide release [8]. Similarly, glucocorticoids downregulate cyclooxygenase-1 gene expression and subsequently suppress the production of the vasodilator prostacyclin; meanwhile they increase the synthesis of thromboxane which is a vasoconstrictor [9]. There is also evidence that elevated serum cortisol levels might sensitize the coronary vasoconstricting responses through Rho-kinase activation [10]. Additionally, it reduces endothelial nitric oxide synthase mRNA stability and inhibits the synthesis of tetrahydrobiopterin, which is an important cofactor of endothelial nitric oxide synthase [11].\n\nInterestingly, Okumura hypothesized that corticosteroid-induced vasospastic angina might be underestimated due to being mistakenly confused with its known side effect of epigastric discomfort. Wei et al. reported that, among patients using high dose glucocorticoids (>7.5 mg/day), the relative risk for cardiovascular events occurrence was 2.56 [12].\n\nIn 2007, Varas-Lorenzo et al. performed a cohort study with nested case-control analysis to estimate the risk of acute myocardial infarction (AMI) associated with the use of oral corticosteroids by dose and duration. The study included 4795 hospitalized cases of AMI or CAD deaths and randomly sampled 20,000 controls and frequency matched by sex, age, and calendar year.\n\nThe adjusted OR for AMI in current users of oral corticosteroids compared to nonusers was 1.42 (95% CI: 1.17–1.72). The risk during the first 30 days of use (OR = 2.24; 95% CI: 1.56–3.20) was greater than with longer duration (OR = 1.22; 95% CI 0.98–1.52). The risk was more pronounced (OR = 2.15; 95% CI 1.45–3.14) among users of prednisolone equivalent doses >10 mg/day. The study concluded that there is a small increased risk of AMI with oral corticosteroid use with a greater risk observed among users of high corticosteroid dose [13].\n\nIn 2013, Coloma et al. identified 163 drugs reported to cause acute MI in various case reports, out of which 39 had a more probable association with MI including betamethasone, prednisolone, and dexamethasone (RR (95% confidence interval) 3.2 (2.9, 3.5), OR 1.9 (1.7, 2.2), and IRR 5.4 (4.1, 7.2)). Of note, 285 excess cases representing patients on dexamethasone who had an AMI however with other more plausible causes were identified [3]. All the previous mechanisms might explain a possible “spasm-thrombosis” sequence that occurred in our patient in the setting of her long standing other risk factors including diabetes mellitus, hypertension, and hyperlipidemia as mentioned. Interestingly, two prior cases reported angiographically normal coronaries in androgen using athletes who ended up having a coronary occlusion [14]. We are including a comparison between six prior cases of AMI associated with steroid use shedding the light on their different clinical scenarios and other preexisting risk factors for coronary artery disease (Table 1).\n\n4. Conclusion\nDifferent forms of steroids have been linked to CAD either through promoting its traditional risk factors or by other unidentified mechanisms. In most reported cases of steroid-associated AMI, the temporal relation was the main factor suggesting causality. We believe that, with the wide use of corticosteroids for a variety of indications, physicians should be aware of this possible association. Cautious use should be considered particularly in patients with other risk factors for CAD until there is a larger and more convincing pool of evidence.\n\nCompeting Interests\nThe authors have no conflict of interests to disclose.\n\nFigure 1 (a) Baseline EKG with RBBB. (b) EKG showing ST elevation in leads V2–V5. (c) EKG showing resolution of the ST elevation following LAD intervention.\n\nFigure 2 (a) First left heart catheterization showing LAD with minor luminal irregularities. (b) Second left heart catheterization (4 days later) showing the mid-LAD lesion. (c) LAD after intervention.\n\nTable 1 Comparison between six other cases of MI associated with steroid use.\n\nCase\tFerenchick and Adelman [14]\tYildirim et al. [15]\tArslan et al.\n[16]\tTakamatsu et al. [17]\tOwecki and Sowiński [18]\tPoorzand et al. [2]\t\nAge (years)\t37\t64\t20\t79\t66\t23\t\n\n\n\t\nRisk factors\tFamily history of CAD\tHLD\tSmoking\n(7 years)\tBortezomib use\tSmoking\nHLD\t \t\n\n\n\t\nGender\tMale\tMale\tMale\tFemale\tFemale\tMale\t\n\n\n\t\nSteroid type\tNandrolone-decanoate,\nBoldenone,\ntestosterone-cypionate,\nStanozolol,\nand veterinary\noxandrolone\tPrednisolone\tMethylprednisolone\tDexamethasone\tMethylprednisolone\tDexamethasone\t\n\n\n\t\nIndication\tAnabolic steroids (weightlifting)\tIdiopathic intracranial HTN\n(papilledema)\tAnaphylaxis\tMultiple\nmyeloma\tGraves\tAnabolic steroids\n(wrestling)\t\n\n\n\t\nRoute\tIntramuscular & oral\tOral\tIntravenous\tIntravenous\tIntravenous\tIntramuscular\t\n\n\n\t\nDose\t200 mg/week for 16 weeks\n1.5 cc q3 days/16 weeks\n1.5 cc q4 days/16 weeks\n1.5 cc q3 days/16 weeks\n50 mg daily for 16 weeks\t40 mg\ndaily\t40 mg\tNA\t1 gm daily\tNA\t\n\n\n\t\nDuration of use\tIntermittent for 7 years\nand then 16 weeks before the event\tOne month\t7 minutes\t5 days\t5 days\t6 months\t\n\n\n\t\nPossible confounders\t \t \tHypotension secondary to anaphylaxis\tBortezomib use\t \t \t\n\n\n\t\nAcute coronary syndrome type\tSTEMI\tNSTEMI and then STEMI few days later\tSTEMI\tSTEMI\tNSTEMI\tSTEMI\t\n\n\n\t\nEKG\tST elevation,\nII, III, and aVF\tST elevation, II, III, and aVF;\nST depression,\nI, aVL\tST elevation,\nI, aVL\tST elevation,\naVR;\nST depression,\nI, II, and aVF\nV2–6\tNA\tST elevation,\nI, aVL\t\n\n\n\t\nEcho\tNormal\tNormal\tEF 35% apical & posterolateral wall motion abnormality\tEF 68%\nposterior &\nanterolateral akinesia\tAnteroseptal akinesia\tEF 35%\napical, midanterior, anteroseptal\nakinesia\t\n\n\n\t\nLeft heart catheterization findings\tNormal coronaries\n(3 days following tissue plasminogen activator)\tRCA: slow flow\nand then PDA total occlusion\n& LAD slow flow\tNormal coronaries 10 days later\n(normal IVUS)\n(treated with Aspirin & Heparin)\tLM/LCX significant lesions LAD mod stenosis\tLAD total occlusion RCA critical stenosis\tNonobstructive CAD (4 days after streptokinase)\t\n\n\n\t\nComplications\t \t \t \t \t \tLV thrombus\n==== Refs\n1 Roe M. T. Messenger J. C. Weintraub W. S. Treatments, trends, and outcomes of acute myocardial infarction and percutaneous coronary intervention Journal of the American College of Cardiology 2010 56 4 254 263 10.1016/j.jacc.2010.05.008 2-s2.0-77955641943 20633817 \n2 Poorzand H. Jafarzadeh Esfehani R. Hosseinzadeh P. Vojdanparast M. Acute myocardial infarction in a young male wrestler: a case report ARYA Atheroscler 2015 11 6 366 369 26862345 \n3 Coloma P. M. Schuemie M. J. Trifirò G. Drug-induced acute myocardial infarction: identifying ‘prime suspects’ from electronic healthcare records-based surveillance system PLoS ONE 2013 8 8, article e72148 10.1371/journal.pone.0072148 2-s2.0-84883144641 \n4 Walker B. R. Glucocorticoids and cardiovascular disease European Journal of Endocrinology 2007 157 5 545 559 10.1530/eje-07-0455 2-s2.0-36549001222 17984234 \n5 Jilma B. Cvitko T. Winter-Fabry A. Petroczi K. Quehenberger P. Blann A. D. High dose dexamethasone increases circulating P-selectin and von Willebrand factor levels in healthy men Thrombosis and Haemostasis 2005 94 4 797 801 10.1160/T04-10-0652 2-s2.0-27144545040 16270633 \n6 Brotman D. J. Girod J. P. Posch A. Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers Thrombosis Research 2006 118 2 247 252 10.1016/j.thromres.2005.06.006 2-s2.0-33744809252 16005496 \n7 Okumura W. Nakajima M. Tateno R. Fukuda N. Kurabayashi M. Three cases of vasospastic angina that developed following the initiation of corticosteroid therapy Internal Medicine 2014 53 3 221 225 10.2169/internalmedicine.53.1008 2-s2.0-84893500177 24492690 \n8 Rogers K. M. Bonar C. A. Estrella J. L. Yang S. Inhibitory effect of glucocorticoid on coronary artery endothelial function American Journal of Physiology—Heart and Circulatory Physiology 2002 283 5 H1922 H1928 10.1152/ajpheart.00364.2002 2-s2.0-0036839107 12384470 \n9 Jun S. S. Chen Z. Pace M. C. Shaul P. W. Glucocorticoids downregulate cyclooxygenase-1 gene expression and prostacyclin synthesis in fetal pulmonary artery endothelium Circulation Research 1999 84 2 193 200 10.1161/01.res.84.2.193 2-s2.0-0033524664 9933251 \n10 Hizume T. Morikawa K. Takaki A. Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm Circulation Research 2006 99 7 767 775 10.1161/01.res.0000244093.69985.2f 2-s2.0-33749336971 16960099 \n11 Wallerath T. Witte K. Schäfer S. C. Down-regulation of the expression of endothelial NO synthase is likely to contribute to glucocorticoid-mediated hypertension Proceedings of the National Academy of Sciences of the United States of America 1999 96 23 13357 13362 10.1073/pnas.96.23.13357 2-s2.0-0033539502 10557325 \n12 Wei L. MacDonald T. M. Walker B. R. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease Annals of Internal Medicine 2004 141 10 764 770 10.7326/0003-4819-141-10-200411160-00007 2-s2.0-19644401171 15545676 \n13 Varas-Lorenzo C. Rodriguez L. A. G. Maguire A. Castellsague J. Perez-Gutthann S. Use of oral corticosteroids and the risk of acute myocardial infarction Atherosclerosis 2007 192 2 376 383 10.1016/j.atherosclerosis.2006.05.019 2-s2.0-34248578281 16787647 \n14 Ferenchick G. S. Adelman S. Myocardial infarction associated with anabolic steroid use in a previously healthy 37-year-old weight lifter American Heart Journal 1992 124 2 507 508 10.1016/0002-8703(92)90620-b 2-s2.0-0026777921 1636596 \n15 Yildirim U. Gulel O. Soylu K. Yuksel S. Sahin M. Steroid-induced recurrent myocardial ischemia Revista Portuguesa de Cardiologia (English Edition) 2014 33 7-8 473.e1 473.e4 10.1016/j.repc.2014.02.016 2-s2.0-84908291487 \n16 Arslan Z. Iyisoy A. Tavlasoglu M. Acute myocardial infarction after prednisolone administration for the treatment of anaphylaxis caused by a wasp sting Cardiovascular Journal of Africa 2013 24 4 e4 e6 10.5830/cvja-2013-013 2-s2.0-84880905597 24217126 \n17 Takamatsu H. Yamashita T. Kotani T. Sawazaki A. Okumura H. Nakao S. Ischemic heart disease associated with bortezomib treatment combined with dexamethasone in a patient with multiple myeloma International Journal of Hematology 2010 91 5 903 906 10.1007/s12185-010-0586-9 2-s2.0-77954539849 20458563 \n18 Owecki M. Sowiński J. Acute myocardial infarction during high-dose methylprednisolone therapy for Graves' ophthalmopathy Pharmacy World and Science 2006 28 2 73 75 10.1007/s11096-006-9013-y 2-s2.0-33749438522 16791713\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6404", "issue": "2016()", "journal": "Case reports in cardiology", "keywords": null, "medline_ta": "Case Rep Cardiol", "mesh_terms": null, "nlm_unique_id": "101576452", "other_id": null, "pages": "4970858", "pmc": null, "pmid": "27504205", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": "16787647;24492690;16270633;12384470;9933251;10557325;24217126;24015213;17984234;1636596;16791713;16960099;26862345;20458563;16005496;20633817;25155001;15545676", "title": "Dexamethasone Associated ST Elevation Myocardial Infarction Four Days after an Unremarkable Coronary Angiogram-Another Reason for Cautious Use of Steroids: A Case Report and Review of the Literature.", "title_normalized": "dexamethasone associated st 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DEXAMETHASONE ASSOCIATED ST ELEVATION MYOCARDIAL INFARCTION FOUR DAYS AFTER AN UNREMARKABLE CORONARY ANGIOGRAM - ANOTHER REASON FOR CAUTIOUS USE OF STEROIDS: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DEXAMETHASONE ASSOCIATED ST ELEVATION MYOCARDIAL INFARCTION FOUR DAYS AFTER AN UNREMARKABLE CORONARY ANGIOGRAM - ANOTHER REASON FOR CAUTIOUS USE OF STEROIDS: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DEXAMETHASONE ASSOCIATED ST ELEVATION MYOCARDIAL INFARCTION FOUR DAYS AFTER AN UNREMARKABLE CORONARY ANGIOGRAM ANOTHER REASON FOR CAUTIOUS USE OF STEROIDS: A CASE REPORT AND REVIEW OF THE LITERATURE. 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20160321" } }, "primarysource": { "literaturereference": "SHOKR M,RASHED A,LATA K,KONDUR A. DEXAMETHASONE ASSOCIATED ST ELEVATION MYOCARDIAL INFARCTION FOUR DAYS AFTER AN UNREMARKABLE CORONARY ANGIOGRAM - ANOTHER REASON FOR CAUTIOUS USE OF STEROIDS: A CASE REPORT AND REVIEW OF THE LITERATURE. CASE REPORTS IN CARDIOLOGY 2016;4970858:.", "literaturereference_normalized": "dexamethasone associated st elevation myocardial infarction four days after an unremarkable coronary angiogram another reason for cautious use of steroids a case report and review of the literature", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160902", "receivedate": "20160902", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12710303, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]
{ "abstract": "BACKGROUND\nA posterior subtenon injection of triamcinolone acetonide is an alternative to intravitreal injection in diabetic macular edema and is known to have fewer vision-threatening complications. Here, we report a case of periocular abscess following posterior subtenon injection of triamcinolone.\n\n\nMETHODS\nA 62-year-old woman who had diabetic macular edema and disc neovascularization underwent a posterior subtenon injection of triamcinolone acetonide and panretinal laser photocoagulation. One month later a periocular abscess was noted in the inferotemporal area adjacent to the scleral wall. Pus was removed by fine-needle aspiration, and microbiologic cultures identified Pseudallescheria boydii. The patient was given systemic and subconjunctival treatment with itraconazole. However, conjunctival infection and anterior chamber inflammation worsened, and another posterior subtenon abscess was found.\n\n\nRESULTS\nDespite long-term systemic and topical itraconazole therapy, retinal detachment and vitreous opacity were shown on B-scan, and atrophic bulbi resulted.\n\n\nCONCLUSIONS\nPseudallescheria boydii infection of the eye and orbit can result in a poor visual outcome. Prompt surgical debridement and drainage of the abscess, along with appropriate antifungal therapy based on susceptibility testing, must be mandatory.", "affiliations": "Department of Ophthalmology, Anam Hospital, Korea University College of Medicine, 26-1 Anam-dong 5-ga, Sungbuk-gu, Seoul, 136-705, South Korea.", "authors": "Oh\|In Kyung\|IK\|;Baek\|Sehyun\|S\|;Huh\|Kuhl\|K\|;Oh\|Jaeryung\|J\|", "chemical_list": "D000935:Antifungal Agents; D005938:Glucocorticoids; D017964:Itraconazole; D014222:Triamcinolone Acetonide", "country": "Germany", "delete": false, "doi": "10.1007/s00417-006-0325-3", "fulltext": null, "fulltext_license": null, "issn_linking": "0721-832X", "issue": "245(1)", "journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie", "keywords": null, "medline_ta": "Graefes Arch Clin Exp Ophthalmol", "mesh_terms": "D000038:Abscess; D000935:Antifungal Agents; D003238:Connective Tissue; D003930:Diabetic Retinopathy; D015821:Eye Infections, Fungal; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007267:Injections; D017964:Itraconazole; D008269:Macular Edema; D008875:Middle Aged; D008271:Mycetoma; D009916:Orbital Diseases; D011541:Pseudallescheria; D014057:Tomography, X-Ray Computed; D014222:Triamcinolone Acetonide", "nlm_unique_id": "8205248", "other_id": null, "pages": "164-6", "pmc": null, "pmid": "16612634", "pubdate": "2007-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "16207168;15078688;15733990;1841583;10364610;9261319;7574531;12352630", "title": "Periocular abscess caused by Pseudallescheria boydii after a posterior subtenon injection of triamcinolone acetonide.", "title_normalized": "periocular abscess caused by pseudallescheria boydii after a posterior subtenon injection of triamcinolone acetonide" }	[ { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-01058", "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": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Infective scleritis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pseudallescheria infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OH IK, BAEK S, HUH K AND OH J.. PERIOCULAR ABSCESS CAUSED BY PSEUDALLESCHERIA BOYDII AFTER A POSTERIOR SUBTENON INJECTION OF TRIAMCINOLONE ACETONIDE. GRAEFES ARCH CLIN EXP OPHTHALMOL.. 2007?245:164?6", "literaturereference_normalized": "periocular abscess caused by pseudallescheria boydii after a posterior subtenon injection of triamcinolone acetonide", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180306", "receivedate": "20180306", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14601962, "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" }, { "companynumb": "KR-G+W LABS-GW2016KR000128", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "089129", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LOTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MACULAR OEDEMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "089129", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LOTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL NEOVASCULARISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "EYE OINTMENT", "drugdosagetext": "UNK, QHS", "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": "OFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "EYE DROPS", "drugdosagetext": "UNK, QID", "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": "OFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eye abscess", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pseudallescheria infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "IK OH, S BAEK, K HUH. PERIOCULAR ABSCESS CAUSED BY PSEUDALLESCHERIA BOYDII AFTER A POSTERIOR SUBTENON INJECTION OF TRIAMCINOLONE ACETONIDE.. GRAEFE^S ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY. 2007;245(1):164-166", "literaturereference_normalized": "periocular abscess caused by pseudallescheria boydii after a posterior subtenon injection of triamcinolone acetonide", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160922", "receivedate": "20160922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12771893, "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": "OBJECTIVE\nIntra-arterial chemotherapy is a promising strategy for intra-ocular retinoblastoma. Neutropenia is the most commonly encountered systemic toxicity and in this study we aimed to determine the risk factors associated with the development of severe (≥ grade 3) neutropenia.\n\n\nMETHODS\nRetrospective review of 187 evaluable cycles of melphalan-containing intra-arterial chemotherapy from the first three cycles administered to 106 patients with intra-ocular retinoblastoma from May 2006 to June 2011. Cycles were considered to be evaluable if (1) blood count results were available in the 7 to 14 days post-treatment interval and (2) concurrent intravenous chemotherapy was not administered. Toxicity was assessed via the Common Terminology Criteria for Adverse Events version 4.0.\n\n\nRESULTS\n54 cycles (29%) were associated with grade 3 (n = 43) or grade 4 (n = 11) neutropenia. Multivariate stepwise logistic regression revealed that a higher melphalan dose (>0.40 mg/kg) was significantly associated with severe neutropenia during all 3 cycles (odds ratio during cycle one 4.11, 95% confidence interval 1.33-12.73, p = 0.01), but the addition of topotecan and/or carboplatin were not. Prior treatment with systemic chemotherapy was not associated with severe neutropenia risk in any analysis.\n\n\nCONCLUSIONS\nIntra-arterial melphalan-based chemotherapy can cause severe neutropenia, especially when a dose of greater than 0.40 mg/kg is administered. Further study with a larger sample may be warranted.", "affiliations": "Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America; Department of Pediatrics, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America.;Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America.;Department of Neurosurgery, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America.;Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America; Department of Ophthalmology, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America.;Department of Ophthalmology, Mount Sinai Medical Center, New York, NY, United States of America.;Department of Neurosurgery, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America.;Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America; Department of Ophthalmology, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America.", "authors": "Dunkel\|Ira J\|IJ\|;Shi\|Weiji\|W\|;Salvaggio\|Kim\|K\|;Marr\|Brian P\|BP\|;Brodie\|Scott E\|SE\|;Gobin\|Y Pierre\|YP\|;Abramson\|David H\|DH\|", "chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0108692", "fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, USA 25303673PONE-D-14-0594910.1371/journal.pone.0108692Research ArticleMedicine and Health SciencesOncologyCancers and NeoplasmsBlastomasRetinoblastomaOphthalmologic TumorsCancer TreatmentOncology AgentsPediatric OncologyOphthalmologyOcular TumorsPediatric OphthalmologyPediatricsRadiology and ImagingInterventional RadiologyRisk Factors for Severe Neutropenia following Intra-Arterial Chemotherapy for Intra-Ocular Retinoblastoma Risk for Neutropenia Post-IA ChemotherapyDunkel Ira J. \n1\n\n2\n\n\nShi Weiji \n3\nSalvaggio Kim \n4\nMarr Brian P. \n5\n\n6\nBrodie Scott E. \n7\nGobin Y. Pierre \n4\nAbramson David H. \n5\n\n6\n\n1 \nDepartment of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America\n\n2 \nDepartment of Pediatrics, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America\n\n3 \nDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America\n\n4 \nDepartment of Neurosurgery, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America\n\n5 \nDepartment of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America\n\n6 \nDepartment of Ophthalmology, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America\n\n7 \nDepartment of Ophthalmology, Mount Sinai Medical Center, New York, NY, United States of America\nGlod John W. Editor\nNational Cancer Institute, United States of America\n E-mail: [email protected] Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: IJD BPM SEB YPG DHA. Analyzed the data: IJD WS. Contributed reagents/materials/analysis tools: IJD KS BPM SEB YPG DHA. Wrote the paper: IJD WS KS BPM SEB YPG DHA.\n\n2014 10 10 2014 9 10 e10869211 2 2014 2 9 2014 © 2014 Dunkel et al2014Dunkel et alThis 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 properly credited.Purpose\nIntra-arterial chemotherapy is a promising strategy for intra-ocular retinoblastoma. Neutropenia is the most commonly encountered systemic toxicity and in this study we aimed to determine the risk factors associated with the development of severe (≥grade 3) neutropenia.\n\nMethods\nRetrospective review of 187 evaluable cycles of melphalan-containing intra-arterial chemotherapy from the first three cycles administered to 106 patients with intra-ocular retinoblastoma from May 2006 to June 2011. Cycles were considered to be evaluable if (1) blood count results were available in the 7 to 14 days post-treatment interval and (2) concurrent intravenous chemotherapy was not administered. Toxicity was assessed via the Common Terminology Criteria for Adverse Events version 4.0.\n\nResults\n54 cycles (29%) were associated with grade 3 (n = 43) or grade 4 (n = 11) neutropenia. Multivariate stepwise logistic regression revealed that a higher melphalan dose (>0.40 mg/kg) was significantly associated with severe neutropenia during all 3 cycles (odds ratio during cycle one 4.11, 95% confidence interval 1.33–12.73, p = 0.01), but the addition of topotecan and/or carboplatin were not. Prior treatment with systemic chemotherapy was not associated with severe neutropenia risk in any analysis.\n\nConclusions\nIntra-arterial melphalan-based chemotherapy can cause severe neutropenia, especially when a dose of greater than 0.40 mg/kg is administered. Further study with a larger sample may be warranted.\n\nThis work was supported by Perry's Promise Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Body\nIntroduction\nRetinoblastoma is the most common primary ocular tumor of childhood. In the United States and other socio-economically advantaged parts of the world, the vast majority of patients have intra-ocular disease at diagnosis. During the past 15 to 20 years advanced intra-ocular disease has most often been treated with enucleation, but super selective intra-arterial chemotherapy appears to be a promising option [1]–[2]. It is generally well tolerated, but grade 3 and 4 neutropenia may occur. We performed this analysis to try to determine risk factors associated with the development of severe neutropenia and hypothesized that factors associated with development of grade 3 or 4 neutropenia would be (1) the melphalan dose, (2) administration of topotecan and/or carboplatin in addition to melphalan, and (3) prior treatment with systemic chemotherapy.\n\nMethods\nEthics statement\nThe Memorial Sloan-Kettering Cancer Center's Institutional Review Board/Privacy Board approved this retrospective review of existing data, granting a waiver for this to be done without obtaining consent from the subjects or their parents/legal guardians. All protected health information was handled in accordance with institutional policies that did not require the information to be anonymized and de-identified prior to analysis.\n\nPatients\nWe retrospectively reviewed the first 106 consecutive patients with intra-ocular retinoblastoma treated with intra-arterial chemotherapy at our centers from May 2006 to June 2011.\n\nPatients most frequently were treated with intra-arterial single-agent melphalan, but some cycles also included treatment with intra-arterial topotecan and/or carboplatin (Table 1). The number of agents to be used and the doses of chemotherapy administered were determined on a case by case basis. In general, patients received more than one agent if they had more severe disease or had been extensively pre-treated with intravenous chemotherapy and/or external beam radiation therapy, especially if we were treating the only remaining eye. In cycle 1, the dose was primarily determined by the patient's age. Patients 3 to 6 months of age generally received 2.5 mg of melphalan, 6 to 12 months of age, 3 mg of melphalan, 1 to 3 years of age, 4 mg of melphalan, and ≥3 years of age, 5 mg of melphalan [1]. In subsequent cycles we would consider increasing the dose(s) if the ophthalmic artery had large extra-ocular branches or if an inadequate response had been encountered without significant toxicity. We would consider decreasing the dose(s) if wedge flow was encountered or significant toxicity was encountered, such as an interval decrease in the eye's electroretinogram or an ocular inflammatory reaction. The median topotecan dose administered was 0.4 mg (range 0.2 to 2 mg) and the median carboplatin dose administered was 30 mg (range 25 to 80 mg).\n\n10.1371/journal.pone.0108692.t001Table 1 The number of patients treated per cycle with the various chemotherapy agents and the number of patients evaluable for analysis of neutropenia.\nCycle\tPatient\tM only\tM + T\tM+C\tM+T+C\tInevaluable\tEvaluable\t\n1\t106\t74\t21\t1\t10\t33\t73\t\n2\t100\t67\t25\t1\t7\t36\t64\t\n3\t86\t53\t24\t1\t8\t36\t50\t\n M: melphalan; T: topotecan; C: carboplatin.\n\nWe asked the parents to have a complete blood count performed 7 to 10 days after each dose of intra-arterial chemotherapy. However, many families did not reside in the New York area and returned home after the treatment, and so compliance was variable. Intra-arterial chemotherapy cycles were considered to be evaluable if (1) blood count results were available in the 7 to 14 days post-treatment interval, and (2) concurrent intravenous chemotherapy was not administered. However, if a blood count was not available within the 7 to 14 day post-treatment window, but grade 3 or 4 neutropenia was documented earlier or later in the cycle, the cycle was considered evaluable. Toxicity was assessed via the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.\n\nStatistics\nA binary melphalan dose is of interest in potential prediction. An optimal cut-off point of the dose was selected using Miller and Siegmund's minimum p-value approach and Altman, Lausen, Sauerbrei, and Schumacher's formula to adjust the minimum p-value selected from the systematic dependent multiple testing [3]–[4]. The highest and lowest 10% of the melphalan dose data were eliminated from the selection procedure. A univariate analysis of relationship between treatment factors and severe neutropenia (defined as grade 3 or 4 neutropenia) was performed using Chi-square, or Fisher's exact test. A multivariate analysis of the joint relationship was performed using a stepwise logistical regression method. Variables with p-value ≤0.20 on univariate analysis were candidates for the initial multivariate model. The statistical analysis was performed with the software SAS version 9.2 (SAS Institute Cary, NC) and r package ROCR (version 2.9.2). A p-value<0.05 was considered significant.\n\nAll analyses were based on evaluable cycles only. Grade 3 and 4 neutropenia were combined into the entity of severe neutropenia due to the small number of grade 4 neutropenia events (n = 5, 3, and 3 during cycles 1, 2 and 3, respectively).\n\nResults\nMelphalan dose and analysis of optimal cut-off point\nA preliminary analysis showed that a higher melphalan dose (continuous variable) was significantly associated with severe neutropenia during cycles 2 and cycle 3 (p<0.0001, p<0.0001 by t-test, respectively). The minimum p-value approach showed that 0.50 mg/kg was the best cut-off point during cycle 2 (>0.50 versus ≤50 mg/kg, χ2 = 18.55, adjusted p = 0.0007) and 0.40 mg/kg during cycle 3 (>0.40 versus ≤0.40 mg/kg, χ2 = 26.26, adjusted p<0.0001). Melphalan dose>0.40 mg/kg was also associated with severe neutropenia during cycle 2 (χ2 = 12.34, adjusted p = 0.01).\n\nAnalyses of treatment factors and severe neutropenia\nCycle 1\nA univariate analysis regarding cycle 1 showed that a higher dose of melphalan (>0.40 versus ≤0.40 mg/kg) was significantly associated with severe neutropenia (p = 0.01, Table 2). The univariate analysis also showed that the severe neutropenia rate was significantly different among patients treated with different chemotherapy regimens (melphalan alone versus melphalan and either topotecan or carboplatin versus melphalan, topotecan and carboplatin, p = 0.04). Further pairwise comparison showed that patients treated with three chemotherapy agents more frequently experienced severe neutropenia compared to those treated with two agents (50% versus 9%, p = 0.02). However, a stepwise logistic regression revealed that while higher melphalan dose remained associated with severe neutropenia (odds ratio (OR) 4.11, 95% CI 1.33–12.73, p = 0.01), the number of chemotherapy agents administered did not.\n\n10.1371/journal.pone.0108692.t002Table 2 Cycle 1: Univariate analysis of severe neutropenia.\nVariable\tSevere neutropenia (25%)\tp-value\t\n\tNo (n = 55)\tYes (n = 18)\t\t\nM dose, mg/kg (mean ± SD)\t0.39±0.14\t0.43±0.12\t\t\nMedian (range)\t0.35 (0.15–0.89)\t0.46 (0.27–0.68)\t\t\n≤0.40\t37 (67%)\t6 (33%)\t0.01\t\n>0.40\t18 (33%)\t12 (67%)\t\t\nChemotherapy agents\t\t\t0.04\t\nM only\t30 (55%)\t11 (61%)\t\t\nM+ T/C\t20 (36%)\t2 (11%)\t\t\nM+ T + C\t5 (9%)\t5 (28%)\t\t\nPrior treatmenta\n\t\t\t0.77\t\nNo\t24 (45%)\t7 (41%)\t\t\nYes\t29 (55%)\t10 (59%)\t\t\n M: melphalan; T: topotecan; C: carboplatin.\n\na Data not available for 3 patients (2 had and 1 did not have severe neutropenia).\n\nCycle 2\nA univariate analysis revealed that a higher cycle 2 melphalan dose (>0.50 versus ≤0.50 mg/kg) was significantly associated with severe neutropenia (p<0.0001 by Chi-square test, adjusted p = 0.0007, Table 3). A stepwise logistic regression showed melphalan dose remained associated with severe neutropenia during cycle 2 (p = 0.0005, OR 10.86, 95% CI 2.84–41.57).\n\n10.1371/journal.pone.0108692.t003Table 3 Cycle 2: Univariate analysis of severe neutropeniaa.\nVariable\tSevere neutropenia (30%)\tp-value\t\n\tNo (n = 45)\tYes (n = 19)\t\t\nM dose, mg/kg (mean ± SD)\t0.36±0.12\t0.51±0.13\t\t\nMedian (range)\t0.34 (0.04–0.57)\t0.52 (0.26–0.71)\t\t\n≤0.50\t40 (89)\t7 (37)\t<0.001c\n\t\n>0.50\t5 (11)\t12 (63)\t\t\n≤0.40\t31 (69%)\t4 (21%)\t0.01c\n\t\n>0.40\t14 (31%)\t15 (79%)\t\t\nChemotherapy agents\t\t\t0.26\t\nM only\t22 (49%)\t9 (47%)\t\t\nM+ T/C\t20 (44%)\t6 (32%)\t\t\nM+ T + C\t3 (7%)\t4 (21%)\t\t\nPrior treatmentb\n\t\t\t0.13\t\nNo\t22 (51%)\t5 (29%)\t\t\nYes\t21 (49%)\t12 (71%)\t\t\nCycle 1 grade 3 or 4 neutropenia\t\t\t0.66\t\nNo\t27 (60%)\t9 (47%)\t\t\nNo record\t10 (22%)\t5 (26%)\t\t\nYes\t8 (18%)\t5 (26%)\t\t\n M: melphalan; T: topotecan; C: carboplatin.\n\na Only one variable was associated with severe neutropenia at p≤0.05 on univariate analysis; multivariate analysis was not performed.\n\nb Data not available for 4 patients (2 had and 2 did not have severe neutropenia).\n\nc Cut-off point selection adjusted p-value.\n\nCycle 3\nA univariate analysis demonstrated that a higher cycle 3 melphalan dose (>0.40 versus ≤0.40 mg/kg) was once again significantly associated with severe neutropenia (p<0.0001, adjusted p<0.0001, Table 4). The univariate analysis and further pairwise comparison also showed that patients who had severe neutropenia during cycle 1 or 2 more frequently experienced severe neutropenia during cycle 3 compared to those who did not (yes versus unknown versus no, p = 0.02; yes versus no, p = 0.01). A stepwise multivariate logistic regression analysis revealed that while the higher melphalan dose remained associated with severe neutropenia (p = 0.0001, OR 72.0, 95% CI 7.93–653.4), severe neutropenia during cycle 1 or 2 did not.\n\n10.1371/journal.pone.0108692.t004Table 4 Cycle 3: Univariate analysis of severe neutropenia.\nVariable\tSevere neutropenia (34%)\tp-value\t\n\tNo (n = 33)\tYes (n = 17)\t\t\nM dose, mg/kg (mean ± SD)\t0.34±0.11\t0.50±0.08\t\t\nMedian (range)\t0.33 (0.13–0.70)\t0.50 (0.33–0.69)\t\t\n≤0.40\t27 (82%)\t1 (6%)\t<0.001b\n\t\n>0.40\t6 (18%)\t16 (94%)\t\t\nChemotherapy agents\t\t\t0.15\t\nM only\t13 (39%)\t4 (24%)\t\t\nM+ T/C\t17 (52%)\t8 (47%)\t\t\nM+ T + C\t3 (9%)\t5 (29%)\t\t\nPrior treatmenta\n\t\t\t0.83\t\nNo\t16 (50%)\t7 (47%)\t\t\nYes\t16 (50%)\t8 (53%)\t\t\nCycle 1 or 2, grade 3 or 4 neutropenia\t\t\t0.02\t\nNo\t14 (42%)\t3 (18%)\t\t\nNo record\t11 (33%)\t3 (18%)\t\t\nYes\t8 (24%)\t11 (65%)\t\t\n M: melphalan; T: topotecan; C: carboplatin.\n\na Data not available for 3 patients (1 had and 2 did not have severe neutropenia).\n\nb Cut-off point selection adjusted p-value.\n\nImpact of inevaluable cycles\nA greater proportion of later cycles were inevaluable (31%, 36%, and 42% in cycles 1, 2, and 3, respectively) and that could introduce bias on generalization. However, there was no significant difference in melphalan dose (continuous or binary>0.40 versus ≤0.40 mg/kg), chemotherapy regimen, prior treatment, and severe neutropenia during cycle 1, 2 or 3 between the patients who had or had no record (at cycle 1, 2, or 3, p = 0.11 to 0.95), except that patients with record received a higher mean melphalan dose during cycle 1 (0.40±0.14 versus 0.34±0.14, p = 0.04). In addition, patients with record received a higher binary melphalan dose (>0.50 versus ≤0.50 mg/kg) during cycle 2 (27% versus vs 8%, p = 0.03).\n\nClinical consequences of severe neutropenia\nMost patients who developed severe neutropenia were asymptomatic. Two patients were admitted to the hospital during three periods of severe neutropenia due to fever and/or mucositis. Both patients made complete recoveries.\n\nOther severe hematological toxicities\nSevere (grade 3 or 4) anemia or thrombocytopenia were encountered infrequently. Five patients suffered 1 episode each (5 episodes total) of grade 3 anemia and 2 patients suffered 1 episode each (2 episodes total) of grade 4 thrombocytopenia.\n\nDiscussion\nIntra-arterial chemotherapy was first introduced into the treatment regimen for patients with intra-ocular retinoblastoma by Reese and colleagues in 1955 when they administered triethylenemelamine via the internal carotid artery [2]. It then fell out of favor due to toxicity concerns (that included death) and lack of clear benefit over other treatments until 1987 when Kaneko and colleagues began to administer selective ophthalmic arterial injection of melphalan using a balloon catheter. Their group recently reported a retrospective series of 343 patients (408 eyes) treated with 1452 procedures from 1988 to 2007 [5]. They generally used single-agent melphalan at a dose of 5 to 7.5 mg/m2 and did not encounter any> grade 1 decrease of white blood cells. Using a 30∶1 conversion factor, these doses are approximately 0.17 to 0.25 mg/kg of melphalan.\n\nIn the patients reported in this series, we used a higher dose of melphalan (median dose of evaluable cycles 0.36 mg/kg, range 0.04 to 0.89 mg/kg) and have encountered severe neutropenia in 29% of the cycles. Fortunately, most of the episodes of severe neutropenia were grade 3 (n = 43) rather than grade 4 (n = 11) and were generally clinically insignificant. We counseled the parents about the risk of fever and neutropenia, but did not routinely prescribe filgrastim. We did not encounter any severe neutropenia during cycles in which the melphalan dose was ≤0.25 mg/kg (the approximate dose used in Japan). A limitation is that we may have overestimated the risk of neutropenia due to our decision to consider cycles with blood counts performed outside of the 7 to 14 day window without neutropenia to be inevaluable, but to consider cycles evaluable if grade 3 or 4 neutropenia was documented earlier or later in the cycle. We felt that potentially overestimating rather than underestimating the risk of neutropenia associated with the intra-arterial chemotherapy was the more conservative approach.\n\nWe hypothesized that (1) adding topotecan and/or carboplatin to the melphalan regimen and (2) a history of prior patient exposure to intravenous chemotherapy might be associated with increased risk for severe neutropenia, but that turned out not to be the case. The only factor that remained significant in analyses was melphalan dose, particularly when a dose of greater than 0.40 mg/kg was administered. Due to the relatively small number of events and sample size, we may not have enough power to detect some difference. We were also unable to select an optimal cut-off point of melphalan dose in a multivariate setting. Further study with a larger sample size may be warranted. This increased risk of neutropenia associated with a melphalan dose of greater than 0.40 mg/kg is comparable to the results in a small series reported by Argentine investigators. They noted that children receiving more than 0.48 mg/kg for bilateral tandem infusions had a significantly higher systemic area under the curve and a 50% probability of grade 3 or 4 neutropenia [6].\n\nThese data may help assist in the selection of safe intra-arterial chemotherapy doses for patients with intra-ocular retinoblastoma, but it is important to note that most patients who developed severe neutropenia were asymptomatic and did not require hospital admission for fever and neutropenia or an infection. To minimize the risk of severe neutropenia patients should be treated with a melphalan dose of 0.40 mg/kg or less, but should higher doses be required to adequately treat the retinoblastoma and cure the eye, the risk of severe neutropenia may be acceptable.\n\nA preliminary version of this work was presented at the 2009 International Congress of Ocular Oncology meeting in Cambridge, UK.\n==== Refs\nReferences\n1 \nGobin YP , Dunkel IJ , Marr BP , Brodie SE , Abramson DH (2011 ) Intra-arterial chemotherapy in the management of retinoblastoma: Four-year experience . Arch Ophthalmol \n129 : 732 –737 .21320950 \n2 \nReese AB , Hyman GA , Merriam GR Jr, Forrest AW , Kligerman MM (1954 ) Treatment of retinoblastoma by radiation and triethylenemelamine . AMA Arch Ophthalmol \n53 : 505 –513 .14360881 \n3 \nMiller R , Siegmund D (1982 ) Maximally selected chi square statistics . Biometrics \n38 : 1011 –1016 .\n4 \nAltman DG , Lausen B , Sauerbrei W , Schumacher M (1994 ) Dangers of using “optimal” cutpoints in the evaluation of prognostic factors . J Natl Cancer Inst \n86 : 829 –835 .8182763 \n5 \nSuzuki S , Yamane T , Mohri M , Kaneko A (2011 ) Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: The long term prognosis . Ophthalmology \n118 : 2081 –2087 .21715012 \n6 \nSchaiquevich P , Buitrago E , Taich P , Torbidoni A , Ceciliano A , et al (2012 ) Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients . Invest Ophthalmol Vis Sci \n53 : 4205 –4212 .22628208\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "9(10)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D008558:Melphalan; D009503:Neutropenia; D009504:Neutrophils; D012160:Retina; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies; D012307:Risk Factors", "nlm_unique_id": "101285081", "other_id": null, "pages": "e108692", "pmc": null, "pmid": "25303673", "pubdate": "2014", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "8182763;21715012;14360881;21320950;22628208", "title": "Risk factors for severe neutropenia following intra-arterial chemotherapy for intra-ocular retinoblastoma.", "title_normalized": "risk factors for severe neutropenia following intra arterial chemotherapy for intra ocular retinoblastoma" }	[ { "companynumb": "US-GLAXOSMITHKLINE-US2014GSK012727", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "014691", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPOTECAN\\TOPOTECAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPOTECAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUNKEL I, SHI W, SALVAGGIO K, MARR B, BRODIE S. RISK FACTORS FOR SEVERE NEUTROPENIA FOLLOWING INTRA-ARTERIAL CHEMOTHERAPY FOR INTRA-OCULAR RETINOBLASTOMA.. PLOS ONE. 2014;10", "literaturereference_normalized": "risk factors for severe neutropenia following intra arterial chemotherapy for intra ocular retinoblastoma", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141027", "receivedate": "20141027", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10544587, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]
{ "abstract": "We report a case of necrotizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia complicated by a bronchopleural fistula and treated by decortication and salvage lobectomy. Owing to the unknown characteristics of the underlying SARS-CoV-2 infection, treatment of the abscess and bronchopleural fistula was delayed. This may have resulted in further deterioration of the patient, with ensuing multiple organ dysfunction. Complications of SARS-CoV-2 pneumonia, such as a bacterial abscess and a bronchopleural fistula, should be treated as if the patient were not infected with SARS-CoV-2.", "affiliations": "Department of Thoracovascular Surgery, Ziekenhuis Oost-Limburg, Genk, Belgium. Electronic address: [email protected].;Department of Anesthesiology, Ziekenhuis Oost-Limburg, Genk, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium.;Department of Anesthesiology, Ziekenhuis Oost-Limburg, Genk, Belgium.;Department of Pathology, Ziekenhuis Oost-Limburg, Genk, Belgium.;Department of Thoracovascular Surgery, Ziekenhuis Oost-Limburg, Genk, Belgium.;Department of Thoracovascular Surgery, Ziekenhuis Oost-Limburg, Genk, Belgium.", "authors": "Peeters\|Karen\|K\|;Mesotten\|Dieter\|D\|;Willaert\|Xavier\|X\|;Deraedt\|Karen\|K\|;Nauwelaers\|Sigi\|S\|;Lauwers\|Geert\|G\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.athoracsur.2020.10.038", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-4975", "issue": "111(4)", "journal": "The Annals of thoracic surgery", "keywords": null, "medline_ta": "Ann Thorac Surg", "mesh_terms": "D000328:Adult; D001983:Bronchial Fistula; D000086382:COVID-19; D005260:Female; D006801:Humans; D008168:Lung; D010995:Pleural Diseases; D011013:Pneumonectomy; D011024:Pneumonia, Viral; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "15030100R", "other_id": null, "pages": "e241-e243", "pmc": null, "pmid": "33279555", "pubdate": "2021-04", "publication_types": "D002363:Case Reports", "references": null, "title": "Salvage Lobectomy to Treat Necrotizing SARS-CoV-2 Pneumonia Complicated by a Bronchopleural Fistula.", "title_normalized": "salvage lobectomy to treat necrotizing sars cov 2 pneumonia complicated by a bronchopleural fistula" }	[ { "companynumb": "BE-FRESENIUS KABI-FK202103729", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040583", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "HIGH?DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFLAMMATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALPHA HAEMOLYTIC STREPTOCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "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": "PIPERACILLIN SODIUM/TAZOBACTAM SODIUM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUCONAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANDIDA INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCONAZOLE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess bacterial", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PEETERS K, MESOTTEN D, WILLAERT X, DERAEDT K, NAUWELAERS S, LAUWERS G. SALVAGE LOBECTOMY TO TREAT NECROTIZING SARS?COV?2 PNEUMONIA COMPLICATED BY A BRONCHOPLEURAL FISTULA. ANNALS OF THORACIC SURGERY. 2021 APR?111 (4):E241?E243.", "literaturereference_normalized": "salvage lobectomy to treat necrotizing sars cov 2 pneumonia complicated by a bronchopleural fistula", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20210414", "receivedate": "20210414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19132394, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "NVSC2021BE081658", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NOREPINEPHRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE ABNORMAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NORADRENALINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALPHA HAEMOLYTIC STREPTOCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "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": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "40104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "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": "FLUCONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CANDIDA INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCONAZOLE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PEETERS K, MESOTTEN D, WILLAERT X, DERAEDT K, NAUWELAERS S, LAUWERS G. SALVAGE LOBECTOMY TO TREAT NECROTIZING SARS?COV?2 PNEUMONIA COMPLICATED BY A BRONCHOPLEURAL FISTULA. 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFLAMMATION", "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": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PEETERS K, MESOTTEN D, WILLAERT X, DERAEDT K, NAUWELAERS S, LAUWERS G. SALVAGE LOBECTOMY TO TREAT NECROTIZING SARS?COV?2 PNEUMONIA COMPLICATED BY A BRONCHOPLEURAL FISTULA. ANN THORAC SURG. 2021?111(4):E241?E243", "literaturereference_normalized": "salvage lobectomy to treat necrotizing sars cov 2 pneumonia complicated by a bronchopleural fistula", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20210423", "receivedate": "20210423", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19172323, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "OBJECTIVE\nAcute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment.\n\n\nMETHODS\nA 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250 mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10 U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76 L/min/m2). She developed acute renal failure, ischaemic hepatitis and disseminated intravascular coagulopathy. Inotropes and high-dose insulin were weaned over four days with complete recovery. Metoprolol was quantified with liquid chromatography-tandem mass spectrometry and concentration-time data were analysed using MONOLIX® vs 4.3 ( www.lixoft.com ). Admission metoprolol concentration was 2.39 μg/mL (therapeutic reference range: 0.035-0.5 μg/mL). Data best fitted a one compartmental model with Michaelis-Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4 L, maximum rate [Vm], 9.57 mg h-1, Michaelis constant [Km], 1.97 mg L-1. Predicted elimination half-life decreased from 20 h over time until there was first order elimination with a half-life 9 h.\n\n\nCONCLUSIONS\nThe time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes.", "affiliations": "a Clinical Toxicology Research Group , University of Newcastle , New South Wales , Australia.;b Department of Intensive Care , John Fawkner Private Hospital , Victoria , Australia.;b Department of Intensive Care , John Fawkner Private Hospital , Victoria , Australia.;a Clinical Toxicology Research Group , University of Newcastle , New South Wales , Australia.;c Department of Pharmaceutical Chemistry , Helwan University , Helwan , Egypt.;d Therapeutics Research Centre, School of Medicine , University of Queensland , Brisbane , Australia.", "authors": "Isbister\|Geoffrey K\|GK\|;Ang\|Karyn\|K\|;Gorman\|Kieron\|K\|;Cooper\|Joyce\|J\|;Mostafa\|Ahmed\|A\|;Roberts\|Michael S\|MS\|", "chemical_list": "D058672:Adrenergic beta-2 Receptor Antagonists; D007328:Insulin; D014662:Vasoconstrictor Agents; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol", "country": "England", "delete": false, "doi": "10.1080/15563650.2016.1209768", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-3650", "issue": "54(9)", "journal": "Clinical toxicology (Philadelphia, Pa.)", "keywords": "Beta-blocker; Michaelis–Menten; high-dose insulin therapy; pharmacokinetics; toxicity", "medline_ta": "Clin Toxicol (Phila)", "mesh_terms": "D058672:Adrenergic beta-2 Receptor Antagonists; D000369:Aged, 80 and over; D002853:Chromatography, Liquid; D019389:Cytochrome P-450 CYP2D6; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007022:Hypotension; D007328:Insulin; D008790:Metoprolol; D012770:Shock, Cardiogenic; D053719:Tandem Mass Spectrometry; D014662:Vasoconstrictor Agents", "nlm_unique_id": "101241654", "other_id": null, "pages": "881-885", "pmc": null, "pmid": "27442605", "pubdate": "2016-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Zero-order metoprolol pharmacokinetics after therapeutic doses: severe toxicity and cardiogenic shock.", "title_normalized": "zero order metoprolol pharmacokinetics after therapeutic doses severe toxicity and cardiogenic shock" }	[ { "companynumb": "AU-MYLANLABS-2016M1049905", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "POTASSIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POTASSIUM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076704", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LATER, INCREASED TO 50MG THRICE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5MG", "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": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076704", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LATER, INCREASED TO 100MG IN THE MORNING, 50 MG AT MID DAY AND 100MG AT THE NIGHT", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076704", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG IN THE MORNING, 50 MG AT MID DAY AND 100MG AT THE NIGHT", "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": "METOPROLOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALBUTEROL" }, "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": "SALBUTAMOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ISBISTER GK, ANG K, GORMAN K, COOPER J, MOSTAFA A, ROBERTS MS. ZERO-ORDER METOPROLOL PHARMACOKINETICS AFTER THERAPEUTIC DOSES: SEVERE TOXICITY AND CARDIOGENIC SHOCK. 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ZERO-ORDER METOPROLOL PHARMACOKINETICS AFTER THERAPEUTIC DOSES: SEVERE TOXICITY AND CARDIOGENIC SHOCK. 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ZERO-ORDER METOPROLOL PHARMACOKINETICS AFTER THERAPEUTIC DOSES: SEVERE TOXICITY AND CARDIOGENIC SHOCK. 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"reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cyanosis central", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ischaemic hepatitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ISBISTER GK, ANG K, GORMAN K, COOPER J, MOSTAFA A, ROBERTS MS. ZERO-ORDER METOPROLOL PHARMACOKINETICS AFTER THERAPEUTIC DOSES: SEVERE TOXICITY AND CARDIOGENIC SHOCK. CLINICAL TOXICOLOGY. 2016;1-5", "literaturereference_normalized": "zero order metoprolol pharmacokinetics after therapeutic doses severe toxicity and cardiogenic shock", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20161007", "receivedate": "20160823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12677992, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "AU-FRESENIUS KABI-FK201609084", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", 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"drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL INJECTION (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "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": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091045", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "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": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "90", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ISBISTER G,ANG K,GORMAN K,COOPER J,MOSTAFA A,ROBERTS M. ZERO-ORDER METOPROLOL PHARMACOKINETICS AFTER THERAPEUTIC DOSES: SEVERE TOXICITY AND CARDIOGENIC SHOCK. CLINICAL TOXICOLOGY 2016;NO. 9:881-885.", "literaturereference_normalized": "zero order metoprolol pharmacokinetics after therapeutic doses severe toxicity and cardiogenic shock", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20161123", "receivedate": "20161123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12969795, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" } ]
{ "abstract": "The lack of a randomized trial comparing carfilzomib (K) versus elotuzumab (Elo) associated with lenalidomide and dexamethasone (Rd) prompted us to assess the relative usefulness of one triplet over the other. Five independent retrospective cohorts of 883 relapsed/refractory multiple myeloma (RRMM) patients, including 300 EloRd and 583 KRd cases, outside clinical trials, entered this non-randomized comparison. KRd cohort accounted for a higher incidence of younger patients, cases with ≥3 lines of therapy, already exposed to lenalidomide, International Staging System (ISS) stage III, and abnormal lactic dehydrogenase (LDH) level compared with EloRd cohort. Moreover, cytogenetic risk categories, detected in roughly one-third of cases, were equally distributed between the two therapy arms. The probability of CR+VGPR response was significantly higher in KRd (n = 314, 53.9%) than in EloRd patients (n = 111, 37.0%). Likewise, the cumulative incidence function of CR+VGPR, taking into account the competitive risk of death, was significantly higher in KRd arm patients than those in the EloRd arm (p = .003). Moreover, KRd treatment significantly reduced the progression or death risk by 46% in an adjusted multivariate analysis (HR: 0.54, 95% CI 0.42-0.69, p < .0001). Finally, in an adjusted illness-progression/death model, the effect of KRd versus EloRd was of higher magnitude among those who achieved CR+VGPR (-39% hazard ratio reduction, p = .02) than among those who achieved < VGPR (-29% hazard ratio reduction, p = .007). With limitations characteristic to any retrospective analysis, this current clinical practice study's overall results demonstrated potential benefits of KRd therapy compared with EloRd. This observation may help the daily clinical practice.", "affiliations": "Biothecnology Research Unit, AO of Cosenza, Cosenza, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, Catania, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Tricase (LE), Italy.;Hematology Unit, Ospedale Cardarelli, Napoli, Italy.;Division of Hematology, University of Torino, AOU Città della Salute e della Scienza di Torino, Torino, Italy.;Hematology and Bone Marrow Transplant Unit, Azienda Socio-Sanitaria Territoriale-Papa Giovanni XXIII, Bergamo, Italy.;Hematology Division, Department of Hematology-Oncology, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.;Department of Hematology, Businco Hospital, Cagliari, Italy.;Istituto di Ematologia, Università Cattolica, Fondazione Policlinico Gemelli IRCCS, Roma, Italy.;Department of Biomedical Science, University of Bari \"Aldo Moro\" Medical School, Internal Medicine \"G. Baccelli\", Policlinico, Bari, Italy.;AUOP \"Federico II\", Naples, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;Department of Hematology, Hospital Perrino, Brindisi, Italy.;Hematology Unit, Department of Hemato-Oncology and Radiotherapy, Great Metropolitan Hospital \"Bianchi-Melacrino-Morelli\", Reggio Calabria, Italy.;Hematology Unit AO of Cosenza, Cosenza, Italy.;Hematology Unit AO of Cosenza, Cosenza, Italy.;Hematology Unit AO of Cosenza, Cosenza, Italy.;Hematology Unit AO of Cosenza, Cosenza, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Tricase (LE), Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, Catania, Italy.;Department of Hematology and Bone Marrow Transplant, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;Institute of Haematology and Stem Cell transplantation, Ospedale Santa Maria della Misericordia, University of Perugia, Perugia, Italy.;Nephrology Center of National Research Institute of Biomedicine and Molecular Immunology, Reggio Calabria, Italy.;UOC Ematologia a Indirizzo Oncologico, AORN \"Sant'Anna e San Sebastiano\", Caserta, Italy.;Department of Hematology and Bone Marrow Transplant, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;U.O.C. Ematologia A. O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Department of Hematology, Hospital Vito Fazzi, Lecce, Italy.;UOC Ematologia a Indirizzo Oncologico, AORN \"Sant'Anna e San Sebastiano\", Caserta, Italy.;Onco-Hematology, \"Tortora\" Hospital, Pagani, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;Hematology Section, University of Bari, Italy.;Istituto di Ematologia, Università Cattolica, Fondazione Policlinico Gemelli IRCCS, Roma, Italy.;U.O.C. OncoEmatologia e TMO, Dipartimento Oncologico, La Maddalena, Palermo, Italy.;Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.;Hematology Unit, AOU Ospedali Riuniti di Ancona, Ancona, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.;Department of Hematology, Hospital Vito Fazzi, Lecce, Italy.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, Catania, Italy.;Division of Hematology, University of Torino, AOU Città della Salute e della Scienza di Torino, Torino, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;Hematology Unit AO of Cosenza, Cosenza, Italy.", "authors": "Morabito\|Fortunato\|F\|https://orcid.org/0000-0002-2585-7073;Zamagni\|Elena\|E\|;Conticello\|Concetta\|C\|;Pavone\|Vincenzo\|V\|;Palmieri\|Salvatore\|S\|;Bringhen\|Sara\|S\|;Galli\|Monica\|M\|;Mangiacavalli\|Silvia\|S\|;Derudas\|Daniele\|D\|;Rossi\|Elena\|E\|;Ria\|Roberto\|R\|;Catalano\|Lucio\|L\|;Tacchetti\|Paola\|P\|;Mele\|Giuseppe\|G\|;Donatella Vincelli\|Iolanda\|I\|;Antonia Martino\|Enrica\|E\|;Vigna\|Ernesto\|E\|;Botta\|Cirino\|C\|https://orcid.org/0000-0002-1522-4504;Bruzzese\|Antonella\|A\|;Mele\|Anna\|A\|;Pantani\|Lucia\|L\|;Rocchi\|Serena\|S\|;Garibaldi\|Bruno\|B\|;Cascavilla\|Nicola\|N\|;Ballanti\|Stelvio\|S\|;Tripepi\|Giovanni\|G\|;Frigeri\|Ferdinando\|F\|;Pia Falcone\|Antonetta\|A\|;Cangialosi\|Clotilde\|C\|;Reddiconto\|Giovanni\|G\|;Farina\|Giuliana\|G\|;Barone\|Marialucia\|M\|;Rizzello\|Ilaria\|I\|;Musto\|Pellegrino\|P\|;De Stefano\|Valerio\|V\|;Musso\|Maurizio\|M\|;Teresa Petrucci\|Maria\|M\|;Offidani\|Massimo\|M\|;Neri\|Antonino\|A\|;Di Renzo\|Nicola\|N\|;Di Raimondo\|Francesco\|F\|;Boccadoro\|Mario\|M\|;Cavo\|Michele\|M\|;Gentile\|Massimo\|M\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/ejh.13723", "fulltext": null, "fulltext_license": null, "issn_linking": "0902-4441", "issue": null, "journal": "European journal of haematology", "keywords": "carfilzomib; dexamethasone; elotuzumab; lenalidomide; multiple myeloma; salvage therapy", "medline_ta": "Eur J Haematol", "mesh_terms": null, "nlm_unique_id": "8703985", "other_id": null, "pages": null, "pmc": null, "pmid": "34716957", "pubdate": "2021-10-30", "publication_types": "D016428:Journal Article", "references": null, "title": "Adjusted comparison between elotuzumab and carfilzomib in combination with lenalidomide and dexamethasone as salvage therapy for multiple myeloma patients.", "title_normalized": "adjusted comparison between elotuzumab and carfilzomib in combination with lenalidomide and dexamethasone as salvage therapy for multiple myeloma patients" }	[ { "companynumb": "IT-AMGEN-ITASP2021171927", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARFILZOMIB" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "202714", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unknown formulation", "drugdosagetext": "20 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARFILZOMIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARFILZOMIB" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "202714", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unknown formulation", "drugdosagetext": "27 MILLIGRAM/SQ. METER ON DAY 1, 2, 8, 9, 15, 16", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "27", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARFILZOMIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MILLIGRAM ON DAYS 1-21", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ELOTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM/KILOGRAM ON DAYS 1,8, 15, AND 22 DURING THE FIRST TWO CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELOTUZUMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": null, "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": "DIPHENHYDRAMINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RANITIDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM", "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": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANITIDINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": null, "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": "ACETAMINOPHEN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Morabito F. Adjusted comparison between elotuzumab and carfilzomib in combination with lenalidomide and dexamethasone as salvage therapy for multiple myeloma patients. European journal of haematology. 2021", "literaturereference_normalized": "adjusted comparison between elotuzumab and carfilzomib in combination with lenalidomide and dexamethasone as salvage therapy for multiple myeloma patients", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20211110", "receivedate": "20211110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20052065, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "Necrobiosis lipoidica (NL) is a rare granulomatous disease of unknown etiology. Multiple therapies may be used with varying efficacy. We report a pediatric patient with a history of type I diabetes mellitus and NL with minimal response to an ultrapotent topical steroid, topical calcineurin inhibitor, and intralesional triamcinolone, complicated by steroid atrophy, who rapidly responded after addition of doxycycline.", "affiliations": "Baylor College of Medicine, Houston, TX, USA.;Department of Dermatology, Baylor College of Medicine, Houston, TX, USA.;Department of Dermatology, Baylor College of Medicine, Houston, TX, USA.", "authors": "Burns\|Emily\|E\|https://orcid.org/0000-0002-9532-5339;Ukoha\|Uzoamaka\|U\|;Chan\|Audrey\|A\|", "chemical_list": "D065095:Calcineurin Inhibitors; D014221:Triamcinolone; D004318:Doxycycline", "country": "United States", "delete": false, "doi": "10.1111/pde.14295", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-8046", "issue": "37(5)", "journal": "Pediatric dermatology", "keywords": "doxycycline; necrobiosis lipoidica", "medline_ta": "Pediatr Dermatol", "mesh_terms": "D065095:Calcineurin Inhibitors; D002648:Child; D003922:Diabetes Mellitus, Type 1; D004318:Doxycycline; D006801:Humans; D009335:Necrobiosis Lipoidica; D014221:Triamcinolone", "nlm_unique_id": "8406799", "other_id": null, "pages": "981-982", "pmc": null, "pmid": "32681529", "pubdate": "2020-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Necrobiosis lipoidica with rapid response to doxycycline.", "title_normalized": "necrobiosis lipoidica with rapid response to doxycycline" }	[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-062160", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "012041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "7.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROBIOSIS LIPOIDICA DIABETICORUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "012041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OINTMENT", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROBIOSIS LIPOIDICA DIABETICORUM", "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": "3", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "012041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "15 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOBETASOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OINTMENT", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROBIOSIS LIPOIDICA DIABETICORUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBETASOL" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "012041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "30 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin atrophy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BURNS E, UKOHA U, CHAN A. NECROBIOSIS LIPOIDICA WITH RAPID RESPONSE TO DOXYCYCLINE. PEDIATRIC DERMATOLOGY. 2020", "literaturereference_normalized": "necrobiosis lipoidica with rapid response to doxycycline", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200820", "receivedate": "20200806", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18117543, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]
{ "abstract": "Asthma is a highly prevalent chronic respiratory disease\naffecting millions of people worldwide. Short-acting\nbeta 2-agonists induce bronchodilation and usually are\nprescribed as a rescue medication. They are recognized\nas a cause of hyperlactatemia and, less frequently,\nlactic acidosis. Short-acting beta 2-agonists are also\nknown for their potentially adverse cardiovascular\neffects, such as atrial fibrillation. Differential diagnosis\nand subsequent treatment of the latter entity are\nimportant due to the adverse prognosis related to it. In\nthis case report, we describe the unusual association\nbetween albuterol-induced lactic acidosis and atrial\nfibrillation in a patient with an asthma exacerbation.", "affiliations": null, "authors": "Reyes-Mondragon\|Alan\|A\|;Delgado-García\|Guillermo\|G\|;Pacheco-Cantú\|Adán\|A\|;Contreras-Garza\|Nancy\|N\|;Galarza-Delgado\|Dionicio Ángel\|DÁ\|;González-Aguirre\|Julio\|J\|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D001993:Bronchodilator Agents; D014700:Verapamil; D000420:Albuterol", "country": "Romania", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "2067-2993", "issue": "65(3)", "journal": "Pneumologia (Bucharest, Romania)", "keywords": null, "medline_ta": "Pneumologia", "mesh_terms": "D000140:Acidosis, Lactic; D000420:Albuterol; D000889:Anti-Arrhythmia Agents; D001249:Asthma; D001281:Atrial Fibrillation; D001993:Bronchodilator Agents; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014700:Verapamil", "nlm_unique_id": "100941067", "other_id": null, "pages": "150-1", "pmc": null, "pmid": "29542893", "pubdate": "2016", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Atrial fibrillation in an asthmatic patient with albuterol-induced lactic acidosis.", "title_normalized": "atrial fibrillation in an asthmatic patient with albuterol induced lactic acidosis" }	[ { "companynumb": "MX-BAUSCH-BL-2018-013792", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL SULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75358", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PATIENT RECEIVED FIVE DOSES OF NEBULIZED ALBUTEROL THROUGH A MOUTHPIECE (TOTAL DOSE OF 32.5 MG)", "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": "ALBUTEROL SULFATE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75835", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NEBULIZED IPRATROPIUM BROMIDE (0.5 MG EVERY 4 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "4", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75835", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THREE OR FOUR PUFFS OF IPRATROPIUM BROMIDE PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL SULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75358", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THREE OR FOUR PUFFS OF ALBUTEROL SULFATE PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALBUTEROL SULFATE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75835", "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "REYES-MONDRAGON A, DELGADO-GARCIA G, PACHECO-CANTU A, CONTRERAS-GARZA N, GALARZA-DELGADO D, GONZALEZ-AGUIRRE J. ATRIAL FIBRILLATION IN AN ASTHMATIC PATIENT WITH ALBUTEROL-INDUCED LACTIC ACIDOSIS. ARTICLE IN PNEUMOLOGIA. 2016 OCT?65 (3):150-151.", "literaturereference_normalized": "atrial fibrillation in an asthmatic patient with albuterol induced lactic acidosis", "qualification": "3", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180518", "receivedate": "20180518", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14915404, "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": "MX-MYLANLABS-2018M1030448", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL\\IPRATROPIUM BROMIDE" }, "drugadditional": "1", "drugadministrationroute": "055", "drugauthorizationnumb": "020950", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "IPRATROPIUM BROMIDE/SALBUTAMOL SULFATE: 0.5MG/32.5MG; 3-4 PUFFS PER DAY, THROUGH A MOUTH PIECE; F...", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM/SALBUTAMOL" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "REYES-MONDRAGON A, DELGADO-GARCIA G, PACHECO-CANTU A, CONTRERAS-GARZA N, GALARZA-DELGADO DA, GONZALEZ-AGUIRRE J. ATRIAL FIBRILLATION IN AN ASTHMATIC PATIENT WITH ALBUTEROL-INDUCED LACTIC ACIDOSIS. PNEUMOLOGIA 2016?65(3):150-1.", "literaturereference_normalized": "atrial fibrillation in an asthmatic patient with albuterol induced lactic acidosis", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180509", "receivedate": "20180509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14870666, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "MX-VISTAPHARM, INC.-VER201804-000618", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "077788", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALBUTEROL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "077788", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FIVE DOSES OF NEBULIZED ALBUTEROL THROUGH A MOUTHPIECE (TOTAL DOSE OF 32.5 MG)", "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": "ALBUTEROL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DELGADO-GARCIA G,REYES-MONDRAGON A,PACHECO-CANTU A,CONTRERAS-GARZA N,GALARZA-DELGADO D,GONZALEZ-AGUIRRE J. ATRIAL FIBRILLATION IN AN ASTHMATIC PATIENT WITH ALBUTEROL-INDUCED LACTIC ACIDOSIS. PNEUMOLOGIA 2016?65(3):150-1.", "literaturereference_normalized": "atrial fibrillation in an asthmatic patient with albuterol induced lactic acidosis", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180503", "receivedate": "20180503", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14840372, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "MX-TEVA-2018-MX-891926", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL\\IPRATROPIUM" }, "drugadditional": "1", "drugadministrationroute": "055", "drugauthorizationnumb": "76724", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "IPRATROPIUM BROMIDE/SALBUTAMOL SULFATE: 0.5MG/32.5MG; 3-4 PUFFS PER DAY, THROUGH A MOUTH PIECE; F...", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALBUTAMOL W/IPRATROPIUM" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "REYES-MONDRAGON A, DELGADO-GARCIA G, PACHECO-CANTU A, CONTRERAS-GARZA N, GALARZA-DELGADO DA, GONZALEZ-AGUIRRE J. ATRIAL FIBRILLATION IN AN ASTHMATIC PATIENT WITH ALBUTEROL-INDUCED LACTIC ACIDOSIS. PNEUMOLOGIA 2016?65(3):150-1.", "literaturereference_normalized": "atrial fibrillation in an asthmatic patient with albuterol induced lactic acidosis", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180609", "receivedate": "20180522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14921962, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" } ]
{ "abstract": "OBJECTIVE\nThe present study was designed to determine the toxicity and maximum tolerated doses of oral intermittent oral capecitabine and subcutaneous (s.c.) rHuIFNalpha2a in patients with metastatic renal cell carcinoma (RCC). The pharmacokinetics of capecitabine and its metabolites were also investigated.\n\n\nMETHODS\nA total of 27 patients were treated at four dose levels of capecitabine (825 or 1000 mg/m2 twice daily orally, days 1-14, 22-36) and rHuIFNalpha2a (1.5 or 3.0 MU/m2 s.c. three times weekly). Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chroatography/mass spectrometry in ten patients.\n\n\nRESULTS\nThe toxicity of combined capecitabine and rHuIFNalpha2a was moderate. Patients experienced mild nausea/vomiting (70%) and diarrhea (63%). The hand-foot syndrome was seen in 67% of patients and was generally mild, as was hematologic toxicity. Dose-limiting toxicity included diarrhea, mucositis, neutropenia and the hand-foot syndrome. The dose level recommended for further trials included capecitabine 1000 mg/m2 twice daily and rHuIFNalpha2a 3.0 MU/m2 three times weekly. One patient had a partial response of a liver lesion (duration > 200 days). Pharmacokinetic parameters of capecitabine and its metabolites (5'-deoxy-5-fluorouridine, 5-fluorouracil and alpha-fluoro-beta-alanine) were similar to those reported by other authors. There was rapid conversion to 5'-deoxyuridine. The peak plasma concentrations of capecitabine occurred between 0.5 and 3.0 h.\n\n\nCONCLUSIONS\nThe combination of capecitabine and rHuIFNalpha2a was well tolerated. The recommended dose levels for phase II trials are: rHuIFNalpha2a 3.0 MU/m2 s.c. three times weekly and oral capecitabine 1000 mg/m2 twice daily for 2 weeks. No evidence of an effect of rHuIFNalpha2a on the pharmacokinetics of capecitabine or its metabolites was apparent. A phase II trial in untreated patients with metastatic RCC is planned.", "affiliations": "Experimental Therapeutics Program, Cleveland Clinic Taussig Cancer Center, OH 44195, USA.", "authors": "Chang\|D Z\|DZ\|;Olencki\|T\|T\|;Budd\|G T\|GT\|;Peereboom\|D\|D\|;Ganapathi\|R\|R\|;Osterwalder\|B\|B\|;Bukowski\|R\|R\|", "chemical_list": "D016898:Interferon-alpha; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil", "country": "Germany", "delete": false, "doi": "10.1007/s002800100366", "fulltext": null, "fulltext_license": null, "issn_linking": "0344-5704", "issue": "48(6)", "journal": "Cancer chemotherapy and pharmacology", "keywords": null, "medline_ta": "Cancer Chemother Pharmacol", "mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002853:Chromatography, Liquid; D003841:Deoxycytidine; D003967:Diarrhea; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007279:Injections, Subcutaneous; D016898:Interferon-alpha; D007680:Kidney Neoplasms; D008297:Male; D013058:Mass Spectrometry; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms; D009503:Neutropenia; D010523:Peripheral Nervous System Diseases", "nlm_unique_id": "7806519", "other_id": null, "pages": "493-8", "pmc": null, "pmid": "11800031", "pubdate": "2001-12", "publication_types": "D016430:Clinical Trial; D017426:Clinical Trial, Phase I; D016428:Journal Article", "references": null, "title": "Phase I trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer: toxicity and pharmacokinetics.", "title_normalized": "phase i trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer toxicity and pharmacokinetics" }	[ { "companynumb": "US-ROCHE-2411765", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INTERFERON ALFA-2A" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3.0 MU/M2 THREE TIMES WEEKLY ON MONDAY-WEDNESDAY-FRIDAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL CANCER METASTATIC", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERFERON ALFA-2A" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "020896", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "DAYS 1-14 AND 22-36, CYCLES REPEATED EVERY 6 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL CANCER METASTATIC", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHANG D, OLENCKI T, BUDD G, PEEREBOOM D, GANAPATHI R, OSTERWALDER B AND BUKOWSKI R. PHASE I TRIAL OF CAPECITABINE IN COMBINATION WITH INTERFERON ALPHA IN PATIENTS WITH METASTATIC RENAL CANCER: TOXICITY AND PHARMACOKINETICS. CANCER CHEMOTHERAPY AND PHARMACOLOGY 2001 DEC?48 (6):493-8.", "literaturereference_normalized": "phase i trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer toxicity and pharmacokinetics", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190916", "receivedate": "20190916", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16808743, "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": "Antimuscarinic agents are now widely used as the pharmacological therapy for overactive bladder (OAB) because neuronal (parasympathetic nerve) and non-neuronal acetylcholine play a significant role for the bladder function. In this review, we will highlight basic and clinical aspects of eight antimuscarinic agents (oxybutynin, propiverine, tolterodine, solifenacin, darifenacin, trospium, imidafenacin, and fesoterodine) clinically used to treat urinary dysfunction in patients with OAB. The basic pharmacological characteristics of these eight antimuscarinic agents include muscarinic receptor subtype selectivity, functional bladder selectivity, and muscarinic receptor binding in the bladder and other tissues. The measurement of drug-receptor binding after oral administration of these agents allows for clearer understanding of bladder selectivity by the integration of pharmacodynamics and pharmacokinetics under in vivo conditions. Their central nervous system (CNS) penetration potentials are also discussed in terms of the feasibility of impairments in memory and cognitive function in elderly patients with OAB. The clinical aspects of efficacy focus on improvements in the daytime urinary frequency, nocturia, bladder capacity, the frequency of urgency, severity of urgency, number of incontinence episodes, OAB symptom score, and quality of life (QOL) score by antimuscarinic agents in patients with OAB. The safety of and adverse events caused by treatments with antimuscarinic agents such as dry mouth, constipation, blurred vision, erythema, fatigue, increased sweating, urinary retention, and CNS adverse events are discussed. A dose-dependent relationship was observed with adverse events, because the risk ratio generally increased with elevations in the drug dose of antimuscarinic agents. Side effect profiles may be additive to or contraindicated by other medications.", "affiliations": "Center for Pharma-Food Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. Electronic address: [email protected].;Center for Pharma-Food Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.;Southern Knights' Laboratory, 1-1-823 Miyagi, Chatan, Okinawa, 904-0113, Japan.;Southern Knights' Laboratory, 1-1-823 Miyagi, Chatan, Okinawa, 904-0113, Japan.;Southern Knights' Laboratory, 1-1-823 Miyagi, Chatan, Okinawa, 904-0113, Japan.", "authors": "Yamada\|Shizuo\|S\|;Ito\|Yoshihiko\|Y\|;Nishijima\|Saori\|S\|;Kadekawa\|Katsumi\|K\|;Sugaya\|Kimio\|K\|", "chemical_list": "D018727:Muscarinic Antagonists", "country": "England", "delete": false, "doi": "10.1016/j.pharmthera.2018.04.010", "fulltext": null, "fulltext_license": null, "issn_linking": "0163-7258", "issue": "189()", "journal": "Pharmacology & therapeutics", "keywords": "Antimuscarinics; Basic pharmacology; Bladder selectivity; Clinical efficacy and tolerability; Muscarinic receptor binding; Overactive bladder", "medline_ta": "Pharmacol Ther", "mesh_terms": "D000818:Animals; D001921:Brain; D006801:Humans; D018727:Muscarinic Antagonists; D053201:Urinary Bladder, Overactive", "nlm_unique_id": "7905840", "other_id": null, "pages": "130-148", "pmc": null, "pmid": "29709423", "pubdate": "2018-09", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder.", "title_normalized": "basic and clinical aspects of antimuscarinic agents used to treat overactive bladder" }	[ { "companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2018-07684", "fulfillexpeditecriteria": "2", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTONIC BLADDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YAMADA S, ITO Y, NISHIJIMA S, KADEKAWA K, ET AL.. BASIC AND CLINICAL ASPECTS OF ANTIMUSCARINIC AGENTS USED TO TREAT OVERACTIVE BLADDER.. PHARMACOLOGY + THERAPEUTICS. 2018?189:130-148", "literaturereference_normalized": "basic and clinical aspects of antimuscarinic agents used to treat overactive bladder", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "CA", "receiptdate": "20190107", "receivedate": "20190107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15792667, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2018-07682", "fulfillexpeditecriteria": "2", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTONIC BLADDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YAMADA S, ITO Y, NISHIJIMA S, KADEKAWA K, ET AL. BASIC AND CLINICAL ASPECTS OF ANTIMUSCARINIC AGENTS USED TO TREAT OVERACTIVE BLADDER.. PHARMACOLOGY + THERAPEUTICS. 2018?189:130?148", "literaturereference_normalized": "basic and clinical aspects of antimuscarinic agents used to treat overactive bladder", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "CA", "receiptdate": "20190107", "receivedate": "20190107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15792666, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2018-07687", "fulfillexpeditecriteria": "2", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTONIC BLADDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YAMADA S, ITO Y, NISHIJIMA S, KADEKAWA K, ET AL.. BASIC AND CLINICAL ASPECTS OF ANTIMUSCARINIC AGENTS USED TO TREAT OVERACTIVE BLADDER.. PHARMACOLOGY + THERAPEUTICS. 2018?189:130?148", "literaturereference_normalized": "basic and clinical aspects of antimuscarinic agents used to treat overactive bladder", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "CA", "receiptdate": "20190107", "receivedate": "20190107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15792669, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2018-07679", "fulfillexpeditecriteria": "2", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTONIC BLADDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YAMADA S, ITO Y, NISHIJIMA S, KADEKAWA K, ET AL. 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{ "abstract": "BACKGROUND\nThe risk of gastrointestinal (GI) bleeding of dabigatran and rivaroxaban is relatively unexplored. The aim of our study was to compare this risk in both drugs.\n\n\nMETHODS\nWe examined the medical records of patients on either dabigatran or rivaroxaban from October 2010 to April 2013 in two hospitals.\n\n\nRESULTS\nA total of 374 patients (147 rivaroxaban vs. 227 dabigatran) were identified. GI bleeding occurred in 5.3% in the dabigatran when compared to 4.8% in the rivaroxaban group (p = 0.8215). Multivariate analysis showed that the odds of GI bleeding while on dabigatran for ≤40 days when compared to ≥40 days was 8.3 (p < 0.0001). In the rivaroxaban group, patients who were on the drug for ≤40 days had a higher incidence of bleeding when compared to those >40 days (OR = 2.8, p = 0.023). Concomitant use of antiplatelets (single or dual) or non-steroidal anti-inflammatory drugs was not associated with increased bleeding in the dabigatran group; however, the use of dual antiplatelet agents with rivaroxaban was associated with an increased risk of GI bleeding (OR = 7.4, p = 0.0378). Prior GI bleeding had a higher risk of bleeding in the rivaroxaban group (OR = 15.5, p = 0.0002).\n\n\nCONCLUSIONS\nDabigatran was not associated with a higher incidence of GI bleeding. Both drugs had a higher bleeding risk in the first 40 days.", "affiliations": "Section of Gastroenterology and Hepatology, Georgia Regents University, Augusta, Ga., USA.", "authors": "Sherid\|Muhammed\|M\|;Sifuentes\|Humberto\|H\|;Sulaiman\|Samian\|S\|;Samo\|Salih\|S\|;Husein\|Husein\|H\|;Tupper\|Ruth\|R\|;Thiruvaiyaru\|Dharma\|D\|;Spurr\|Charles\|C\|;Sridhar\|Subbaramiah\|S\|", "chemical_list": "D000991:Antithrombins; D001562:Benzimidazoles; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D015091:beta-Alanine; D000069552:Rivaroxaban; D000069604:Dabigatran", "country": "Switzerland", "delete": false, "doi": "10.1159/000365967", "fulltext": null, "fulltext_license": null, "issn_linking": "0012-2823", "issue": "90(2)", "journal": "Digestion", "keywords": null, "medline_ta": "Digestion", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001562:Benzimidazoles; D000069604:Dabigatran; D065427:Factor Xa Inhibitors; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D012189:Retrospective Studies; D012307:Risk Factors; D000069552:Rivaroxaban; D013876:Thiophenes; D015091:beta-Alanine", "nlm_unique_id": "0150472", "other_id": null, "pages": "137-46", "pmc": null, "pmid": "25278002", "pubdate": "2014", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Risk of gastrointestinal bleeding with dabigatran: a head-to-head comparative study with rivaroxaban.", "title_normalized": "risk of gastrointestinal bleeding with dabigatran a head to head comparative study with rivaroxaban" }	[ { "companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-49528GD", "fulfillexpeditecriteria": "1", "occurcountry": "US", "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": "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": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHERID M,SIFUENTES H,SULAIMAN S,SAMO S,HUSEIN H,TUPPER R,ET AL. RISK OF GASTROINTESTINAL BLEEDING WITH DABIGATRAN: A HEAD-TO-HEAD COMPARATIVE STUDY WITH RIVAROXABAN. DIGESTION 2014;90:2:137-146.", "literaturereference_normalized": "risk of gastrointestinal bleeding with dabigatran a head to head comparative study with rivaroxaban", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20141017", "receivedate": "20141017", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10525155, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150528" } ]
{ "abstract": "BACKGROUND\nThe calcineurin (CaN) inhibitor, tacrolimus, is widely used in patients undergoing allogeneic organ transplantation and in those with certain allergic diseases. Recently, several reports have suggested that CaN is also associated with schizophrenia. However, little data are currently available on the direct effect of tacrolimus on the human brain.\n\n\nMETHODS\nA 23-year-old Japanese female experienced severe delusion of persecution, delusional mood, suspiciousness, aggression, and excitement. She visited our hospital and was diagnosed with schizophrenia. When she was 27 years old, she had severe general fatigue, persistent fever, systemic joint pain, gingival bleeding, and breathlessness and was diagnosed with acute myelomonocytic leukemia. Later she underwent bone marrow transplantation (BMT), she was administered methotrexate and cyclosporin A to prevent graft versus host disease (GVHD). Three weeks after BMT, she showed initial symptoms of GVHD and was prescribed tacrolimus instead of cyclosporin A. Seven months after BMT at the age of 31 years, she died of progression of GVHD. Pathological anatomy was examined after her death, including immunohistochemical analysis of her brain using anti-CaN antibodies. For comparison, we used our previous data from both a schizophrenia group and a healthy control group. No significant differences were observed in the percentage of CaN-immunoreactive neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-immunoreactive neurons in layers III-VI of the BA46 and the putamen tended to be lower in the tacrolimus case.\n\n\nCONCLUSIONS\nTacrolimus may decrease CaN immunoreactivity in some regions of the human brain. Thus, tacrolimus may introduce side effects such as cognitive dysfunction and extrapyramidal symptoms. In addition, we also found that the effect of tacrolimus on CaN immunore-activity in human brain was stronger than the effect of schizophrenia.", "affiliations": "Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima; Department of Neuropsychiatry, The University of Tokyo Hospital, Bunkyo-ku, Tokyo.;Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima.;Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima.;Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima.;Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima.;Department of Psychiatry, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu City, Fukushima, Japan.;Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima.", "authors": "Wada\|Akira\|A\|;Kunii\|Yasuto\|Y\|;Matsumoto\|Jyunya\|J\|;Hino\|Mizuki\|M\|;Nagaoka\|Atsuko\|A\|;Niwa\|Shin-Ichi\|S\|;Yabe\|Hirooki\|H\|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/NDT.S106371", "fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S106371ndt-12-1645Case ReportDecreased calcineurin immunoreactivity in the postmortem brain of a patient with schizophrenia who had been prescribed the calcineurin inhibitor, tacrolimus, for leukemia Wada Akira 12Kunii Yasuto 1Matsumoto Jyunya 1Hino Mizuki 1Nagaoka Atsuko 1Niwa Shin-ichi 3Yabe Hirooki 11 Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima2 Department of Neuropsychiatry, The University of Tokyo Hospital, Bunkyo-ku, Tokyo3 Department of Psychiatry, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu City, Fukushima, JapanCorrespondence: Akira Wada, Department of Neuropsychiatry, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan, Tel +81 24 547 1331, Fax +81 24 548 6735, Email [email protected] 06 7 2016 12 1645 1650 © 2016 Wada et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background\nThe calcineurin (CaN) inhibitor, tacrolimus, is widely used in patients undergoing allogeneic organ transplantation and in those with certain allergic diseases. Recently, several reports have suggested that CaN is also associated with schizophrenia. However, little data are currently available on the direct effect of tacrolimus on the human brain.\n\nCase\nA 23-year-old Japanese female experienced severe delusion of persecution, delusional mood, suspiciousness, aggression, and excitement. She visited our hospital and was diagnosed with schizophrenia. When she was 27 years old, she had severe general fatigue, persistent fever, systemic joint pain, gingival bleeding, and breathlessness and was diagnosed with acute myelomonocytic leukemia. Later she underwent bone marrow transplantation (BMT), she was administered methotrexate and cyclosporin A to prevent graft versus host disease (GVHD). Three weeks after BMT, she showed initial symptoms of GVHD and was prescribed tacrolimus instead of cyclosporin A. Seven months after BMT at the age of 31 years, she died of progression of GVHD. Pathological anatomy was examined after her death, including immunohistochemical analysis of her brain using anti-CaN antibodies. For comparison, we used our previous data from both a schizophrenia group and a healthy control group. No significant differences were observed in the percentage of CaN-immunoreactive neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-immunoreactive neurons in layers III–VI of the BA46 and the putamen tended to be lower in the tacrolimus case.\n\nConclusion\nTacrolimus may decrease CaN immunoreactivity in some regions of the human brain. Thus, tacrolimus may introduce side effects such as cognitive dysfunction and extrapyramidal symptoms. In addition, we also found that the effect of tacrolimus on CaN immunore-activity in human brain was stronger than the effect of schizophrenia.\n\nKeywords\ncalcineurincalcineurin inhibitorsschizophreniapostmortem brainimmunohistochemistry\n==== Body\nIntroduction\nThe calcineurin (CaN) inhibitor, tacrolimus, is a nonsteroidal, anti-inflammatory immunosuppressive drug mainly used to treat patients undergoing allogeneic organ transplantation and those with atopic dermatitis.1 CaN is a heterodimeric calcium-dependent serine/threonine protein phosphatase, consisting of a catalytic (CaN A) and a regulatory (CaN B) subunits, and plays a critical role in cellular responses and calcium signaling.2 Tacrolimus induces not only mild neurological side effects such as tremor but also psychiatric side effects such as manic-like psychosis and relapse of schizophrenia.3,4 On the other hand, several reports suggested that CaN dysfunction may be a risk factor for schizophrenia. Forebrain-specific PPP3CC (encodes the CaN A γ-catalytic subunit) knockout mice display multiple abnormal activities related to schizophrenia, such as increased locomotor activity, decreased social interaction, impairments in prepulse inhibition, and latent inhibition.5,6 Another report showed decreased CaN A protein levels and decreased mRNA of the three subunits of CaN A in the hippocampus of schizophrenia patients.7\n\nChang et al8 reported on the B-cell lymphoma-2 (Bcl-2)–CaN–dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) feedback mechanism in regulating serine 1755 phosphorylation and apoptosis in primary human chronic lymphocytic leukemia cells. However, there were no previous reports that acute myelomonocytic leukemia (AML) itself has direct influence on CaN in the brain.\n\nTo investigate the effect of tacrolimus in the brain, we examined the immunoreactivity of CaN using immunohistochemistry in the dorsolateral prefrontal cortex, hippocampus, caudate, and putamen of a postmortem brain of a patient with schizophrenia who had been treated with tacrolimus. As healthy and disease controls, we used our previously reported data.9 There were no previous reports of AML itself having a direct influence on CaN in the brain. If we only aimed to investigate the effect of tacrolimus on the brain, we would have focused on characterizing the effect of tacrolimus in AML patients without prior history of schizophrenia. We aimed to investigate whether tacrolimus treatment or acquiring schizophrenia had a stronger effect on the CaN immunoreactivity in the brain.\n\nCase report\nA 23-year-old Japanese female visited a local psychiatric clinic in May 1990 due to nonspecific physical symptoms. She had poor premorbid functioning, and her mother had been diagnosed with schizophrenia. She had no history of neurological disorders or substance abuse. She first received a diagnosis of psychogenic reaction. Several months after she first visited that clinic, she experienced severe delusion of persecution, delusional mood, suspiciousness, aggression, and excitement. She first visited our hospital in November 1992 and was diagnosed with schizophrenia. She was prescribed antipsychotics, but she initially refused them. She and her mother had “shared psychotic disorder”. Because they shared the same delusion of persecution, they moved together many times to various places based on delusions. In November 1992, she began to take haloperidol (4.5 mg/d) and chlorpromazine (200 mg/d) for her psychotic symptoms. Five months after starting antipsychotics, her psychotic symptoms had improved.\n\nIn June 1996, she experienced severe general fatigue, persistent fever (≥38°C), systemic joint pain, gingival bleeding, and breathlessness. Her blood tests showed pancytopenia (white blood cells, 3.1×103/mm2; red blood cells, 2.6×106/μL; hemoglobin, 7.5 g/dL; and platelets, 8.8×104/μL) and the presence of blast cells. We consulted a hematologist, and she was diagnosed with AML. In September 1996, she underwent bone marrow transplantation (BMT). After BMT, she was administered methotrexate and cyclosporin A to prevent graft versus host disease (GVHD). At the same time, we stopped prescribing antipsychotics. Three weeks after BMT, she had diarrhea and systemic eruption. We judged that she had initial symptoms of GVHD, and the hematologist prescribed tacrolimus instead of cyclosporine A. In December 1996, her auditory hallucination, delusions, and excitement recurred. We needed to prescribe risperidone so that she could continue her treatment safely. Her general condition gradually worsened. In February 1997, she experienced disturbance of consciousness, hypotension, and respiratory failure. In April 1997, she died of progression of GVHD at the age of 31 years.\n\nPathological anatomy was examined after her death. The use of postmortem human brain tissues for the present study was approved by the Ethics Committee of Fukushima Medical University (FMU) and complied with the Declaration of Helsinki. All procedures were carried out with the informed written consent of the next of kin. The postmortem interval was 9.5 hours. Her brain weight was 1,232 g with no indication of gross neurological pathology. Brain tissue blocks were obtained from the right hemisphere of the dorsolateral prefrontal cortex (BA46), hippocampus, caudate, and putamen and fixed in 10% formalin, embedded in paraffin, and sliced into 5 μm sections. We obtained ten sections and used one section in this analysis. Immunohistochemistry was performed in accordance with our previous protocol.9–11 The sections were deparaffinized in xylene and rehydrated through a decreasing alcohol series (100%, 90%, 80%, and 70% ethanol). Endogenous peroxidase activity was quenched by incubating in 0.3% hydrogen peroxide in methanol at room temperature for 20 minutes. The sections were washed with phosphate-buffered saline (PBS: 0.01 M sodium phosphate, pH 7.3), microwaved for 15 minutes in 10 mM citrate buffer for antigen recovery, and washed with PBS. The sections were incubated in 5% skim milk in PBS for 30 minutes at room temperature to reduce nonspecific binding, incubated overnight at 4°C in rabbit polyclonal antibodies against human CaN (1717-0909; AbD Serotec, Oxford, UK, 1:50), which recognizes the 60 kDa mammalian CaN catalytic subunit (CaN A), in PBS, and washed in PBS three times for 5 minutes each. We used normal rabbit serum instead of the primary antibody as a negative control. The sections were incubated with the second antibody (biotinylated anti-rabbit IgG; Nichirei Corporation, Tokyo, Japan) for 20 minutes at room temperature and washed in PBS three times for 5 minutes each. Subsequently, the sections were incubated with peroxidase-labeled streptavidin for 15 minutes at room temperature and washed in PBS three times for 5 minutes each. The sections were treated with diaminobenzidine (Wako Pure Chemical Industries, Ltd., Osaka, Japan) for 5 minutes at room temperature to visualize the immunoreaction products and then washed with PBS to terminate the reaction. For nuclear counterstaining, the sections were treated with Carracci’s hematoxylin for 20 seconds. CaN-immunoreactive (CaN-IR) cells were examined under a microscope equipped with a digital camera (Olympus BX51; Olympus Corporation, Tokyo, Japan) at 100× magnification, and parenchymal cell numbers were counted using WinROOF Version 5.5 (Mitani Corporation, Tokyo, Japan). Neurons and neuroglial cells were distinguished by morphology, nuclear size, nuclear membrane thickness, and chromatin homogeneity.10–12 We defined neurons in which staining was more intense than background as CaN-IR. Image acquisition was performed to show the representative staining pattern of each region and to include approximately the same number of total neurons. In the BA46, three images were randomly selected from each of layers II–VI. The mean percentage of CaN-IR neurons (number of CaN-IR neurons/number of total neurons) was calculated for each layer. In the hippocampus, the CA1, CA2, CA3, and CA4 subfields and dentate gyrus were investigated by randomly selecting three, one, one, three, and two images, respectively. The caudate and putamen were analyzed separately by randomly selecting three images each. A single researcher blinded to the tissue source was responsible for all cell counting and data analyses.\n\nThe percentages of CaN-IR neurons in the BA46, hippocampus, caudate nucleus, and putamen are shown in Figure 1A–C. To compare this patient with a schizophrenia group and healthy control group, we used previously reported data.9 No significant differences were observed in the percentage of CaN-IR neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-IR neurons in layers III–VI of the BA46 and the putamen tended to be lower in the tacrolimus case (Figure 1A and C). Representative images of CaN-IR neurons in the prefrontal cortex (BA46, layers V–VI) are shown in Figure 2.\n\nFirst, we considered the possibility of an association between our patient’s psychiatric symptoms and tacrolimus. The percentage of CaN-IR neurons in layers III–VI of the BA46 tended to be lower in patients with schizophrenia compared with the healthy control group. Furthermore, the percentage of CaN-IR neurons was even lower in the tacrolimus patient compared with the schizophrenia alone group. Cognitive dysfunction due to hypofunction of the frontal lobe is well known in schizophrenia.13 In addition, a side effect of tacrolimus is delirium, and this form of cognitive dysfunction is more severe than schizophrenia without delirium. Thus, the decrease in CaN immunoreactivity in the frontal lobe may reflect cognitive dysfunction.\n\nNext, we considered the results from the caudate and putamen. The percentage of CaN-IR neurons in the putamen tended to be higher in patients with schizophrenia compared with healthy subjects, but the percentage of CaN-IR neurons was lower in the tacrolimus case than in the schizophrenia group. Tacrolimus may cause side effects of tremor and dysarthria, which occur when a patient has dysfunction of the striatum. Lower immunoreactivity of CaN induced by tacrolimus in the striatum may mediate these extrapyramidal symptoms.\n\nLee et al14 reported that tacrolimus reduces nuclear expression of CaN in a renal ischemia–reperfusion injury mouse model. They suggested that tacrolimus decreases CaN expression both in the cytoplasm and in the nucleus. Our data indicated that the percentages of CaN-IR neurons in layers III–VI of the BA46 and putamen tended to be lower in the tacrolimus case compared with the schizophrenia group. As in the report by Lee et al, tacrolimus may decrease the expression of CaN in some regions of the human brain. Overall, when we considered the results from the frontal, caudate, and putamen together, we found that the effect of tacrolimus in the human brain may be stronger than the effect of schizophrenia.\n\nEastwood et al7 reported decreased CaN A protein levels and decreased mRNA of the three subunits of CaN A in the hippocampus of schizophrenia patients. This report does not support our findings in the hippocampus. This discrepancy could be attributed to the small sample numbers in our study.\n\nOur study has a number of limitations. Only one tacrolimus case was included in this report. The effect of tacrolimus on the human brain might be subject to intersubject differences in CaN immunoreactivity and thus generalization of these findings might be difficult. In addition, the lack of a control group (patients with leukemia but without tacrolimus treatment and schizophrenia, patients with leukemia treated using tacrolimus but without schizophrenia) makes drawing firm conclusion regarding efficacy difficult. It is also possible that the AML might have directly influenced CaN immunoreactivity in the brain. Further studies using a larger sample size are warranted to investigate CaN immunoreactivity in the postmortem brains of leukemia patients without tacrolimus treatment and schizophrenia, leukemia patients treated with tacrolimus but without schizophrenia, and schizophrenia patients with tacrolimus-treated AML. Second, this research was conducted using immunohistochemical analysis only. Further studies using other methods, such as in situ hybridization, are warranted. Third, CaN-IR neurons were defined as having greater staining intensity compared to background. This method allows for ambiguity because it is dependent on human assessment. In this context, the use of in situ hybridization for future studies is warranted. Finally, if the patient carried the PPP3CC SNP, the level of CaN might have already been low, instead of attributable to the tacrolimus treatment. However, we could not obtain the SNPs data because we were unable to use frozen brain samples in the tacrolimus case. Further studies are needed to obtain the SNPs data from frozen samples.\n\nConclusion\nWe performed immunohistochemical analysis using human brain tissue from a patient with schizophrenia and AML treated with tacrolimus. Our data suggested that tacrolimus may decrease the immunoreactivity of CaN in some regions of the human brain. In addition, the percentage of CaN-IR neurons in layers III–VI of the BA46, caudate, and putamen tended to be lower in patients with schizophrenia complicated by tacrolimus-treated AML compared to the schizophrenia group. These data also suggested that the effect of tacrolimus in the human brain was stronger than the effect of schizophrenia.\n\nAcknowledgments\nWe thank Hiromi Onuma for her assistance with coordinating tissue donations. We also thank the families of the deceased for the donations of brain tissue and the time and effort devoted to the consent process and interviews.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Quantitative analysis of CaN-IR neurons: layers II–VI of the prefrontal cortex (BA46), hippocampus, caudate nucleus, and putamen.\n\nNotes: In each histogram, “Sz” indicates the schizophrenia group, “cont” indicates the control group, and “tacrolimus” indicates the tacrolimus case. Analysis of covariance was used to compare the percentage of CaN-IR neurons among the three groups. (A) Percentage of CaN-IR neurons in each layer of the prefrontal cortex (BA46). (B) Percentage of CaN-IR neurons in each subfield of the hippocampus. (C) Percentage of CaN-IR neurons in the caudate and putamen.\n\nAbbreviations: CaN-IR, calcineurin-immunoreactive; DG, dentate gyrus.\n\nFigure 2 CaN-IR neurons in brain sections from controls, patients with schizophrenia, and a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus.\n\nNotes: (A) Calcineurin-immunoreactive (CaN-IR) cells in the prefrontal cortex (BA46, layers V–VI) of a control brain (72-year-old male with a postmortem interval [PMI] of 12.5 hours). (B) CaN-IR cells in the prefrontal cortex (BA46, layers V–VI) of the brain of a patient with schizophrenia (48-year-old male with a PMI of 10 hours). (C) CaN-IR cells in prefrontal cortex (BA46, layers V–VI) in the brain of a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus (31-year-old female with a PMI of 9.5 hours). Immunopositive neurons are indicated by arrows, and immunonegative neurons are indicated by arrowheads. Magnification ×200.\n==== Refs\nReferences\n1 Miyata S Ohkubo Y Mutoh S A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis Inflamm Res 2005 54 1 1 9 15723198 \n2 Rusnak F Mertz P Calcineurin: form and function Physiol Rev 2000 80 4 1483 1521 11015619 \n3 Bersani G Marino P Valeriani G Manic-like psychosis associated with elevated trough tacrolimus blood concentrations 17 years after kidney transplant Case Rep Psychiatry 2013 2013 926395 23762723 \n4 Lin Y Sun IW Liu SI Loh el-W Lin YC Tacrolimus ointment-induced relapse of schizophrenia: a case report Int J Neuropsychopharmacol 2007 10 6 851 854 18077846 \n5 Miyakawa T Leiter LM Gerber DJ Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia Proc Natl Acad Sci U S A 2003 100 15 8987 8992 12851457 \n6 Zeng H Chattarji S Barbarosie M Forebrain-specific calcineu-rin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory Cell 2001 107 5 617 629 11733061 \n7 Eastwood SL Burnet PW Harrison PJ Decreased hippocampal expression of the susceptibility gene PPP3CC and other calcineurin subunits in schizophrenia Biol Psychiatry 2005 57 7 702 710 15820226 \n8 Chang MJ Zhong F Lavik AR Parys JB Berridge MJ Distelhorst CW Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival Proc Natl Acad Sci U S A 2014 111 3 1186 1191 24395794 \n9 Wada A Kunii Y Ikemoto K Increased ratio of calcineurin immunoreactive neurons in the caudate nucleus of patients with schizophrenia Prog Neuropsychopharmacol Biol Psychiatry 2012 37 1 8 14 22285318 \n10 Kunii Y Ikemoto K Wada A Detailed DARPP-32 expression profiles in postmortem brains from patients with schizophrenia: an immunohistochemical study Med Mol Morphol 2011 44 4 190 199 22179181 \n11 Kunii Y Yabe H Wada A Yang Q Nishiura K Niwa S Altered DARPP-32 expression in the superior temporal gyrus in schizophrenia Prog Neuropsychopharmacol Biol Psychiatry 2011 35 4 1139 1143 21453742 \n12 Selemon LD Rajkowska G Goldman-Rakic PS Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17 Arch Gen Psychiatry 1995 52 10 805 818 discussion 819–820 7575100 \n13 Yoon JH Minzenberg MJ Ursu S Association of dorsolateral prefrontal cortex dysfunction with disrupted coordinated brain activity in schizophrenia: relationship with impaired cognition, behavioral disorganization, and global function Am J Psychiatry 2008 165 8 1006 1014 18519527 \n14 Lee SH Choi J Kim H FK506 reduces calpain-regulated calcineurin activity in both the cytoplasm and the nucleus Anat Cell Biol 2014 47 2 91 100 24987545\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1176-6328", "issue": "12()", "journal": "Neuropsychiatric disease and treatment", "keywords": "calcineurin; calcineurin inhibitors; immunohistochemistry; postmortem brain; schizophrenia", "medline_ta": "Neuropsychiatr Dis Treat", "mesh_terms": null, "nlm_unique_id": "101240304", "other_id": null, "pages": "1645-50", "pmc": null, "pmid": "27462157", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "24395794;24987545;7575100;11733061;11015619;22179181;18519527;15820226;22285318;23762723;12851457;18077846;21453742;15723198", "title": "Decreased calcineurin immunoreactivity in the postmortem brain of a patient with schizophrenia who had been prescribed the calcineurin inhibitor, tacrolimus, for leukemia.", "title_normalized": "decreased calcineurin immunoreactivity in the postmortem brain of a patient with schizophrenia who had been prescribed the calcineurin inhibitor tacrolimus for leukemia" }	[ { "companynumb": "JP-MYLANLABS-2016M1037351", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090596", "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": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Altered state of consciousness", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination, auditory", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delusion", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 199612" } }, "primarysource": { "literaturereference": "WADA A, KUNII Y, MATSUMOTO J, HINO M, NAGAOKA A, NIWA S-I, ET AL. DECREASED CALCINEURIN IMMUNOREACTIVITY IN THE POSTMORTEM BRAIN OF A PATIENT WITH SCHIZOPHRENIA WHO HAD BEEN PRESCRIBED THE CALCINEURIN INHIBITOR, TACROLIMUS, FOR LEUKEMIA. 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"reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delusion", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft versus host disease", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 1996" } }, "primarysource": { "literaturereference": "WADA A, KUNII Y, MATSUMOTO J, HINO M, NAGAOKA A, NIWA S, ET AL.. DECREASED CALCINEURIN IMMUNOREACTIVITY IN THE POSTMORTEM BRAIN OF A PATIENT WITH SCHIZOPHRENIA WHO HAD BEEN PRESCRIBED THE CALCINEURIN INHIBITOR, TACROLIMUS, FOR LEUKEMIA. 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{ "abstract": "Acetaminophen or paracetamol, a commonly used over-the-counter analgesic, is known to elicit severe adverse reactions when taken in overdose, chronically at therapeutic dosage or, sporadically, following single assumptions of a therapeutic dose. Damage patterns including liver damage and, rarely, acute tubular necrosis or a fixed drug exanthema. We present a case of fatal acetaminophen toxicity with postmortem blood concentration 78 μg/mL and unusual clinical features, including a visually striking and massive epidermolysis and rhabdomyolysis, disseminated intravascular coagulation and myocardial ischemia. This case is compared with the most similar previous reports in terms of organ damage, clinical presentation, and cause of death. We conclude that a number of severe patterns of adverse effects to acetaminophen are emerging that were previously greatly underestimated, thus questioning the adequacy of the clinical spectrum traditionally associated with acetaminophen intoxication and leading to the need to review this spectrum and the associated diagnostic criteria.", "affiliations": "Institute of Legal Medicine Catholic University, School of Medicine, L.go F. Vito, 1 00168, Rome, Italy. [email protected]", "authors": "De-Giorgio\|Fabio\|F\|;Lodise\|Maria\|M\|;Chiarotti\|Marcello\|M\|;d'Aloja\|Ernesto\|E\|;Carbone\|Arnaldo\|A\|;Valerio\|Luca\|L\|", "chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen", "country": "United States", "delete": false, "doi": "10.1111/1556-4029.12205", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-1198", "issue": "58(5)", "journal": "Journal of forensic sciences", "keywords": "acetaminophen; epidermolysis; forensic pathology; forensic science; forensic toxicology; intoxication; paracetamol; rhabdomyolysis; skin necrosis", "medline_ta": "J Forensic Sci", "mesh_terms": "D000082:Acetaminophen; D058186:Acute Kidney Injury; D018712:Analgesics, Non-Narcotic; D004211:Disseminated Intravascular Coagulation; D004820:Epidermolysis Bullosa; D005260:Female; D049429:Forensic Pathology; D053593:Forensic Toxicology; D006801:Humans; D007668:Kidney; D008099:Liver; D008875:Middle Aged; D018482:Muscle, Skeletal; D017202:Myocardial Ischemia; D012206:Rhabdomyolysis; D012867:Skin", "nlm_unique_id": "0375370", "other_id": null, "pages": "1397-400", "pmc": null, "pmid": "23822653", "pubdate": "2013-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Possible fatal acetaminophen intoxication with atypical clinical presentation.", "title_normalized": "possible fatal acetaminophen intoxication with atypical clinical presentation" }	[ { "companynumb": "IT-JNJFOC-20130908820", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myocardial ischaemia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epidermolysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DE-GIORGIO F, LODISE M, CHIAROTTI M, D^ALOJA E, CARBONE A, VALERIO L. POSSIBLE FATAL ACETAMINOPHEN INTOXICATION WITH ATYPICAL CLINICAL PRESENTATION. JOURNAL FORENSIC SCIENCES SEP-2013;58(5):1397-400.", "literaturereference_normalized": "possible fatal acetaminophen intoxication with atypical clinical presentation", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20150224", "receivedate": "20130919", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9536562, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "IT-RANBAXY-2014RR-88431", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076200", "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": "PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Epidermolysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myocardial ischaemia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Liver injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DE-GIORGIO F, LODISE M, CHIAROTTI M, D^ALOJA E, CARBONE A, VALERIO L. POSSIBLE FATAL ACETAMINOPHEN INTOXICATION WITH ATYPICAL CLINICAL PRESENTATION. J-FORENSIC-SCI. 2013;58 (5):1397-400", "literaturereference_normalized": "possible fatal acetaminophen intoxication with atypical clinical presentation", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20141215", "receivedate": "20141204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10627360, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" } ]
{ "abstract": "The impact of genomic profiling on the outcomes of patients with advanced gastrointestinal (GI) malignancies remains unknown. The primary objectives of the study were to investigate the clinical benefit of genomic-guided therapy, defined as complete response (CR), partial response (PR), or stable disease (SD) at 3 months, and its impact on progression-free survival (PFS) in patients with advanced GI malignancies. Clinical and genomic data of all consecutive GI tumor samples from April, 2013 to April, 2016 sequenced by FoundationOne were obtained and analyzed. A total of 101 samples from 97 patients were analyzed. Ninety-eight samples from 95 patients could be amplified making this approach feasible in 97% of the samples. After removing duplicates, 95 samples from 95 patients were included in the further analysis. Median time from specimen collection to reporting was 11 days. Genomic alteration-guided treatment recommendations were considered new and clinically relevant in 38% (36/95) of the patients. Rapid decline in functional status was noted in 25% (9/36) of these patients who could therefore not receive genomic-guided therapy. Genomic-guided therapy was utilized in 13 patients (13.7%) and 7 patients (7.4%) experienced clinical benefit (6 PR and 1 SD). Among these seven patients, median PFS was 10 months with some ongoing durable responses. Genomic profiling-guided therapy can lead to clinical benefit in a subset of patients with advanced GI malignancies. Attempting genomic profiling earlier in the course of treatment prior to functional decline may allow more patients to benefit from these therapies.", "affiliations": "Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Gastrointestinal Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.", "authors": "Dhir\|Mashaal\|M\|0000-0002-1426-1098;Choudry\|Haroon A\|HA\|;Holtzman\|Matthew P\|MP\|;Pingpank\|James F\|JF\|;Ahrendt\|Steven A\|SA\|;Zureikat\|Amer H\|AH\|;Hogg\|Melissa E\|ME\|;Bartlett\|David L\|DL\|;Zeh\|Herbert J\|HJ\|;Singhi\|Aatur D\|AD\|;Bahary\|Nathan\|N\|", "chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077146:Irinotecan; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin", "country": "United States", "delete": false, "doi": "10.1002/cam4.992", "fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 10.1002/cam4.992CAM4992Original ResearchClinical Cancer ResearchOriginal ResearchImpact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies Dhir Mashaal http://orcid.org/0000-0002-1426-1098\n1\nChoudry Haroon A. \n1\nHoltzman Matthew P. \n1\nPingpank James F. \n1\nAhrendt Steven A. \n1\nZureikat Amer H. \n1\nHogg Melissa E. \n1\nBartlett David L. \n1\nZeh Herbert J. \n1\nSinghi Aatur D. \n2\nBahary Nathan [email protected] \n3\n1 Division of Surgical OncologyUniversity of Pittsburgh Medical CenterPittsburghPennsylvania152322 Division of Gastrointestinal PathologyUniversity of Pittsburgh Medical CenterPittsburghPennsylvania152323 Division of OncologyUniversity of Pittsburgh Medical CenterPittsburghPennsylvania15232* Correspondence\n\nNathan Bahary, Division of Oncology, Co‐Director UPMC Pancreatic Cancer Center of Excellence, UPMC Cancer Pavilion, 5150 Centre Avenue, 5th floor, Pittsburgh, PA 15232. Tel: 412‐864‐7764; Fax: 412‐648‐6579; E‐mail: [email protected]\n28 12 2016 1 2017 6 1 10.1002/cam4.2017.6.issue-1195 206 07 8 2016 28 9 2016 12 11 2016 © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.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\nThe impact of genomic profiling on the outcomes of patients with advanced gastrointestinal (GI) malignancies remains unknown. The primary objectives of the study were to investigate the clinical benefit of genomic‐guided therapy, defined as complete response (CR), partial response (PR), or stable disease (SD) at 3 months, and its impact on progression‐free survival (PFS) in patients with advanced GI malignancies. Clinical and genomic data of all consecutive GI tumor samples from April, 2013 to April, 2016 sequenced by FoundationOne were obtained and analyzed. A total of 101 samples from 97 patients were analyzed. Ninety‐eight samples from 95 patients could be amplified making this approach feasible in 97% of the samples. After removing duplicates, 95 samples from 95 patients were included in the further analysis. Median time from specimen collection to reporting was 11 days. Genomic alteration‐guided treatment recommendations were considered new and clinically relevant in 38% (36/95) of the patients. Rapid decline in functional status was noted in 25% (9/36) of these patients who could therefore not receive genomic‐guided therapy. Genomic‐guided therapy was utilized in 13 patients (13.7%) and 7 patients (7.4%) experienced clinical benefit (6 PR and 1 SD). Among these seven patients, median PFS was 10 months with some ongoing durable responses. Genomic profiling‐guided therapy can lead to clinical benefit in a subset of patients with advanced GI malignancies. Attempting genomic profiling earlier in the course of treatment prior to functional decline may allow more patients to benefit from these therapies.\n\nClinical benefitgastrointestinal malignanciesgenomic‐guided therapygenomicsprecision medicine source-schema-version-number2.0component-idcam4992cover-dateJanuary 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.0.3 mode:remove_FC converted:27.01.2017\n\nCancer Medicine \n2017 , 6 (1 ):195 –206\n==== Body\nIntroduction\nGenomics‐driven cancer treatments have provided new hope to cancer patients with advanced malignancies. This approach is often termed as precision oncology or personalized cancer care 1, 2. Although oncologists have been customizing the treatment of various malignancies based on site, stage, and tolerability, etc., genetic guidance in selection of therapies has added another level of complexity. Data from retrospective analyses and early‐phase clinical trials have demonstrated that strategy of matching targeted agents with genomic alterations is associated with encouraging results in the treatment of patients with various cancers 3, 4, 5, 6. Schwaederle et al. in their meta‐analysis of phase II clinical trials noted that, across various malignancies, a personalized strategy was an independent predictor of better outcomes and fewer toxicity‐related deaths 6.\n\nHowever, integration of genomics‐driven care into routine oncology practice remains challenging given the practical and cost implications 1, 2, 7. At the time of their genomic evaluation, many of these patients have advanced refractory disease and a rapidly declining clinical course, disqualifying them from participating in molecular target‐driven clinical trials. There are few prospective studies validating the feasibility of a genomics‐driven approach in solid tumors including single‐disease and multidisease settings 8, 9. Sohal et al. in their prospective study of solid tumors reported that 49% of the 223 evaluable patients were recommended a specific therapy, but only 11% received such therapy 9. However, data evaluating genomics‐driven therapy specifically for advanced gastrointestinal (GI) malignancies are limited. In addition, it remains unknown whether such therapy would impact outcomes as mutations detected late in the treatment course of the disease may not be the current disease drivers. Therefore, the percentage of patients with advanced GI malignancies whose treatment plan is altered after genomic testing remains unknown. Consequently, the aim of this study was to evaluate the impact of next‐generation sequencing on the treatment plan and outcomes in patients with advanced gastrointestinal malignancies.\n\nPatients and Methods\nThe study was approved by the University of Pittsburgh Institutional Review Board (PRO16020064). All patients with advanced gastrointestinal malignancies treated at University of Pittsburgh Cancer Institute and allied cancer centers who underwent next‐generation sequencing (NGS) were included in this study. The unique setup of the University of Pittsburgh Medical Center—Cancer Centers Network connects the main institution with >40 network community sites covering a geographic area of >200 miles around greater Pittsburgh allowing us to include patients treated at both academic and community oncology centers.\n\nTumor specimens were shipped to Foundation Medicine, Inc. (Cambridge, MA), for sequencing using the FoundationOne platform. This platform is designed to include all genes known to be somatically altered in human solid tumors that are validated targets for therapy, either approved or in clinical trials, and/or that are unambiguous drivers of oncogenesis based on current knowledge 10. Technical specifications for the test are provided at the FoundationOne website (http://foundationone.com/learn.php#4). Briefly, FoundationOne applied next‐generation sequencing to identify all four types [base substitutions, insertions and deletions (indels), copy number alterations (CNAs), and rearrangements] of genomic alterations across the coding region of 315 cancer‐related genes plus introns from 28 genes. Funding for testing was borne as standard of care through each individual's insurance plan.\n\nGenomic data were collected from the standard FoundationOne patient reports. Alterations which have been previously characterized in the literature were categorized as gene alterations (GAs), whereas the alterations which have not been characterized in the literature were referred to as variants of unknown significance (VUS). VUSs were not considered to make any therapeutic decisions in this study. Electronic chart review was performed to evaluate for demographic variables of the patients as well as to ascertain if the genomics‐guided therapy was utilized in the treatment of the patients. Statistical analyses were performed using STATA 14.1 (Statacorp, 4905 Lakeway Drive, College Station, Texas, US). Continuous variables were summarized as medians with interquartile range (IQR) and categorical variables were summarized as frequencies and percentages. Progression‐free survival was calculated from the start of genomic‐guided therapy until evidence of disease progression by imaging or tumor markers. Kaplan–Meier method was used to estimate the probability of progression‐free survival. Clinical benefit was defined as complete response (CR) or partial response (PR) or stable disease (SD) at 3 months.\n\nResults\nA total of 101 consecutive samples from 97 patients consisting of all samples sent from the University of Pittsburgh Medical Center—Cancer Centers Network to FoundationOne from April, 2013 to April, 2016 were analyzed. Ninety‐eight samples from 95 patients could be amplified to provide meaningful genetic information making this approach feasible in 97% of the samples. Three patients had two samples each sent for testing; only one sample was included in the analysis to avoid duplication of the genetic information. Therefore, 95 samples from 95 patients were included in the further analysis.\n\nThe median age of the studied patients was 50 years; women comprised 40% of patients. Table 1 summarizes the baseline characteristics of the patients and tested samples. Colorectal adenocarcinoma (36%), pancreatic adenocarcinoma (20%), and appendiceal adenocarcinoma (9.5%) were the most common diagnoses. Approximately 28% of the reports were qualified, that is, genomic alterations could be confirmed, but the data obtained may have been insufficient for comprehensive detection of genomic alterations due to poor specimen quality. Median time from specimen receipt to reporting of the genomic data was 11 days and 75% of the samples were reported within 2 weeks. Median number of GAs (excluding VUS) detected per sample were 4 and median number of VUS per sample were 7. Median time from the original diagnosis to genomic profiling was 20 months. A median of 1 FDA‐approved therapy in other tumor types which could be implicated in the tumor being sequenced was suggested. A median of six clinical trials, mainly phase I trials, based on GAs were suggested.\n\nTable 1 Baseline characteristics of the patients/samples N = 95\n\n\t\nN (%)/median (iqr)\t\nAge, year\t50 (39–61)\t\nFemales\t38 (40)\t\nDiagnosis\t\nPancreatic Adenocarcinoma\t19 (20)\t\nColorectal Adenocarcinoma\t34 (35.8)\t\nAppendiceal Adenocarcinoma\t9 (9.5)\t\nNET—pancreas/small bowel\t6 (6.3)\t\nUnknown primary adenocarcinoma including PB/UGI type\t5 (5.3)\t\nCholangiocarcinoma\t5 (5.3)\t\nUnknown primary—neuroendocrine carcinoma\t3 (3.1)\t\nOther\t14 (14.7)\t\nTime from specimen collection to receipt, days\t0\t\nTime from receipt to reporting, days\t11 (9–13)\t\nTime since cancer diagnosis, months\t20 (10–39)\t\nQualified reports\t27 (28.4)\t\nGene Alterations per sample\t4 (2–6)\t\nVUS per sample\t7 (5–11)\t\nNumber of FDA‐approved therapies in the tested tumor type suggested based on genetic testing\t0 (0)\t\nNumber of FDA‐approved therapies in other tumor types implicated in treatment\t1 (0–3)\t\nNumber of suggested clinical trials\t6 (3–10)\t\nPrediction of lack of response to standard therapies\t15 (16)\t\nNET, Neuroendocrine tumor; PB, pancreaticobiliary; UGI, Upper gastrointestinal; VUS, Variants of unknown significance; FDA, Food and drug administration.\n\nJohn Wiley & Sons, LtdTP53, APC, KRAS, and SMAD4 were the most frequently mutated genes in colorectal adenocarcinoma. KRAS, CDKN2A, and TP53 were frequently mutated in pancreatic adenocarcinoma. Interestingly, 25% of tumors from patients with pancreatic adenocarcinoma harbored a BRCA2 mutation. GNAS, KRAS, TP53, and ATM were frequently mutated in appendiceal adenocarcinoma tumors. Figure 1 provides a summary of genetic alterations discovered in the three most common tumor types, that is, colorectal adenocarcinoma, pancreatic adenocarcinoma, and appendiceal adenocarcinoma.\n\nFigure 1 Mutation frequencies of genes in colorectal, pancreatic, and appendiceal adenocarcinoma.\n\nTreatment recommendations based on GAs were suggested for 75% (71/95) of the patients (Fig. 2). However, in our institution, KRAS and BRAF mutations were not considered clinically relevant as most patients with CRC already had these tests performed as a matter of protocol, and no directed KRAS therapies exist. Therefore, recommendations were considered new and clinically relevant in 38% (36/95) of the patients. In approximately two thirds of these patients (23/36), genomic‐guided therapy was not instituted due to several reasons including: (1) rapid functional decline in the patient (N = 9), (2) use of alternative standard of care therapies (N = 5), (3) enrollment in other clinical trials (N = 4), (4) observation/no evidence of disease (NED) after only site of disease was resected (N = 2), (5) lost to follow‐up (N = 2) and (6) insurance denial of therapy (N = 1). Genomic‐driven therapy was utilized in 13 patients (13.7%, 13/95). A summary of these patients is provided in Table S1. Only one patient received such therapy under a clinical trial (described below).\n\nFigure 2 Flow diagram providing a summary of samples.\n\nMany of the patients who responded to treatment based on a GA had alterations in the DNA damage repair pathway. Four patients with metastatic pancreatic cancer were found to have BRCA2 mutations. Two of these patients had a partial radiologic response and normalization of their CA 19‐9 in response to irinotecan and cisplatin. A third patient in this group received 5‐Fluorouracil and mitomycin C–based therapy due to chronic renal insufficiency and also had an excellent partial radiological response with necrosis in areas of disease and CA 19‐9 normalization. A fourth patient with a BRCA2 mutation and metastatic pancreatic cancer only recently started platinum‐based therapy and was not evaluable. Given limited open regional protocols, we have reserved therapy with PARP inhibitors for a later time point. A 30‐year‐old woman with a past history of treated early‐stage colon cancer at age 17 presented with recurrent metastatic colon cancer. Tumor analysis revealed a hypermutator phenotype; her tumor harbored more than 600 mutations/Megabase (Mb). Further evaluation of her tumor failed to reveal an underlying mismatch repair (MMR), DNA excision repair, and POLE or POLD mutations. Having failed all standard previous therapies (multiple surgeries including left colectomies, three cytoreductive procedures; two of which were accompanied with intraperitoneal hyperthermic chemoperfusion with mitomycin C, FOLFOX, FOLFIRI, and FOLFIRINOX with cetuximab) she was approved for, and responded to the anti‐PD‐1 agent nivolumab 11. Three patients with mutations in the MMR genes were treated with PD‐1 inhibitors: (1) one patients with unresectable cholangiocarcinoma who had an MLH1 mutation had a near‐complete and persistent response to pembrolizumab (discussed below), and (2) another heavily pretreated patient's metastatic CRC tumor had an MSH6 mutation and another patient's metastatic well‐differentiated high‐grade pancreatic neuroendocrine tumor harbored an MSH2 mutation (this patient's microsatellite status could not be confirmed by IHC). However, as they had exhausted all standard treatments options (mCRC KRAS mut—FOLFOX and bevacizumab, NET—interferon, long‐acting octreotide analogues, everolimus, peptide receptor radiotherapy ×2, multiple chemoembolizations, combination of everolimus and bevacizumab, temozolamide and capecitabine, XELOX, sunitinib alone, and in combination with hydroxychloroquine) they were treated with, but failed to respond to Nivolumab and ultimately succumbed to their disease. Interestingly, one patient with metastatic pancreatic cancer was found to have an ALK translocation and responded to ALK inhibition. Additionally, one patient with metastatic adenocarcinoma of unknown primary was found to have FGFR amplification and was treated with the FGFR inhibitor dovitinib on a clinical trial, resulting in stabilization of disease. In addition to the two patients with defects in mismatch repair genes (MHS2 and MSH6) who did not respond to nivolumab, three patients with therapies guided by ERBB3 amplification, NF1 mutation, and PDGFRA amplification failed to respond to directed therapy. Figure 3 provides summary of all the study patients. Median progression‐free survival (PFS) was approximately 4 months in all patients who received genomic‐guided therapy and was 10 months among those who derived any clinical benefit. A description of three patients who derived benefit from genomic‐guided therapy is provided below. These three patients were chosen as they had both a biochemical and radiologic response for illustration.\n\nFigure 3 Summary of patients treated with genomic‐guided therapy and progression‐free survival. One patient with BRCA2 mutation and metastatic pancreatic cancer recently started irinotecan and cisplatin and was not evaluable.\n\nCase 1—BRCA2 mutation and use of irinotecan with cisplatin in metastatic pancreatic cancer\nThe patient was a 38‐year‐old man, with no family history of cancer, initially diagnosed with biopsy‐proven locally advanced unresectable pancreatic (head/body) adenocarcinoma in 2013. He was treated with 8 months of FOLFIRINOX (5‐Fluorouracil, Leucovorin, Irinotecan, and Oxaliplatin) therapy and had a partial response to therapy. He subsequently underwent total pancreatectomy with portal vein resection with negative margins. Final pathology revealed a 6.5‐cm tumor, ypT3N1, and 13/47 lymph nodes positive for adenocarcinoma. No adjuvant therapy was given due to decline in functional status at that time. Eighteen months postresection, an elevation in CA 19‐9 was noted along with soft tissue thickening around the celiac axis, gastrohepatic ligament, subtle hypodensity in the segment 7 of the liver, and omental nodularity suggestive of early carcinomatosis. An endoscopic ultrasound‐guided biopsy of the celiac region was positive for adenocarcinoma and this specimen was submitted for genomic analysis. Genomic analysis identified biallelic BRCA2 mutation along with KRAS, SMAD4, and CDKN2A mutations. He was started on irinotecan and cisplatin. Pretherapy CA 19‐9 was 1673 IU/L and after four cycles CA 19‐9 decreased to 52.9 IU/L (Fig. 4A). He is currently continuing on therapy with continued response at 4 months.\n\nFigure 4 (A) CA 19‐9 and radiologic response in a patient with metastatic pancreatic cancer found to have BRCA2 mutation and treated with irinotecan and cisplatin; (B) CA 19‐9 and radiologic response in a patient with metastatic pancreatic cancer treated with ALK inhibitors crizotinib and ceritinib; (C) CA 19‐9 and radiologic response in a patient with unresectable cholangiocarcinoma treated with pembrolizumab. Pre and Post indicate pretherapy and posttherapy scans. Arrows mark the index lesions that were most easy to demonstrate and compare on the scans.\n\nCase 2—ALK translocation and use of ceritinib in metastatic pancreatic cancer\nThis patient was a 35‐year‐old man diagnosed with biopsy‐proven locally advanced pancreatic head adenocarcinoma in 2012 and underwent 3 months of therapy with FOLFIRINOX. Therapy was subsequently switched to gemcitabine and nab‐paclitaxel due to lack of response. He underwent another 3 months of gemcitabine and nab‐paclitaxel followed by pancraticoduodenectomy with negative margins. Final pathology revealed a 2‐cm tumor, ypT3N1, and 2/56 lymph nodes positive for adenocarcinoma. Postoperative adjuvant therapy was deferred due to poor functional and nutritional status. Ten months postresection CA 19‐9 was noted to be 585 U/mL and CT imaging revealed multiple newly enlarged retroperitoneal, periaortic, and retrocaval lymph nodes. At this time gemcitabine and nab‐paclitaxel were reinstituted. His CA 19‐9 normalized, but therapy was discontinued after 3 months secondary to severe neuropathy and fatigue. At that time, tumor from his resection specimen was sent for genomic analysis revealing an ALK‐EML4 translocation. He was started on Crizotinib without significant biochemical response possibly due to multiple needed dose reductions for hematologic toxicity. Treatment was then subsequently changed to Ceritinib leading to normalization of his CA 19‐9 as well as radiographic response and clinical improvement until progression after approximately 6 months of therapy (Fig. 4B). At this time repeat genomic analysis was performed which revealed the same ALK translocation. A recommendation was made for changing to an alternative ALK inhibitor—alectinib and insurance approval is currently pending.\n\nCase 3—MLHI mutation and use of pembrolizumab in unresectable cholangiocarcinoma\nA 60‐year‐old man presented in October 2012 with abdominal pain. A CT scan demonstrated a 4.6‐cm mass in the left liver with extension into the portahepatis and encasement of the common hepatic artery and portal vein; biopsy was consistent with cholangiocarcinoma. Within a month he developed jaundice. His EUS confirmed T4N0 disease and ERCP was performed with placement of a stent. The patient underwent eight cycles of gemcitabine and cisplatin, which was discontinued due to toxicity. A repeat CT scan in June, 2013, revealed stable disease. He then underwent six cycles of irinotecan and cetuximab followed by a CT scan in September 2013, which demonstrated progression of disease. His therapy was changed to FOLFOX, which was discontinued after 13 cycles due to thrombocytopenia and progressive peripheral neuropathy. In July, 2014, NGS/FoundationOne testing identified biallelic MLH1 loss. The patient subsequently enrolled in a clinical trial with pembrolizumab. After approximately 6 months, he had an excellent partial response to therapy and is currently continuing treatment on pembrolizumab (Fig. 4C).\n\nDiscussion\nThis study highlights the role of genomic profiling using a commercially available platform in patients with advanced GI malignancies being treated in a GI oncology practice including both academic and community cancer centers. Our data suggest that this approach is feasible as 97% of the samples could be successfully amplified and median time to reporting was 11 days. Recommendations for therapy were new and clinically relevant in 38% of the patients, but only 13.7% eventually received genomic‐guided therapy. The majority of these patients had advanced disease and a rapid clinical decline that prevented them from receiving genomic‐guided therapy off‐label or enrollment in an appropriate clinical trial. This suggests that undertaking genomic tumor profiling earlier in a patient's disease course may facilitate the identification and utility of directed protocol therapies. Of those screened in this analysis, however, approximately 7% of the patients eventually experienced clinical benefit. The most common single targetable alteration identified was a previously undetected BRCA2 mutations in pancreatic cancers. Multiple specific chemotherapy regimens can target this mutational landscape and we present responses with both platinum‐ and mitomycin C‐based regimens in BRCA2‐mutated patients. Trials with PARP inhibition in patients with BRCA2 mutations are also underway. Given the prevalence of BRCA pathway mutations in pancreatic adenocarcinoma (PDAC), we believe that BRCA pathway testing should be routinely undertaken in PDAC. The next most common clinically useful alteration was in the pathway of genomic instability; including one patient with metastatic CRC and hypermutator phenotype of unknown source and another patient with unresectable cholangiocarcinoma and MLH1 mutation who is responding to pembrolizumab. However, other unique molecular alterations were also identified that proved useful in offering targeted treatments (Fig. 3).\n\nThe potential for molecular‐guided therapy to affect the treatment of an individual patient has been recognized 12, 13. Initial studies by Sjoblom et al. defined the genetic landscapes of breast and colorectal cancer in 2006 and not only described several novel genes but also identified some of the key dysregulated pathways which could be the targets of therapy in future 14. Since then a team approach to defining the mutational landscape of various cancers have been taken by The Cancer Genome Atlas Project and International Cancer Genome Consortium, and new mutations and dysregulated pathways have been defined in several cancers 15, 16. Several authors have previously reported cases where drugable targets were identified and significant improvement in progression‐free survival was observed 5, 17. Others have verified the feasibility of high‐throughput testing of clinical samples for various mutations 18. Boland et al. reported their results of 500 patients who underwent next‐generation sequencing of a panel of 46 genes in a phase I clinical trials program 19. Seventy‐two percent of these patients had a mutation or variant among the 46 tested genes and 30% of the patients had alterations which were potentially actionable 19. Additionally, a recent meta‐analysis of phase II clinical trials suggested that a personalized approach compared to a nonpersonalized approach was associated with an improvement in response rates (31% vs. 10.5%, P < 0.001), progression‐free survival (5.9 months vs. 2.7 months, P < 0.001), overall survival (13.7 months vs. 8.9 months, P < 0.001), and led to fewer toxic deaths. These studies have encouraged many to consider genomics‐guided therapies in patients with advanced malignancies.\n\nMajor areas of investigation with molecular‐derived therapy include: (1) feasibility and timeliness of high‐throughput testing, (2) actionability of the targets identified, (3) and most importantly, effect on patient outcomes. Our results are discussed in these three contexts.\n\nFeasibility and timeliness of reporting\nOur results are comparable to others studies which reported a median time of 18–26 days from consent to reporting 8, 9, 20, 21. Of note, as this was a retrospective analysis, time from consent to dispatch of the specimens was not evaluable and this may have led to a shorter median time to reporting of 11 days in this study. Similarly, previous studies have reported feasibility of genomic analyses in 61–86% of the patients 9, 20, 21. In this study only patients who had specimens available for genomic profiling were analyzed and we could not evaluate the number of patients who could not undergo genomic testing due to inadequate specimens. Although molecular profiling could be performed in 97% of the specimens, approximately 30% of the reports were qualified. This could be due to poor specimen quality or sequencing failure, but the exact reasons could not be ascertained.\n\n“Actionability” of identified targets\nThe definition of actionability is not uniform and different terms such as “druggable”, “actionable”, “therapy matching”, “genomic guidance”, etc. have been used. Similarly, the impact of a genetic alteration and response to treatment may be different in different tumors, for example, BRAF V600E mutation predicts response to single‐agent vemurafenib in melanoma but not in colorectal cancer 22. Most of the studies have previously reported a targetable/actionable/druggable mutation in 30–49% of the patients 8, 9, 19, 20. In contrast to the study by Boland et al. (discussed above), KRAS mutations were not considered clinically actionable for therapy in this study due to (1) lack of effective agents that target RAS pathway and (2) most patients with metastatic colorectal cancer undergo expanded RAS analysis at our institute prior to Foundations testing 23. Although this study confirmed the presence of previously known mutations in GI tumors, one of the interesting findings was the presence of BRCA2 mutations in 25% of the tested pancreatic adenocarcinoma samples allowing for tailored therapy using platinum‐based or mitomycin‐based agents for these patients. They also support the investigational use of PARP inhibitors in available clinical trials at progression. These results are consistent with the recent reports which suggested a 17–24% incidence of BRCA2/PALB2 mutations in patients with pancreatic adenocarcinoma 24, 25. Additionally, based on the NGS results identifying the MLH1 mutation in one patient with cholangiocarcinoma, as well as other data supporting the incidence of a deficient mismatch repair (dMMR) phenotype in multiple GI cancers, we have routinely started screening all GI tumors for mismatch repair deficiency. Although the true incidence of dMMR in various GI tumors remains uncertain, we believe this is a prudent algorithm given the efficacy of PD‐1 inhibitors in tumors with mismatch repair deficiency 26. As a result, another patient with advanced pancreatic cancer not reported here was found to have an MLH1 gene mutation on our routine screening for MMR genes and treated with a PD1 inhibitor resulting in a partial response.\n\nEfforts for integration of genomic approaches in clinical practice are ongoing. At some institutions panel testing is undertaken for all patients. Other institutions utilize the FoundationsOne or similar platforms. Our own institution is in the process of creating a panel including BRCA and other DNA repair pathway genes. Rather than dictate a single platform we would recommend the platform that is available to the individual oncologist, which will differ whether they are located in the community or at academic institutions.\n\nPatient outcomes\nIt remains largely unknown as to what percentage of all patients eventually benefit from genomic‐guided therapy as only a small percentage of mutations are drivers and the vast majority are passenger mutations which confer no growth advantage 27. Additionally, clinical significance of many variants remains unknown at this time. No such variants were used to guide therapy in this study. Several randomized controlled trials are underway to assess the effectiveness of genomic‐guided therapy including IMPACT II (Initiative for Molecular Profiling and Advanced Cancer Therapy II, www.clincaltrials.gov NCT02152254), SHIVA (A Randomized Phase II Trial Comparing Therapy Based on Tumor Molecular Profiling Versus Conventional Therapy in Patients With Refractory Cancer, www.clincaltrials.gov NCT01771458), and NCI‐MPACT (National Cancer Institute—Molecular Profiling‐based Assignment of Clinical Trials, www.clincaltrials.gov NCT01827384)3. One of the major barriers to the receipt of genomic‐driven therapy is the rapid functional decline in these patients with advanced malignancies. Most of these clinical trials allow only patients with good functional status which may not be the case in the real world. Sohal et al. in their prospective study of precision oncology in solid tumors reported that 49 (26%) of 109 patients (109/223, 49% of total) who were recommended genomic‐guided therapy could not receive the therapy given rapid functional decline. In this study, 38% of the patients were recommended genomic‐guided therapy, but 25% (9/36) of these patients had rapid functional decline. This raises the question of the timing of genomic profiling with regards to the stage of disease. The median time from diagnosis to genomic profiling in this study was 20 months and was 18 months in the study by Sohal et al. Chantrill et al. in their report of pilot stage of IMPaCT trial identified 22 of 93 patients with potential for receipt of molecular‐guided therapy, but none of these patients were eligible given rapid decline in functional status 8. Earlier testing will allow more patients to have genomic‐guided therapy and possibly positively impact patient outcomes as well.\n\nThis study is unique as it focused on advanced GI malignancies and reported the clinical outcomes in patients who received genomic‐guided therapy. Von Hoff et al. in their pilot study reported that 18 (27%) of the 66 patients who received molecular profiling (MP)‐guided therapy demonstrated an improvement in their PFS, that is, PFS on MP‐guided therapy/PFS on most recent therapy >1.3 28. However, only 6 of the 18 (6/86, 7%) patients had GI malignancies. Definitions such as PFS on MP‐guided therapy/PFS on most recent therapy >1.3 may not assess clinical benefit as transparently as disease control at 3 months, as used in this study. Recently, a large single‐center prospective study by Wheler et al. was published wherein the authors reported their experience in 500 patients who underwent NGS using a similar platform as used in this study 29. Approximately 38% (188/500) of the patients received therapy of which 65% (122/500) received matched (genomic‐guided therapy) and 35% (66/188) received unmatched therapy. These authors reported a significant improvement in time to failure in patients who underwent matched therapy (median 2.8 months vs. 1.9 months, P = 0.001). Additionally, patients who underwent matched therapy also demonstrated a trend toward improved OS (median 9.2 months vs. 6.8 months, P = 0.087) and were more likely to derive clinical benefit (19% vs. 8%, respectively, P = 0.061). Similar to this study the most common reasons for nonreceipt of therapy were functional decline/death or hospice transfer. This study only focuses on GI malignancies, whereas in the Wheler et al. study, the majority of the patients had nongastrointestinal malignancies including ovarian (18%), breast (16%), sarcoma (13%), and renal cell cancers (7%).\n\nThe limitations of this study include its retrospective design, different tumor types, small sample size of each individual tumor type, and the limited variety of analyzed tumors resulting from inherent local referral patterns and patients' insurance willingness to bear the costs of the analysis. As only a single platform was utilized, underdetection of some targetable mutations in genes recently implicated in genomic instability, such as RPA1, XRCC4, and XRCC6, may have occurred 24, 25. As NGS platforms continue to evolve further actionable/targetable mutations will be analyzed. Additionally, given the small sample size distribution of tumor types in this study, these results may not match the tumors' epidemiologic distribution. Mutant allele frequencies (MAFs), which can provide insight into tumor heterogeneity or germline status, were not available for all patients in this study. Finally, given the possibility of uncovering germline mutations, all efforts should be made to determine if the source of mutations is germline. Genetic counseling should then be sought in patients found to have germline mutations.\n\nIn conclusion, current platform genomic profiling results can be obtained in most patients within 2 weeks, and up to one third of the patients may be candidates for genomic‐guided therapy. However, only a small percentage of patients are able to receive such therapies given that most patients had such determinations made late in the clinical course, when they are facing a rapid functional decline. Genomic profiling undertaken earlier in a patient's clinical course may afford an improved chance to undergo directed therapy or afford time to access clinical trials of new agents. In this study, despite the limitations of our testing paradigm, about 7% of the patients experienced clinical benefit from directed treatment encompassing multiple targetable pathways. These data support the utility of early mutational assessments and utilization of targeted therapies. As new agents that can exploit this mutational landscape find their way into clinical practice, the overall utility of this paradigm can only improve. Randomized controlled trials which are under way will shed more light on the subject.\n\nConflicts of Interest\nNone.\n\nSupporting information\n\nTable S1. Summary of previous treatments and genomic alterations among the 12 patients treated with genomic‐guided therapy.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nGarraway , L. A. \n, \nJ. \nVerweij \n, and \nK. V. \nBallman \n. 2013 \nPrecision oncology: an overview . J. Clin. Oncol. \n31 :1803 –1805 .23589545 \n2 \n\nSchilsky , R. 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Cancer Res. \n76 :3690 –3701 .27197177\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-7634", "issue": "6(1)", "journal": "Cancer medicine", "keywords": "Clinical benefit; gastrointestinal malignancies; genomic-guided therapy; genomics; precision medicine", "medline_ta": "Cancer Med", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D002945:Cisplatin; D005260:Female; D005472:Fluorouracil; D005770:Gastrointestinal Neoplasms; D023281:Genomics; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009944:Organoplatinum Compounds; D010180:Pancreatectomy; D057285:Precision Medicine; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D016896:Treatment Outcome", "nlm_unique_id": "101595310", "other_id": null, "pages": "195-206", "pmc": null, "pmid": "28028924", "pubdate": "2017-01", "publication_types": "D016428:Journal Article", "references": "24142049;24687035;23539594;20393554;24857061;19924296;24915778;25658984;24663044;27197177;23589545;24633422;28028924;26028255;27022117;24360397;25896973;25719666;20921468;26015395;16959974;24762958;26909576;26304871;26460303;22948899;18772890;26553780", "title": "Impact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies.", "title_normalized": "impact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies" }	[ { "companynumb": "PHHY2017US031854", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OCTREOTIDE ACETATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021008", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SANDOSTATIN LAR DEPOT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE TUMOUR", "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": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LANREOTIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANREOTIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CAPECITABINE\\OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "XELOX" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE TUMOUR", "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": "6", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIVOLUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DHIR M, CHOUDRY HA, HOLTZMAN MP, PINGPANK JF, AHRENDT SA, ZUREIKAT AH ET AL.. IMPACT OF GENOMIC PROFILING ON THE TREATMENT AND OUTCOMES OF PATIENTS WITH ADVANCED GASTROINTESTINAL MALIGNANCIES. CANCER MEDICINE. 2017;6(1):195-206", "literaturereference_normalized": "impact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170302", "receivedate": "20170302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13287742, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" } ]
{ "abstract": "To systematically describe the clinical and histopathological features of a case series of conjunctival carcinomatous lesions underlying as-and also masquerading-pyogenic granuloma.\n\n\n\nNine cases of conjunctival carcinomatous lesions underlying a pyogenic granuloma (which were clinically predominant) were retrospectively identified. Patients' records were analysed for demographic data, clinical appearance and the postoperative course. Formalin-fixed paraffin-embedded specimens were routinely processed and stained with H&E and periodic acid-Schiff. Immunohistochemical stains for cytokeratin were performed in selected cases.\n\n\n\nAll nine tumours were located in the conjunctiva (bulbar, tarsal, limbal conjunctiva) of patients between 44 and 80 years. The lesions exhibited clinical features of pyogenic granuloma which dominated the clinical appearance. Additional features comprised a papillomatous appearance of the adjacent conjunctiva, a more whitish aspect of the lesion and a history of squamous cell carcinoma (SCC) respectively surgery for other entities. Histopathological analysis revealed a carcinomatous lesion (conjunctival intraepithelial neoplasia or SCC) at the base of a classic pyogenic granuloma in all nine cases. Surgical removal (R0 resection) was performed. Three cases received adjuvant mitomycin C or interferon α2b treatment. Two lesions locally recurred within 2 years after initial presentation.\n\n\n\nCarcinomatous lesions may be accompanied by a pyogenic granuloma which may dominate the clinical pictures. As the tumour is usually located at the base of the lesion, a complete surgical excision followed by histopathological analysis is mandatory for each lesion appearing as conjunctival pyogenic granuloma.", "affiliations": "Division of Ophthalmic Pathology, Department of Ophthalmology, University Hospital Bonn, Bonn, Germany [email protected].;L.F. Montgomery Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Emory University, Atlanta, Georgia, USA.;Division of Ophthalmic Pathology, Department of Ophthalmology, University Hospital Bonn, Bonn, Germany.;Eye Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Division of Ophthalmic Pathology, Department of Ophthalmology, University Hospital Bonn, Bonn, Germany.;Eye Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.", "authors": "Herwig-Carl\|Martina C\|MC\|0000-0002-5943-7675;Grossniklaus\|Hans E\|HE\|;Müller\|Philipp L\|PL\|;Atzrodt\|Lisa\|L\|;Loeffler\|Karin U\|KU\|;Auw-Haedrich\|Claudia\|C\|", "chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077190:Interferon alpha-2; D016685:Mitomycin; D007633:Keratins", "country": "England", "delete": false, "doi": "10.1136/bjophthalmol-2018-312960", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-1161", "issue": "103(10)", "journal": "The British journal of ophthalmology", "keywords": "conjunctival intraepithelial neoplasia; histology; pyogenic granuloma; squamous cell carcinoma; tumour", "medline_ta": "Br J Ophthalmol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002278:Carcinoma in Situ; D002294:Carcinoma, Squamous Cell; D017024:Chemotherapy, Adjuvant; D003230:Conjunctival Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D017789:Granuloma, Pyogenic; D006801:Humans; D000077190:Interferon alpha-2; D007633:Keratins; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D012189:Retrospective Studies", "nlm_unique_id": "0421041", "other_id": null, "pages": "1469-1474", "pmc": null, "pmid": "30709809", "pubdate": "2019-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Pyogenic granuloma associated with conjunctival epithelial neoplasia: report of nine cases.", "title_normalized": "pyogenic granuloma associated with conjunctival epithelial neoplasia report of nine cases" }	[ { "companynumb": "US-009507513-2003USA010240", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "INTERFERON ALFA-2B" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "103132", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 MIO IE/ML 4 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT NEOPLASM OF CONJUNCTIVA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTRON A" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HERWIG C, GROSSNIKLAUS H, MULLER P, ATZRODT L, LOEFFLER K, AUW H, ET AL. PYOGENIC GRANULOMA ASSOCIATED WITH CONJUNCTIVAL EPITHELIAL NEOPLASIA: REPORT OF NINE CASES. THE BRITISH JOURNAL OF OPHTHALMOLOGY. 2019?103 (10):1469-74", "literaturereference_normalized": "pyogenic granuloma associated with conjunctival epithelial neoplasia report of nine cases", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200328", "receivedate": "20200328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17595312, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-2003USA010213", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "INTERFERON ALFA-2B" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "103132", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 MIO IE/ML 4 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT NEOPLASM OF CONJUNCTIVA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTRON A" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HERWIG C, GROSSNIKLAUS H, MULLER P, ATZRODT L, LOEFFLER K, AUW H, ET AL. PYOGENIC GRANULOMA ASSOCIATED WITH CONJUNCTIVAL EPITHELIAL NEOPLASIA: REPORT OF NINE CASES. THE BRITISH JOURNAL OF OPHTHALMOLOGY. 2019?103 (10):1469-74", "literaturereference_normalized": "pyogenic granuloma associated with conjunctival epithelial neoplasia report of nine cases", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200328", "receivedate": "20200328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17595313, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]
{ "abstract": "OBJECTIVE\nTo analyse the incidence and type of epidural steroid injection (ESI)-related adverse events, including procedure-related complications and drug-related systemic effects requiring hospitalisation or emergency room (ER) visits.\n\n\nMETHODS\nThis study included 52,935 ESI procedures performed in 22,059 patients in our department from March 2004 to February 2016. Of these, we retrospectively reviewed the cases of 1570 patients (1713 procedures) who were hospitalised or visited the ER within 1 month after ESI. ESI-related events were classified as procedure-related complications, drug-related systemic effects, or of uncertain relationship. Descriptive data are provided; no statistical analysis was performed.\n\n\nRESULTS\nThere were 244 ESI-related events in 235 patients (males:females = 102:133; mean age: 65.7 years; range: 20-93 years). The incidence of ESI-related events was 0.46% per procedure, including 14 procedure-related complications, 56 drug-related systemic effects, and 174 events of uncertain cause. Of the 52,935 patients, 6 (0.011%) experienced major complications (two spine haematomas and four infections), 1 patient died, and 1 experienced neurological sequelae.\n\n\nCONCLUSIONS\nAlthough major procedure-related complications and drug-related systemic effects of ESI requiring hospitalisation are very rare, infection and haematoma can occur, resulting in serious outcomes. Hence, ESI should be carefully considered in high-risk patients.\n\n\nCONCLUSIONS\n• The incidence of ESI-related events requiring hospitalisation was 0.46%. • The incidence of procedure-related complications was 0.026%. • The incidence of drug-related systemic effects was 0.11%. • The incidence of major complication of ESI was 0.011%. • The major complications were spine infection, haematoma, and sepsis.", "affiliations": "Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea.;Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea.;Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea.;Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea.;Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea.;Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea. [email protected].", "authors": "Lee\|Joon Woo\|JW\|;Lee\|Eugene\|E\|;Lee\|Guen Young\|GY\|;Kang\|Yusuhn\|Y\|;Ahn\|Joong Mo\|JM\|;Kang\|Heung Sik\|HS\|http://orcid.org/0000-0002-7024-388X", "chemical_list": "D013256:Steroids", "country": "Germany", "delete": false, "doi": "10.1007/s00330-017-4977-7", "fulltext": null, "fulltext_license": null, "issn_linking": "0938-7994", "issue": "28(1)", "journal": "European radiology", "keywords": "Complications; Drug-related side effects and adverse reactions; Epidural; Injections; Spine; Steroids", "medline_ta": "Eur Radiol", "mesh_terms": "D059787:Acute Pain; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064420:Drug-Related Side Effects and Adverse Reactions; D004636:Emergency Service, Hospital; D005260:Female; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D007268:Injections, Epidural; D008297:Male; D008875:Middle Aged; D011843:Radiculopathy; D056910:Republic of Korea; D012189:Retrospective Studies; D013256:Steroids; D055815:Young Adult", "nlm_unique_id": "9114774", "other_id": null, "pages": "418-427", "pmc": null, "pmid": "28726118", "pubdate": "2018-01", "publication_types": "D016428:Journal Article", "references": "20616178;21699610;23765044;23159970;17296980;17340166;15749619;18850035;19863744;19404169;21790519;21392252;19543892;24850123;20870478;25903715;16799275;2218714;19369604;26065819;16904497;17114531;26761719;25806907;17940309;27183400;20033148;19165301;16858486;27228513;17853663;25694868;19769520;18675752;11452067;25200706;23756957", "title": "Epidural steroid injection-related events requiring hospitalisation or emergency room visits among 52,935 procedures performed at a single centre.", "title_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre" }	[ { "companynumb": "KR-FRESENIUS KABI-FK201800185", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diabetic gastroparesis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180109", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354868, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083862", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372718, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083882", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebellar infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372318, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800188", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180109", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354446, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083863", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "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": "OMNIPAQUE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372716, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083867", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372239, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800193", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180108", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354749, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083810", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diabetic gastroparesis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372809, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800189", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180108", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354442, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800187", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Duodenal ulcer", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180109", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354552, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800190", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180108", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354420, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800191", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebellar infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180108", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354375, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800192", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lacunar infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180109", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354835, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083875", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "2ML (10MG) WAS ADMINISTERED", "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": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372303, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083843", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" } ], "patientagegroup": null, "patientonsetage": "84", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372713, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]
{ "abstract": "Antipsychotic medications, including risperidone, are widely used in the treatment of psychiatric disorders, including schizophrenia. While hyperthermia is an establish adverse effect of these medications, less is known about the rare occurrence of hypothermia. We present two patients who developed hypothermia, bradycardia and cardiac arrest in association with risperidone. We briefly review previously similarly reported cases.", "affiliations": "Internal Medicine, Wright Center for Graduate Medical Education, Scranton, Pennsylvania, USA [email protected].;Internal Medicine, Wright Center for Graduate Medical Education, Scranton, Pennsylvania, USA.;Internal Medicine, Wright Center for Graduate Medical Education, Scranton, Pennsylvania, USA.;Pulmonary and Critical Care Medicine, Geisinger Community Medical Center, Scranton, Pennsylvania, USA.", "authors": "Sharma\|Nishant\|N\|http://orcid.org/0000-0001-5324-922X;Bhat\|Sangeeta\|S\|;Ravi\|Divya\|D\|;Ochieng\|Pius\|P\|", "chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-234999", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "13(5)", "journal": "BMJ case reports", "keywords": "psychiatry (drugs and medicines); unwanted effects / adverse reactions", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D001919:Bradycardia; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007035:Hypothermia; D008297:Male; D018967:Risperidone; D012559:Schizophrenia", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32439747", "pubdate": "2020-05-20", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Severe hypothermia, bradycardia and cardiac arrest in association with risperidone.", "title_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone" }	[ { "companynumb": "US-EMCURE PHARMACEUTICALS LTD-2020-EPL-000693", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "076228", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FINASTERIDE" }, "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": "FINASTERIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "METFORMIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "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" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LISINOPRIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LISINOPRIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TERAZOSIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TERAZOSIN" } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Sinus bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P.. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REP. 2020?13(5):E234999", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200608", "receivedate": "20200608", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17869524, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0124084", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TERAZOSIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TERAZOSIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FINASTERIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076436", "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": "FINASTERIDE." } ], "patientagegroup": "6", "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus bradycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REPORTS. 2020?13(5):E234999. DOI: 10.1136/BCR?2020?234999.", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200910", "receivedate": "20200615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17894624, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-EMCURE PHARMACEUTICALS LTD-2020-EPL-000692", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "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": "WARFARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "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": "METOPROLOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "076228", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HAD BEEN ON FOR OVER 4 YEARS", "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": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REP. 2020?13(5):E234999", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200608", "receivedate": "20200608", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17869517, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-OXFORD PHARMACEUTICALS, LLC-2020OXF00074", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "078071", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P.. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REP.. 2020?13(5)", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200616", "receivedate": "20200616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17901187, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-TEVA-2020-US-1796926", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR OVER 4 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR OVER 4 YEARS", "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": "METOPROLOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR OVER 4 YEARS", "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": "RISPERIDONE." } ], "patientagegroup": "6", "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE.. DRUG AND THERAPEUTICS BULLETIN. 2021 JAN?59:13?15.", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210217", "receivedate": "20200707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17991076, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20210419" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0124085", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076879", "drugbatchnumb": "UNKNOWN", "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": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL SUCCINATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090617", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL SUCCINATE." } ], "patientagegroup": "6", "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus bradycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REPORTS. 2020?13(5):E234999. DOI: 10.1136/BCR?2020?234999.", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200910", "receivedate": "20200615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17894626, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-AJANTA PHARMA USA INC.-2085850", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "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": "METOPROLOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "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": "WARFARIN SODIUM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201003", "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": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REP.2020? 13(5).", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200615", "receivedate": "20200615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 17896152, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-PRINSTON PHARMACEUTICAL INC.-2020PRN00201", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "077493", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REP. 2020?13(5)", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200612", "receivedate": "20200612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17890520, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2020JUB00202", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "078828", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P.. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE.. BMJ CASE REP. 2020?13(5)", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200616", "receivedate": "20200616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17901085, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-TEVA-2020-US-1796930", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LISINOPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LISINOPRIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TERAZOSIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TERAZOSIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FINASTERIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FINASTERIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "077860", "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": "RISPERIDONE." } ], "patientagegroup": "6", "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. DRUG AND THERAPEUTICS BULLETIN. 2021 JAN?59:13?15.", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210712", "receivedate": "20200707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17991075, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20211014" } ]
{ "abstract": "BACKGROUND\nThe widespread availability of medication without prescription, so-called over the counter (OTC), and the rapid development of health consciousness of Poles is associated with broad access to medical information in the mass media. This causes patients to recognize their own disease, cancel doctor's appointments, and begin self-treatment. This time and money-saving behavior, often signaled by pain, usually leads to the treatment of symptoms alone, without seeking the cause of the disease.The aim of the study was to present life-threatening paracetamol poisoning, and the treatment of acute liver failure.\n\n\nMETHODS\nIn 2002-2014, 35 patients were hospitalized due to acute paracetamol poisoning: 17 female and 18 male patients aged between 17-59 (mean 32.3 years). Patients were treated in the surgical intensive care unit, where their parameters of liver and renal function were continuously monitored. If there was no improvement in the liver function, patients underwent albumin dialysis with the Prometheus system and were qualified for liver transplantation (LTx).\n\n\nRESULTS\n26 patients were treated pharmacologically and 7 out of 9 patients who underwent LTx were dialyzed. Overall, 11 patients had 26 albumin dialysis in total; 4 patients died - 1 post-transplant and 3 pre-transplant.\n\n\nCONCLUSIONS\nParacetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.", "affiliations": "Department of General, Transplant & Liver Surgery, Medical University of Warsaw, Poland.;Department of General, Transplant & Liver Surgery, Medical University of Warsaw, Poland.;Department of General, Transplant & Liver Surgery, Medical University of Warsaw, Poland.;Liver and Internal Medicine Unit of Department of General, Transplant & Liver Surgery, Medical University of Warsaw, Poland.;1. Centre of Postgraduate Medical Education, Warsaw Poland 2. Ministry of Health, Warsaw, Poland.;1. Polish Transplant Coordinating Center \"Poltransplant\", Warsaw, Poland 2. Department of Surgical and Transplant Nursing, Medical University of Warsaw, Poland.;Department of Pathology, Medical University of Warsaw, Poland.;Department of General, Transplant & Liver Surgery, Medical University of Warsaw, Poland.", "authors": "Wróblewski\|Tadeusz\|T\|;Kobryń\|Konrad\|K\|;Kozieł\|Sławomir\|S\|;Ołdakowska-Jedynak\|Urszula\|U\|;Pinkas\|Jarosław\|J\|;Danielewicz\|Roman\|R\|;Ziarkiewicz-Wróblewska\|Bogna\|B\|;Krawczyk\|Marek\|M\|", "chemical_list": "D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D000082:Acetaminophen", "country": "Poland", "delete": false, "doi": "10.5604/12321966.1185790", "fulltext": null, "fulltext_license": null, "issn_linking": "1232-1966", "issue": "22(4)", "journal": "Annals of agricultural and environmental medicine : AAEM", "keywords": null, "medline_ta": "Ann Agric Environ Med", "mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D005260:Female; D006760:Hospitalization; D006801:Humans; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D011044:Poland; D055815:Young Adult", "nlm_unique_id": "9500166", "other_id": null, "pages": "762-7667", "pmc": null, "pmid": "26706992", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": null, "title": "Acetaminophen (Paracetamol) induced acute liver failure - A social problem in an era of increasing tendency to self-treatment.", "title_normalized": "acetaminophen paracetamol induced acute liver failure a social problem in an era of increasing tendency to self treatment" }	[ { "companynumb": "PL-JNJFOC-20160101971", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALCOHOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALCOHOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematuria", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cirrhosis alcoholic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bladder tamponade", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma hepatic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WROBLEWSKI T, KOBRYN K, KOZIEL S, OLDAKOWSKA-JEDYNAK U, PINKAS J, DANIELEWICZ R, ET AL. ACETAMINOPHEN (PARACETAMOL) INDUCED ACUTE LIVER FAILURE - A SOCIAL PROBLEM IN AN ERA OF INCREASING TENDENCY TO SELF-TREATMENT. ANNALS OF AGRICULTURAL AND ENVIRONMENTAL MEDICINE 2015?22(4):762-767.", "literaturereference_normalized": "acetaminophen paracetamol induced acute liver failure a social problem in an era of increasing tendency to self treatment", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20160119", "receivedate": "20160119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11928883, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]
{ "abstract": "Approximately 5% of all women in the world are HBsAg-positive. Chronic hepatitis B is a problem in women of reproductive age. This paper assessed 88 HBsAg-positive pregnant women, of whom 11 began treatment during pregnancy and five became pregnant while receiving treatment. The files of HBsAg-positive pregnant women were reviewed between January 2010 and December 2013-retrospectively. From these 88 pregnant women, 72 did not receive any treatment during their pregnancy, 11 began treatment during their pregnancy, and five became pregnant while receiving treatment. Nine of these 11 pregnant women were given tenofovir disoproxil fumarate and two of them lamivudine. Ten babies of the 11 mothers that began treatment during their pregnancy were healthy, but one was lost due to preterm birth. Of the five patients who became pregnant while receiving treatment, the treatments of four women were discontinued and they were monitored during their pregnancies because mild-moderate (less than stage 3) fibrosis was found in their liver biopsy results. It is important to screen all pregnant women for hepatitis B and to assess those found HBsAg-positive. It is possible to protect both the mother and baby using appropriate approaches.", "affiliations": null, "authors": "Kolgelier\|S\|S\|;Sumer\|S\|S\|;Demir\|N A\|NA\|;Asci\|Z\|Z\|;Demir\|L S\|LS\|;Ozcimen\|S\|S\|;Ural\|O\|O\|", "chemical_list": "D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D019259:Lamivudine; D000068698:Tenofovir", "country": "China", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0390-6663", "issue": "43(6)", "journal": "Clinical and experimental obstetrics & gynecology", "keywords": null, "medline_ta": "Clin Exp Obstet Gynecol", "mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D005260:Female; D006514:Hepatitis B Surface Antigens; D019694:Hepatitis B, Chronic; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D019259:Lamivudine; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D047928:Premature Birth; D012189:Retrospective Studies; D000068698:Tenofovir; D055815:Young Adult", "nlm_unique_id": "7802110", "other_id": null, "pages": "866-870", "pmc": null, "pmid": "29944240", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": null, "title": "Monitoring and treatment results of 88 HBsAg-positive pregnant women.", "title_normalized": "monitoring and treatment results of 88 hbsag positive pregnant women" }	[ { "companynumb": "TR-MYLANLABS-2017M1014828", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "204002", "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": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KOLGELIER S, SUMER S, DEMIR NA, ASCI Z, DEMIR LS, OZCIMEN S, ET AL. MONITORING AND TREATMENT RESULTS OF 88 HBSAG-POSITIVE PREGNANT WOMEN. CLIN-EXP-OBSTET-GYNECOL 2016;43(6):866-870.", "literaturereference_normalized": "monitoring and treatment results of 88 hbsag positive pregnant women", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20170309", "receivedate": "20170309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13313878, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]
{ "abstract": "Chronic airway inflammation and infection drive morbidity and mortality among patients with cystic fibrosis (CF). While Haemophilus influenzae and Staphylococcus aureus predominate in children, the prevalence of Pseudomonas aeruginosa increases as patients age. Other bacteria, including species within the Burkholderia cepacia complex (Bcc), are also more prevalent among adults with CF. Species within the Bcc accelerate lung function decline and can trigger development of \"cepacia syndrome,\" both before and after lung transplantation. As a result, some centers advise against lung transplantation for Bcc-infected patients; however, little is known about the relative virulence of uncommon Bcc species. We describe a successful lung re-transplant in a patient with CF, chronic Burkholderia ambifaria airway infection, and cepacia syndrome.", "affiliations": "Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Glendale, AZ, United States.;Deparment of Pharmacy Services, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.;Division of Transplant Pulmonology, Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.;Division of Transplant Surgery, Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.;Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, United States.;Division of Transplant Pulmonology, Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.;Division of Transplant Pulmonology, Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States. Electronic address: [email protected].", "authors": "Goodlet\|Kellie J\|KJ\|;Nailor\|Michael D\|MD\|;Omar\|Ashraf\|A\|;Huang\|Jasmine L\|JL\|;LiPuma\|John J\|JJ\|;Walia\|Rajat\|R\|;Tokman\|Sofya\|S\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jcf.2018.08.011", "fulltext": null, "fulltext_license": null, "issn_linking": "1569-1993", "issue": "18(1)", "journal": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society", "keywords": "Burkholderia ambifaria; Burkholderia cepacia complex; cystic fibrosis; lung transplantation", "medline_ta": "J Cyst Fibros", "mesh_terms": "D000328:Adult; D016470:Bacteremia; D019117:Burkholderia; D019121:Burkholderia Infections; D003550:Cystic Fibrosis; D005260:Female; D006801:Humans; D008168:Lung; D016040:Lung Transplantation; D012086:Reoperation; D013577:Syndrome; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101128966", "other_id": null, "pages": "e1-e4", "pmc": null, "pmid": "30224331", "pubdate": "2019-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful Lung Re-transplant in a Patient with Cepacia Syndrome due to Burkholderia ambifaria.", "title_normalized": "successful lung re transplant in a patient with cepacia syndrome due to burkholderia ambifaria" }	[ { "companynumb": "US-BAYER-2019-028597", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019537", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "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, "medicinalproduct": "CIPROFLOXACIN MONOHYDROCHLORIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOCYCLINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "AMIKACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "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": "MINOCYCLINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTAZIDIME" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTAZIDIME." } ], "patientagegroup": "5", "patientonsetage": "41", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "GOODLET KJ, NAILOR MD, OMAR A, HUANG JL, LIPUMA JJ, WALIA R, TOKMAN S. SUCCESSFUL LUNG RE-TRANSPLANT IN A PATIENT WITH CEPACIA SYNDROME DUE TO BURKHOLDERIA AMBIFARIA. JOURNAL OF CYSTIC FIBROSIS (2019). 2019?18:1:(E1-E4)", "literaturereference_normalized": "successful lung re transplant in a patient with cepacia syndrome due to burkholderia ambifaria", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190211", "receivedate": "20190211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15948145, "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-PFIZER INC-2019060552", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKHOLDERIA CEPACIA COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKHOLDERIA CEPACIA COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOCYCLINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": "1", "drugadministrationroute": "055", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKHOLDERIA CEPACIA COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTAZIDIME" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "062662", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKHOLDERIA CEPACIA COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTAZIDIME." } ], "patientagegroup": null, "patientonsetage": "41", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GOODLET, K.. SUCCESSFUL LUNG RE-TRANSPLANT IN A PATIENT WITH CEPACIA SYNDROME DUE TO BURKHOLDERIA AMBIFARIA. JOURNAL OF CYSTIC FIBROSIS. 2019?18 (1):E1-E4", "literaturereference_normalized": "successful lung re transplant in a patient with cepacia syndrome due to burkholderia ambifaria", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190219", "receivedate": "20190213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15956595, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]
{ "abstract": "A 54-year-old man with acute myeloid leukemia (AML) underwent allogeneic bone marrow transplantation from a human leukocyte antigen-matched unrelated donor in nonremission status. Bone marrow aspiration performed on day 14 showed that the patient had achieved complete remission; however, he relapsed on day 28. The patient developed a wet cough, and chest computed tomography performed on day 27 revealed pneumonia. Because pneumonia developed along with the leukemic relapse, we suspected that it was due to pulmonary leukemic infiltration (PLI). Giemsa-stained sputum showed some blast cells and fluorescence in situ hybridization indicated that the patient had monosomy 7, which was also detected in bone marrow blasts. Though we prescribed hydroxycarbamide and decreased tacrolimus rapidly, AML progressed and led to the patient's death on day 45. Histopathological findings of the autopsy performed the next day showed diffuse alveolar damage in both lungs. The blast cells were packed in blood vessels of alveolar septa and were also seen in alveoli. PLI was diagnosed pathologically. In conclusion, our case demonstrates that Giemsa stain of sputum is useful in quick diagnosis of PLI without invasive examination.", "affiliations": "Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Division of Laboratory, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Pathology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Pathology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.", "authors": "Osaki\|Masahide\|M\|;Lee\|Yoonha\|Y\|;Osamura\|Yoko\|Y\|;Ichiki\|Tomoe\|T\|;Okabe\|Motohito\|M\|;Kawaguchi\|Yuka\|Y\|;Obiki\|Marie\|M\|;Ito\|Ai\|A\|;Goto\|Miyo\|M\|;Araie\|Hiroaki\|H\|;Goto\|Tatsunori\|T\|;Morishita\|Takanobu\|T\|;Ozawa\|Yukiyasu\|Y\|;Ito\|Masafumi\|M\|;Miyamura\|Koichi\|K\|", "chemical_list": "D001399:Azure Stains", "country": "Japan", "delete": false, "doi": "10.11406/rinketsu.61.257", "fulltext": null, "fulltext_license": null, "issn_linking": "0485-1439", "issue": "61(3)", "journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology", "keywords": "Acute myeloid leukemia; Pulmonary complication; Pulmonary leukemic infiltration", "medline_ta": "Rinsho Ketsueki", "mesh_terms": "D001399:Azure Stains; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute; D017254:Leukemic Infiltration; D008297:Male; D008875:Middle Aged; D013183:Sputum", "nlm_unique_id": "2984782R", "other_id": null, "pages": "257-261", "pmc": null, "pmid": "32224587", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Leukemic pulmonary infiltration diagnosed by sputum Giemsa-staining.", "title_normalized": "leukemic pulmonary infiltration diagnosed by sputum giemsa staining" }	[ { "companynumb": "JP-ACCORD-178876", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse alveolar damage", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Leukaemic infiltration pulmonary", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "OSAKI M, YOONHA LEE Y, OSAMURA Y, ICHIKI T, OKABE M, KAWAGUCHI Y ET AL. LEUKEMIC PULMONARY INFILTRATION DIAGNOSED BY SPUTUM GIEMSA-STAINING. RINSHO KETSUEKI. 2020?61(3):257-261.", "literaturereference_normalized": "leukemic pulmonary infiltration diagnosed by sputum giemsa staining", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200415", "receivedate": "20200415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17670189, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "JP-PBT-000280", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROXYUREA" }, "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": "HYDROXYCARBAMIDE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE REDUCED", "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": "TACROLIMUS." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "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": "TACROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neoplasm recurrence", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neoplasm progression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Leukaemic infiltration pulmonary", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "OSAKI M, LEE Y, OSAMURA Y, ICHIKI T, OKABE M, KAWAGUCHI Y. ET AL. LEUKEMIC PULMONARY INFILTRATION DIAGNOSED BY SPUTUM GIEMSA-STAINING. RINSHO KETSUEKI. 2020?61(3):257-261. DOI: 10.11406/RINKETSU.61.257", "literaturereference_normalized": "leukemic pulmonary infiltration diagnosed by sputum giemsa staining", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20201011", "receivedate": "20200421", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17688023, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" } ]
{ "abstract": "It has been well known that mesalazine can cause the interstitial lung disease, such as Bronchiolitis obliterans with organizing pneumonia (BOOP), Non-Specific Interstitial Pneumonia (NSIP), or eosinophilic pneumonia. 5-Aminosalicylic acid (5-ASA), mesalazine, and sulfasalazine are important drugs for treating inflammatory bowel disease. Topical products of these limited systemic absorption and have less frequent side effects, therefore suppository form of these drugs have been used more than systemic drug. Most cases of measalzine-induced lung toxicity develop from systemic use of the drug. A 30-year-old woman had an interstitial lung disease after using mesalazine suppository because of ulcerative colitis. The lung biopsy demonstrated eosinophilic pneumonia combined with BOOP. She was recovered after stopping of mesalazine suppository and treatment with systemic steroid.", "affiliations": "Division of Respiratory and Allergy, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 420-767, Korea.", "authors": "Kim\|Jung Hyun\|JH\|;Lee\|June-Hyuk\|JH\|;Koh\|Eun-Suk\|ES\|;Park\|Sung Woo\|SW\|;Jang\|An-Soo\|AS\|;Kim\|Dojin\|D\|;Park\|Choon-Sik\|CS\|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.5415/apallergy.2013.3.2.136", "fulltext": "\n==== Front\nAsia Pac AllergyAsia Pac AllergyAPAAsia Pacific Allergy2233-82762233-8268Asia Pacific Association of Allergy, Asthma and Clinical Immunology 10.5415/apallergy.2013.3.2.136Case ReportAcute eosinophilic pneumonia related to a mesalazine suppository Kim Jung Hyun 1Lee June-Hyuk 1Koh Eun-Suk 2Park Sung woo 1Jang An-Soo 1Kim Dojin 1Park Choon-Sik 11 Division of Respiratory and Allergy, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 420-767, Korea.2 Department of Pathology, Soonchunhyang University Bucheon Hospital, Bucheon 420-767, Korea.\nCorrespondence: June-Hyuk Lee. Division of Respiratory and Allergy, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, 170, jomaru-ro, Wonmi-gu, Bucheon 420-767, Korea. Tel: +82-32-621-5154, Fax: +82-32-621-6950, [email protected] 2013 26 4 2013 3 2 136 139 25 7 2012 24 2 2013 Copyright © 2013. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.2013This 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.It has been well known that mesalazine can cause the interstitial lung disease, such as Bronchiolitis obliterans with organizing pneumonia (BOOP), Non-Specific Interstitial Pneumonia (NSIP), or eosinophilic pneumonia. 5-Aminosalicylic acid (5-ASA), mesalazine, and sulfasalazine are important drugs for treating inflammatory bowel disease. Topical products of these limited systemic absorption and have less frequent side effects, therefore suppository form of these drugs have been used more than systemic drug. Most cases of measalzine-induced lung toxicity develop from systemic use of the drug. A 30-year-old woman had an interstitial lung disease after using mesalazine suppository because of ulcerative colitis. The lung biopsy demonstrated eosinophilic pneumonia combined with BOOP. She was recovered after stopping of mesalazine suppository and treatment with systemic steroid.\n\nEosinophilic pneumoniaBronchiolitis obliterans with organizing pneumoniaMesalazineSuppository\n==== Body\nINTRODUCTION\nMesalazine and sulfasalazine are important drugs for treating inflammatory bowel disease (IBD). Adverse effects of mesalazine include nausea, vomiting, diarrhea, rash, fever, and hepatic dysfunction. The incidence rate of adverse effects is 3%, but most cases are not serious [1-3]. There have been many reports of interstitial lung disease (ILD) induced by sulfasalazine or mesalazine for treating IBD [4, 5]. Sulfasalazine and mesalazine can cause problems in the lung, such as Bronchiolitis obliterans with organizing pneumonia (BOOP), Non-Specific Interstitial Pneumonia (NSIP), or eosinophilic pneumonia, although it has been known that there are associations between IBD and lung involvement [6]. Most cases of mesalazine or sulfasalazine-induced lung toxicity develop from systemic use of the drugs. There were limited reports that lung toxicity associated with using of suppository form of mesalazine. We report a patient with eosiophilc pneumonia combined with BOOP that developed after using mesalazine suppository.\n\nCASE REPORT\nA 30-year-old woman presented with cough that was aggravated at night for 10 days. She had ulcerative colitis and had undergone a left hemi-colectomy with a colostomy 7 weeks ago. She had received a mesalazine suppository (1 g/day) for 19 days after the operation. At the time of presentation, the patient complained of fatigue, general weakness, myalgia, cough, and a small amount of non-purulent sputum. A chest X-ray and high resolution computed tomography showed peripheral patchy consolidations with interlobular septal thickening in both lungs. Blood eosinophils were 24.5%, level of total IgE was 169 KU/L and specific IgE for dust mites were 3+ in UniCAP system. Total cell count was 31.5 × 105 cell/mL with 73.2% macrophages, 19.6% neutrophils, 1.6% eosinophils, 0% lymphocytes in bronchoalveolar lavage fluid. Tests for nine respiratory associated viruses (adenovirus; Rous sarcoma virus; rhinovirus; metapneumovirus; seasonal influenza A and B; parainfluenza virus 1, 2, and 3; and novel H1N1 virus) were all negative by real-time PCR. Test results for antinuclear antibodies, rheumatoid factor, anti-ds DNA antibody, and antineutrophil cytoplasmic antibody were negative. The lung biopsy demonstrated that a patchy interstitial and intra-alveolar histiocytic infiltration was admixed with many eosinophils and some neutrophils and foci of organizing fibrosis, suggestive of eosinophilic pneumonia and BOOP (Fig. 1). The mesalazine suppository was stopped. She was treated with 500 mg methylprednisolone intravenously for 3 days followed by 30 mg prednisolone orally. She recovered completely.\n\nDISCUSSION\nSulfasalazine or mesalazine for treating IBD has been known to be associated with development of ILD [4, 5]. This issue is open to dispute. Because these drugs can cause problems in the lung, such as BOOP, NSIP, or eosinophilic pneumonia, some ILDs are similar to those seen in patients with IBD unexposed to drugs [6]. Lung involvement with IBD as a part of the extra-intestinal manifestations of IBD is not common, and the incidence rate is only 0.4% [7]. In this case, no lesion was found in the mid and lower lung areas on an abdominal computed tomography scan that was performed at the time of IBD evaluation, before the operation, although the whole lung condition was not shown.\n\nThe incidence of mesalazine-associated lung disease is unknown but appears to be low. A study of 1,700 mesalazine treated patients had a 3%-20% incidence of adverse effects and did not include any patients with pulmonary complications [2, 3].\n\nWhen the drug was administrated orally, the mean age of sulfasalazine-induced lung toxicity patients was 48.3 years. Dose-dependent lung toxicity was not defined. The daily dose of sulfasalazine ranged from 1 to 8 g, with a mean of 3 g. The average duration of exposure to sulfasalazine was 17.8 months [1].\n\nMost cases of mesalazine or sulfasalazine-induced lung toxicity developed from systemic use of the drugs. In this case, mesalazine was used as a suppository and the patient had never been exposed to mesalazine or other 5-Aminosalicylic acid (5-ASA) before. The dose of mesalazine suppository was 1 g/day, and the duration of use was only 19 days. The dosage and duration are thought to be smaller and shorter for inducing lung toxicity than when the drugs are used systemically. It is also uncertain whether the lung lesions in this patient were side effects of the drug or hypersensitivity reactions.\n\nThe mechanisms of pharmacologic effect of mesalazine has been thought to block the production of interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) and inhibit nuclear factor-κB (NF-κB) activation. The pathogenesis of mesalazine-induced lung injury is unknown, but four mechanisms are considered as a causes of drug induced lung injury; 1) oxidant injury by a drug, such as nitrofurantoin ingestion; 2) direct cytotoxic effect on alveolar capillary endothelial cells; 3) injury mediated by deposition of phospholipids within the cell; and 4) immune-mediated injury causing clinical symptoms of systemic lupus erythematosus. Currently, it is postulated that mesalazine causes immune-mediated alveolitis as evidenced by lymphocyte stimulation [2, 5, 8].\n\nIt has not been known the incidence rate of hypersensitivity reaction after using 5-ASA suppository form including mesalazine and sulfasalazine. We failed to find a case concerning the side effects or hypersensitivity reactions in the lung after using a mesalazine suppository. Only three cases are available that reported side effects after using topical 5-ASA [9-11]. Two cases were the development of pancreatitis caused by 5-ASA enema [9] or suppository [10] and the other was a case of fever and skin rash by 5-ASA enema [10] (Table 1). The cases of pancreatitis were thought be associated with form of administration. The best indicator of mesalazine's release and subsequent action in the bowel is unknown. Administrating mesalazine as an enema or suppository, effectively bypassing the threat of small bowel absorption [12]. Mesalazine has a lower absorption rate after rectal administration compared to oral administration (10% vs. 35%, respectively) [13, 14]. Because of this, the incidence of systemic side effect of the administration of suppository mesalazine is lower than other form of intake. The common side effects are dizziness (3%), rectal pain (2%), fever, rash, acne, and colitis (1% each) [15].\n\nWe didn't try to administration of mesalazine to the patient for confirm, because the condition of patient was serious at time of diagnosis. Suppository has been thought to be safer than systemic administration, even some adverse effects reported. This is a first report that a patient who experienced lung involvement to mesalazine suppository.\n\nFig. 1 (A) Many chronic inflammatory cells (predominantly macrophages) and some aggregation of eosinophils are seen. (B) Interstitial thickenings with chronic inflammatory cells infiltration and intraluminal young fibroblastic polyps, that are consistent with Bronchiolitis obliterans with organizing pneumonia, are also seen.\n\nTable 1 Cases reported to show side effects associated with topical 5-ASA administration\n\n5-ASA, 5-Aminosalicylic acid.\n==== Refs\n1 Parry SD Barbatzas C Peel ET Barton JR Sulphasalazine and lung toxicity Eur Respir J 2002 19 756 764 11999006 \n2 Foster RA Zander DS Mergo PJ Valentine JF Mesalamine-related lung disease: clinical, radiographic, and pathologic manifestations Inflamm Bowel Dis 2003 9 308 315 14555914 \n3 Brimblecombe R Mesalazine: a global safety evaluation Scand J Gastroenterol Suppl 1990 172 66 1972297 \n4 Salerno SM Ormseth EJ Roth BJ Meyer CA Christensen ED Dillard TA Sulfasalazine pulmonary toxicity in ulcerative colitis mimicking clinical features of Wegener's granulomatosis Chest 1996 110 556 559 8697866 \n5 Tanigawa K Sugiyama K Matsuyama H Nakao H Kohno K Komuro Y Iwanaga Y Eguchi K Kitaichi M Takagi H Mesalazine-induced eosinophilic pneumonia Respiration 1999 66 69 72 9973695 \n6 Camus P Colby TV The lung in inflammatory bowel disease Eur Respir J 2000 15 5 10 10678613 \n7 Carter MJ Lobo AJ Travis SP IBD Section, British Society of Gastroenterology Guidelines for the management of inflammatory bowel disease in adults Gut 2004 53 Suppl 5 V1 V16 15306569 \n8 Sviri S Gafanovich I Kramer MR Tsvang E Ben-Chetrit E Mesalamine-induced hypersensitivity pneumonitis. A case report and review of the literature J Clin Gastroenterol 1997 24 34 36 9013348 \n9 Isaacs KL Murphy D Pancreatitis after rectal administration of 5-aminosalicylic acid J Clin Gastroenterol 1990 12 198 199 1969872 \n10 Kim KH Kim TN Jang BI A case of acute pancreatitis caused by 5-aminosalicylic acid suppositories in a patient with ulcerative colitis Korean J Gastroenterol 2007 50 379 383 18159175 \n11 Borum ML Ginsberg A Hypersensitivity to 5-ASA suppositories Dig Dis Sci 1997 42 1076 1078 9149065 \n12 Qureshi AI Cohen RD Mesalamine delivery systems: do they really make much difference? Adv Drug Deliv Rev 2005 57 281 302 15555743 \n13 Aumais G Lefebvre M Tremblay C Bitton A Martin F Giard A Madi M Spénard J Rectal tissue, plasma and urine concentrations of mesalazine after single and multiple administrations of 500 mg suppositories to healthy volunteers and ulcerative proctitis patients Aliment Pharmacol Ther 2003 17 93 97 12492737 \n14 Williams CN Haber G Aquino JA Double-blind, placebo-controlled evaluation of 5-ASA suppositories in active distal proctitis and measurement of extent of spread using 99mTc-labeled 5-ASA suppositories Dig Dis Sci 1987 32 71S 75S 3319461 \n15 Physicians' desk reference 2004 58th ed Montvale, NJ Thomson PDR 795 796\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2233-8276", "issue": "3(2)", "journal": "Asia Pacific allergy", "keywords": "Bronchiolitis obliterans with organizing pneumonia; Eosinophilic pneumonia; Mesalazine; Suppository", "medline_ta": "Asia Pac Allergy", "mesh_terms": null, "nlm_unique_id": "101561954", "other_id": null, "pages": "136-9", "pmc": null, "pmid": "23667838", "pubdate": "2013-04", "publication_types": "D002363:Case Reports", "references": "9013348;11999006;18159175;9149065;15555743;12492737;15306569;8697866;1969872;3319461;14555914;9973695;1972297;10678613", "title": "Acute eosinophilic pneumonia related to a mesalazine suppository.", "title_normalized": "acute eosinophilic pneumonia related to a mesalazine suppository" }	[ { "companynumb": "KR-ALLERGAN-1661863US", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "054", "drugauthorizationnumb": "021252", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAZINE UNK" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eosinophilic pneumonia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Organising pneumonia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Interstitial lung disease", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lung disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KIM JH, LEE JH, KOH ES, PARK S, JANG AS, KIM D, PARK CS. ACUTE EOSINOPHILIC PNEUMONIA RELATED TO A MESALAZINE SUPPOSITORY. ASIA PACIFIC ASSOCIATION OF ALLERGY, ASTHMA AND CLINICAL IMMUNOLOGY. 2013;3:136-139", "literaturereference_normalized": "acute eosinophilic pneumonia related to a mesalazine suppository", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160707", "receivedate": "20160707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12536857, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]
{ "abstract": "Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT.\n\n\n\nScrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3).\n\n\n\nMedian observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation.\n\n\n\nLong-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.", "affiliations": "Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.;Swabian Children's Cancer Center, University Children's Hospital, University Hospital Augsburg, Augsburg, Germany.;Swabian Children's Cancer Center, University Children's Hospital, University Hospital Augsburg, Augsburg, Germany.;Institute of Neuropathology, University Hospital Münster, Münster, Germany.;West German Proton Therapy Center Essen/Clinic for Particle Therapy, Essen University Hospital, Essen, Germany.;Institute of Diagnostic and Interventional Neuroradiology, University Hospital Wuerzburg, Wuerzburg, Germany.;Department of Pediatrics, Kepler University Hospital and School of Medicine, Johannes Kepler University, Linz, Austria.;PSL Research University, Institut Curie, Pediatric Care and Research Center, Paris, France.;Gustave Roussy, Grand Paris Cancer Campus, Department of Childhood and Adolescent Oncology, Villejuif, France.;S.C. Pediatria, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Oncology Department at Hospital Sant Joan de Deu, Barcelona Children's Hospital, Barcelona, Spain.;Pediatric Oncology Unit, University Hospital, Strasbourg, France.;Department of Pediatric Oncology, University Hospital, Besançon, France.;Institute for Medical Statistics, Medical University of Graz, Graz, Austria.;Division of Neuropathology, Department of Pathology and Neuropathology, Kepler University Hospital and School of Medicine, Johannes Kepler University, Linz, Austria.;Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.;Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.;Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany.;Laboratory of Genetics, Pathology Unit, S. Anna General Hospital, Como, Italy.;University Hospital of Nancy, Pediatric Hematology and Oncology, Nancy, France.;Swabian Children's Cancer Center, University Children's Hospital, University Hospital Augsburg, Augsburg, Germany.", "authors": "Benesch\|Martin\|M\|0000-0001-7827-4130;Nemes\|Karolina\|K\|0000-0003-0270-5875;Neumayer\|Petra\|P\|;Hasselblatt\|Martin\|M\|;Timmermann\|Beate\|B\|;Bison\|Brigitte\|B\|;Ebetsberger-Dachs\|Georg\|G\|;Bourdeaut\|Franck\|F\|;Dufour\|Christelle\|C\|0000-0001-5993-8077;Biassoni\|Veronica\|V\|;Morales La Madrid\|Andrés\|A\|;Entz-Werle\|Natacha\|N\|;Laithier\|Véronique\|V\|;Quehenberger\|Franz\|F\|;Weis\|Serge\|S\|;Sumerauer\|David\|D\|;Siebert\|Reiner\|R\|;Bens\|Susanne\|S\|;Schneppenheim\|Reinhard\|R\|;Kool\|Marcel\|M\|;Modena\|Piergiorgio\|P\|0000-0002-2339-4300;Fouyssac\|Fanny\|F\|;C Frühwald\|Michael\|M\|0000-0002-8237-1854", "chemical_list": "D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases", "country": "United States", "delete": false, "doi": "10.1002/pbc.28022", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "67(1)", "journal": "Pediatric blood & cancer", "keywords": "brain tumors; neuro-oncology; pediatric oncology; teratoid/rhabdoid tumors", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D014408:Biomarkers, Tumor; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D004265:DNA Helicases; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D009687:Nuclear Proteins; D011379:Prognosis; D012189:Retrospective Studies; D018335:Rhabdoid Tumor; D000071796:SMARCB1 Protein; D013120:Spinal Cord Neoplasms; D015996:Survival Rate; D013724:Teratoma; D014157:Transcription Factors", "nlm_unique_id": "101186624", "other_id": null, "pages": "e28022", "pmc": null, "pmid": "31571386", 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SPINAL CORD ATYPICAL TERATOID/RHABDOID TUMORS IN CHILDREN: CLINICAL, GENETIC, AND OUTCOME CHARACTERISTICS IN A REPRESENTATIVE EUROPEAN COHORT.. PEDIATR. 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"drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "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": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "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": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage intracranial", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BENESCH, M.. SPINAL CORD ATYPICAL TERATOID/RHABDOID TUMORS IN CHILDREN: CLINICAL, GENETIC, AND OUTCOME CHARACTERISTICS IN A REPRESENTATIVE EUROPEAN COHORT.. PEDIATR BLOOD CANCER. 2020?JAN:1-8", "literaturereference_normalized": "spinal cord atypical teratoid rhabdoid tumors in children clinical genetic and outcome characteristics in a representative european cohort", "qualification": "1", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20200212", "receivedate": "20200203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17363255, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "DE-MYLANLABS-2020M1018650", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091062", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "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": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "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": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BENESCH M, NEMES K, NEUMAYER P, HASSELBLATT M, TIMMERMANN B, BISON B, ET AL.. SPINAL CORD ATYPICAL TERATOID/RHABDOID TUMORS IN CHILDREN: CLINICAL, GENETIC, AND OUTCOME CHARACTERISTICS IN A REPRESENTATIVE EUROPEAN COHORT.. PEDIATR-BLOOD-CANCER. 2020?67(1):E28022", "literaturereference_normalized": "spinal cord atypical teratoid rhabdoid tumors in children clinical genetic and outcome characteristics in a representative european cohort", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200220", "receivedate": "20200220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17441533, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]
{ "abstract": "In the European Association for Palliative Care recommendations for cancer pain management, there was no consensus regarding the indications, titration, or monitoring of methadone.\n\n\n\nThis national, randomized, multicenter trial aimed to compare two methadone titration methods (stop-and-go vs. progressive) in patients with cancer-related pain who were inadequately relieved by or intolerant to Level 3 opioids.\n\n\n\nThe primary end point was the rate of success/failure at Day 4, defined as pain relief (reduction of at least two points on the visual scale and a pain score <5 for two consecutive days) and no overdose (Rudkin scale ≥3 and respiratory rate <8/minute). The patients were followed for two months after enrollment.\n\n\n\nThe cancer-related pain characteristics of the 146 patients were as follows: 16% were nociceptive, 85% experienced breakthrough pain, and 84% had mixed types of pain. The reasons for switching to methadone were a lack of efficacy that was either isolated (56%) or associated with intolerance (38%). Adequate pain relief was obtained in 80% of the patients (median of three days in both groups [P = 0.12]) and lasted until D56. The rate of success/failure was approximately 40% at Day 4 in both groups, with overdoses in 13% of the patients throughout the study. The two methods were considered equally easy to perform by nearly 60% of the clinicians.\n\n\n\nMethadone is an effective and sustainable second-line alternative opioid for the treatment of cancer-related pain. The methods of titration are comparable in terms of efficacy, safety, and ease of use.", "affiliations": "Polyclinique de l'ormeau, Tarbes, France. Electronic address: [email protected].;Assistance Publique-Hôpitaux de Paris, Paris, France.;Laboratoires Bouchara-Recordati, Puteaux, France.;Centre Oscar Lambret, Lille, France.;Centre Léon Bérard, Lyon, France.;CHU Nord, Amiens, France.;CHU L'Archet2, Nice, France.;CHI Alpes du Sud, Gap, France.;CH Lyon Sud, Pierre Bénite, France.", "authors": "Poulain\|Philippe\|P\|;Berleur\|Marie-Pierre\|MP\|;Lefki\|Shimsi\|S\|;Lefebvre\|Danièle\|D\|;Chvetzoff\|Gisèle\|G\|;Serra\|Eric\|E\|;Tremellat\|Fibra\|F\|;Derniaux\|Alain\|A\|;Filbet\|Marilène\|M\|;\|\|\|", "chemical_list": "D000701:Analgesics, Opioid; D008691:Methadone", "country": "United States", "delete": false, "doi": "10.1016/j.jpainsymman.2016.05.022", "fulltext": null, "fulltext_license": null, "issn_linking": "0885-3924", "issue": "52(5)", "journal": "Journal of pain and symptom management", "keywords": "Cancer pain; methadone; opioid", "medline_ta": "J Pain Symptom Manage", "mesh_terms": "D000701:Analgesics, Opioid; D059390:Breakthrough Pain; D000072716:Cancer Pain; D062787:Drug Overdose; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008691:Methadone; D008875:Middle Aged; D010147:Pain Measurement; D019233:Retreatment; D016896:Treatment Outcome", "nlm_unique_id": "8605836", "other_id": null, "pages": "626-636.e1", "pmc": null, "pmid": "27693901", "pubdate": "2016-11", "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": "Efficacy and Safety of Two Methadone Titration Methods for the Treatment of Cancer-Related Pain: The EQUIMETH2 Trial (Methadone for Cancer-Related Pain).", "title_normalized": "efficacy and safety of two methadone titration methods for the treatment of cancer related pain the equimeth2 trial methadone for cancer related pain" }	[ { "companynumb": "FR-JNJFOC-20161218763", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021217", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OROS (ORAL OSMOTIC) THERAPEUTIC SYSTEM TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANCER PAIN", "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": "OXYCODONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANCER PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUFENTANIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "000000", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANCER PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUFENTANIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019813", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANCER PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANCER PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adverse event", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "P P, BERLEUR M, LEFKI S, LEFEBVRE D, CHVETZOFF G, SERRA E, ET AL. EFFICACY AND SAFETY OF TWO METHADONE TITRATION METHODS FOR THE TREATMENT OF CANCER-RELATED PAIN: THE EQUIMETH2 TRIAL (METHADONE FOR CANCER-RELATED PAIN). JOURNAL OF PAIN AND SYMPTOM MANAGEMENT 01-NOV-2016;52/5:626-636.", "literaturereference_normalized": "efficacy and safety of two methadone titration methods for the treatment of cancer related pain the equimeth2 trial methadone for cancer related pain", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20161228", "receivedate": "20161228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13068757, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]
{ "abstract": "Hyperthermia, which is a noninvasive treatment that causes tumor cells to become heated and that works in synergy with anticancer drugs and radiation therapy, is emerging as a promising treatment for patients with cancer. The purpose of this study is to report the efficacy of hyperthermia combined with chemotherapy (gemcitabine/cisplatin) for the treatment of a patient with unresectable cholangiocarcinoma. A 54-year-old man was diagnosed as hilar cholangiocarcinoma (Klatskin tumor) and was administered neoadjuvant and preoperative radiation with chemotherapy. However, because the treatment with radiation and chemotherapy was not successful, he decided to undergo hyperthermia combined with chemotherapy as a second treatment option. He was suffering from fatigue, dyspepsia, epigastralgia, and jaundice. Hyperthermia combined with chemotherapy was administered 32 times over a period of 4 months. The patient experienced no critical complications, and the patient's condition improved, with the carbohydrate antigen 19-9 (CA 19-9) and the total bilirubin levels being relatively lowered. In addition, the computed tomography scan showed that the cholangiocarcinoma had not progressed. In conclusion, this case report suggests radiofrequency hyperthermia combined with chemotherapy may be a promising treatment option for patients with unresectable cholangiocarcinoma.", "affiliations": "1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea.;1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea.;1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea.;2 Jeonju Korean Medicine Hospital, Wonkwang University, Jeonju, Korea.;1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea.;3 Dunsan Korean Medicine Hospital, Daejeon University, Daejeon, Korea.", "authors": "Ryu\|Juyoung\|J\|;Lee\|Kangwook\|K\|;Joe\|Changmug\|C\|;Joo\|JongCheon\|J\|;Lee\|Namhun\|N\|;Yoo\|Hwa-Seung\|HS\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/1534735417722225", "fulltext": "\n==== Front\nIntegr Cancer TherIntegr Cancer TherICTspictIntegrative Cancer Therapies1534-73541552-695XSAGE Publications Sage CA: Los Angeles, CA 2874508410.1177/153473541772222510.1177_1534735417722225Case StudiesPatient With Unresectable Cholangiocarcinoma Treated With Radiofrequency Hyperthermia in Combination With Chemotherapy: A Case Report Ryu Juyoung MS, KMD1Lee Kangwook BS, KMD1Joe Changmug PhD, MD1Joo JongCheon PhD, KMD2Lee Namhun PhD, KMD1Yoo Hwa-Seung PhD, KMD31 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea2 Jeonju Korean Medicine Hospital, Wonkwang University, Jeonju, Korea3 Dunsan Korean Medicine Hospital, Daejeon University, Daejeon, KoreaNamhun Lee, Department of Clinical Oncology, Cheonan Korean Medical Hospital, Korean Medical College, Daejeon University, 4, Notaesan-ro, Seobuk-gu, Cheonan-si, Chungcheongnam-do 31099, Korea. Email: [email protected] Yoo. East West Cancer Center, Dunsan Korean Medicine Hospital, Korean Medical College, Daejeon University, 75, Daedeok-daero 176 beon-gil, Seo-gu, Daejeon, 35235, Korea. E-mail: [email protected]* These authors contributed equally to this work.\n\n26 7 2017 6 2018 17 2 558 561 6 3 2017 1 6 2017 18 6 2017 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Hyperthermia, which is a noninvasive treatment that causes tumor cells to become heated and that works in synergy with anticancer drugs and radiation therapy, is emerging as a promising treatment for patients with cancer. The purpose of this study is to report the efficacy of hyperthermia combined with chemotherapy (gemcitabine/cisplatin) for the treatment of a patient with unresectable cholangiocarcinoma. A 54-year-old man was diagnosed as hilar cholangiocarcinoma (Klatskin tumor) and was administered neoadjuvant and preoperative radiation with chemotherapy. However, because the treatment with radiation and chemotherapy was not successful, he decided to undergo hyperthermia combined with chemotherapy as a second treatment option. He was suffering from fatigue, dyspepsia, epigastralgia, and jaundice. Hyperthermia combined with chemotherapy was administered 32 times over a period of 4 months. The patient experienced no critical complications, and the patient’s condition improved, with the carbohydrate antigen 19-9 (CA 19-9) and the total bilirubin levels being relatively lowered. In addition, the computed tomography scan showed that the cholangiocarcinoma had not progressed. In conclusion, this case report suggests radiofrequency hyperthermia combined with chemotherapy may be a promising treatment option for patients with unresectable cholangiocarcinoma.\n\nchemotherapycholangiocarcinomahyperthermiaKlatskin tumorradiofrequency\n==== Body\nIntroduction\nCholangiocarcinoma (CCA) is rare malignancy that can occur anywhere along the intrahepatic or the extrahepatic biliary tree. Cholangiocarcinoma can be classified as intrahepatic, perihilar, or distal.1 Hilar CCAs and perihilar CCAs are associated with poor prognosis. Of the 3000 cases seen annually in the United States, less than one-half of the tumors are resectable. Patients typically present with abdominal pain, pruritus, weight loss, and jaundice. Computed tomography (CT), magnetic resonance imaging, and ultrasound are used to diagnose cancer and to characterize biliary lesions. Treatment consists of surgery, radiation therapy, chemotherapy and photodynamic therapy. Standard therapy consists of surgical margin-negative resection with extrahepatic bile duct resection, hepatectomy, and en-bloc lymphadenectomy.2 Complete resection of a hilar cholangiocarcinoma is the most effective and only potentially curative therapy, and it is now clear that concomitant hepatic resection is required in most cases.3 However, complete resection is sometimes difficult because of local extensions, which occur perineurally via lymphatic channels, subepithelial spread in the duct wall, and direct invasion of adjacent hepatic arteries or portal veins.4 Nonresected extrahepatic bile duct carcinoma has a dismal prognosis, with a life expectancy of about 6 month to 1 year.5\n\nIn oncology, the term hyperthermia refers to the treatment of malignant diseases by administering heat and generating electromagnetic induction. Hyperthermia is usually applied as an adjunct to an already established treatment modality (radiotherapy and chemotherapy), and the goal is to kill tumor cells6 and influence the increase in tumor immunogenicity.7 The present study reports the case of a patient with unresectable hilar cholangiocarcinoma who received concurrent hyperthermia and chemotherapy.\n\nCase Report\nThis case study was approved by the institutional review board of Cheonan Korean Medicine Hospital of Daejeon University (authorization number: DJUMC-P-2017-02).\n\nA-54-year-old man was diagnosed with hilar cholangiocarcinoma (Klatskin tumor) and underwent percutaneous transhepatic biliary drainage at Seoul National University Hospital in June 2016. He was administered neoadjuvant and preoperative 28 days of radiation with 2 cycles of chemotherapy from July to August to be able to perform surgery. The patient was administered cisplatin 25mg plus gemcitabine 1000 mg on the first and eighth days of a 21-day cycle for 6 weeks. Unfortunately, the tumor did not respond to radiation with chemotherapy and the patient was diagnosed as being unresectable. In July 2016, the patient, presenting with fatigue, dyspepsia, epigastralgia, and jaundice, visited Cheonan Korean Medicine Hospital of Daejeon University (Cheonan, Republic of Korea) to seek a second treatment option. At the time of the patient’s visit, his Eastern Cooperative Oncology Group (ECOG)8 grade scored 3 points. As a second line therapy, hyperthermia combined with chemotherapy (gemcitabine/cisplatin) was administered a total of 32 times from September to December 2016.\n\nRadiofrequency (RF) hyperthermia was carried out using the REMISSION 1°C device (AdipoLABs Company, Seoul, Korea). Two 12-cm-diameter electrodes were applied in opposition to each other, and 0.46-MHz RF wave was applied. We administered heat to the patient for 70 minutes and measured the surface temperature (39°C to 41°C) continuously. The applied power was gradually increased from 50 to 100 W, depending on the tolerance of the patient.\n\nRF hyperthermia was administered 32 times without the patient exhibiting any critical complications. The carbohydrate antigen 19-9 (CA 19-9) and the total bilirubin levels decreased during treatment (Figures 1 and 2). The patient’s ECOG8 grade had improved from 3 to 2 points. The several symptoms of fatigue, dyspepsia, epigastralgia, and jaundice were reduced. Judging from National Cancer Institute–Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0,9 fatigue was improved from grade 3 to 1 and dyspepsia was improved from grade 2 to 1. The size of tumor during concurrent hyperthermia and chemotherapy was measured by using CT scans; no progression was noted (Figure 3). Thus, we verified stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.10\n\nFigure 1. Change in the carbohydrate antigen 19-9 (CA 19-9) level with time. After neoadjuvant and preoperative radiation with chemotherapy, the CA 19-9 level was significantly lower than it was at the time of initial evaluation, but then started to increase. Hyperthermia combined with chemotherapy decreased the level of CA19-9 again from 328 to 212.6.\n\nFigure 2. Change in the serum total bilirubin level with time. The serum bilirubin level was significantly lower after percutaneous transhepatic biliary drainage, and that low value remained relatively the same throughout the hyperthermia combined with chemotherapy treatment.\n\nFigure 3. Computed tomography (CT) scan images. The size of tumor during concurrent hyperthermia and chemotherapy was measured by using CT scans in September (A), November (B), and December (C) 2016. No tumor progression was noted.\n\nDiscussion\nCCA may arise anywhere within the biliary tree, but tumors involving the biliary confluence (hilar CCAs) are the most common.11 CCA accounts for 3% of all gastrointestinal tumors. Over the past 3 decades, the overall incidence of CCAs appears to have increased.12 The percentage of patients who survive 5 years after diagnosis has not increased during this time period, remaining at 10%.13 In several studies published over the past three decades, the proportion of patients with hilar tumors has remained fairly constant at 40% to 60%, with the remaining tumors arising from intrahepatic biliary radicles or the distal bile duct.11 Even though resection is well established as the conventional treatment, early transitions can occur, and at the time of discovery, surgery to remove the tumor is performed in one-third, or fewer, of the cases.12 The majority of patients with unresectable bile duct cancer die within 12 months of diagnosis, often from hepatic failure or infectious complications secondary to biliary obstruction. The prognosis has been considered to be worse for lesions involving the biliary confluence than for distal lesions.11\n\nHyperthermia is the process of raising the body temperature, either locally or globally, for medicinal purposes. Hyperthermia can kill or weaken tumor cells without affecting normal cells. Tumor cells, with disorganized and compact vascular structures, have difficulty dissipating heat. Hyperthermia may, therefore, let cancerous cells undergo apoptosis in direct response to applied heat while healthy tissues can more easily maintain normal temperature. Even if the cancerous cells do not die outright, they may become more susceptible to ionizing radiation therapy or to certain chemotherapy drugs, which may allow such therapy to be given in smaller doses.6 Hyperthermia generates electromagnetic induction, selectively deposits energy on the cell membrane, and induces apoptosis more efficiently.14,15 Also, hyperthermia can cause the generation of circumstantial antitumor immunity, influence the increase in tumor immunogenicity due to hydrostatic pressure and lead to immunogenic cell death.7\n\nHyperthermia is rarely used as a single cancer treatment modality and is usually added to radiation therapy, chemotherapy, or radiochemotherapy, and recently to gene and immunotherapy. Many studies on hyperthermia are being conducted continuously in the field of oncology.16-18 As to CCA, a case series of 8 patients on regional hyperthermia with 8 MHz frequency in combination with chemoradiation therapy was reported to be a promising treatment, increasing both local control and long-term survival.19 The higher the frequency, the greater the attenuation and the lower is the penetration.20 The REMISSION 1°C device has a frequency of 0.46 MHz, the lowest frequency ever reported. A case study reported good result on a patient suffering from recurred hepatocellular carcinoma, in which the REMISSION 1°C device was combined with sorafenib.21 In this case study, the hyperthermia treatment was done using the REMISSION 1°C device and was combined with chemotherapy (gemcitabine/cisplatin).\n\nThe present case report shows the efficacy of combined RF hyperthermia and chemotherapy for the treatment of patient with unresectable extrahepatic bile duct carcinoma. After the treatment, the CA 19-9 and the total bilirubin levels have been lowered. The patient’s symptoms, fatigue, dyspepsia, epigastralgia, and jaundice, were alleviated because of the combined treatment. Judging from NCI-CTCAE version 4.0,9 fatigue was improved from grade 3 to 1 and dyspepsia was improved from grade 2 to 1. In addition, the patient experienced no critical complications during treatment, and he remained in fine condition. The general toxicity observed in gemicitabin/cisplatin combination is febrile neutropenia, bleeding, anorexia, nausea, fatigue, and reduced white blood cell count, and so forth.22 Judging from NCI-CTCAE version 4.0,9 severe toxicity was not observed. The patient did not suffer from febrile neutropenia or bleeding. White blood cell count maintained a normal range. Anorexia, nausea, and fatigue were improved. And the patient’s ECOG8 grade had improved from 3 to 2 points. Although the results of the CT scans of the patient showed no improvement, neither did they indicate any progression of the disease, according to RECIST version 1.1.10\n\nTo assure the quality for clinical studies in regional deep hyperthermia, the temperature in the target volume and in the area surrounding the target volume must be recorded.23 The REMISSION 1°C device used in this study did not allow that to be done, which is a limitation of this case study.\n\nBased on these results, hyperthermia is thought to have contributed, at least in part, to the patient’s remaining in fine condition and to the reduced toxic effect of chemotherapy. The present case report suggests that RF hyperthermia combined with chemotherapy may be a treatment option for patient with unresectable cholangiocarcinoma.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by a grant from Deajeon University’s Industry-Academic Cooperation Foundation of AdipoLABs Co. (2016).\n==== Refs\nReferences\n1 \nNakeeb A Pitt HA Sohn TA et al \nCholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors . Ann Surg . 1996 ;224 :463 -475 .8857851 \n2 \nSoares KC Kamel I Cosgrove DP Herman JM Pawlik TM \nHilar cholangiocarcinoma: diagnosis, treatment options, and management . Hepatobiliary Surg Nutr . 2014 ;3 :18 -34 .24696835 \n3 \nSchule S Altendorf-Hofmann AK Knösel T Uteß F Settmacher U \nDiagnostic procedures and results in surgical therapy for cholangiocarcinoma [in German] . Zentralbl Chir . 2014 ;139 (suppl 2 ):e25 -e34 .22274918 \n4 \nSakamoto E Nimura Y Hayakawa N et al \nThe pattern of infiltration at the proximal border of hilar bile duct carcinoma: a histologic analysis of 62 resected cases . Ann Surg . 1998 ;227 :405 -411 .9527064 \n5 \nRadtke A Königsrainer A \nSurgical therapy of cholangiocarcinoma . Visc Med . 2016 ;32 :422 -426 .28229077 \n6 \nHegyi G Szigeti GP Szász A \nHyperthermia versus oncothermia: cellular effects in complementary cancer therapy . Evid Based Complement Alternat Med . 2013 ;2013 :672873 .23662149 \n7 \nGarg AD Galluzzi L Apetoh L et al \nMolecular and translational classifications of DAMPs in immunogenic cell death . Front Immunol . 2015 ;6 :588 .26635802 \n8 \nOken MM Creech RH Tormey DC et al \nToxicity and response criteria of the Eastern Cooperative Oncology Group . Am J Clin Oncol . 1982 ;5 :649 -656 .7165009 \n9 \nNational Cancer Institute . Common Terminology Criteria for Adverse Events (CTCAE) v.4 data files . http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed July 10, 2017 .\n10 \nEisenhauer EA Therasse P Bogaerts J et al \nNew response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer . 2009 ;45 :228 -247 .19097774 \n11 \nJarnagin W Winston C \nHilar cholangiocarcinoma: diagnosis and staging . HPB (Oxford) . 2005 ;7 :244 -251 .18333200 \n12 \nKhan SA Davidson BR Goldin RD et al \nGuidelines for the diagnosis and treatment of cholangiocarcinoma: an update . Gut . 2012 ;61 :1657 -1669 .22895392 \n13 \nEverhart JE Ruhl CE \nBurden of digestive diseases in the United States part III: liver, biliary tract, and pancreas . Gastroenterology . 2009 ;136 :1134 -1144 .19245868 \n14 \nAndocs G Rehman MU Zhao QL Tabuchi Y Kanamori M Kondo T \nComparison of biological effects of modulated electro-hyperthermia and conventional heat treatment in human lymphoma U937 cells . Cell Death Discov . 2016 ;2 :16039 .27551529 \n15 \nYang KL Huang CC Chi MS et al \nIn vitro comparison of conventional hyperthermia and modulated electro-hyperthermia . Oncotarget . 2016 ;7 :84082 -84092 .27556507 \n16 \nDesiderio J Chao J Melstrom L et al \nThe 30-year experience—a meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer . Eur J Cancer . 2017 ;79 :1 -14 .28456089 \n17 \nBakrin N Classe JM Pomel C Gouy S Chene G Glehen O \nHyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer . J Visc Surg . 2014 ;151 :347 -353 .25168575 \n18 \nToraya-Brown S Fiering S \nLocal tumour hyperthermia as immunotherapy for metastatic cancer . Int J Hyperthermia . 2014 ;30 :531 -539 .25430985 \n19 \nKamisawa T Tu Y Egawa N et al \nThermo-chemo-radiotherapy for advanced bile duct carcinoma . World J Gastroenterol . 2005 ;11 :4206 -4209 .16015690 \n20 \nSadick NS Makino Y \nSelective electro-thermolysis in aesthetic medicine: a review . Lasers Surg Med . 2004 ;34 :91 -97 .15004818 \n21 \nKim JH Lee JH Joo JC Lee JB Cho CK Yoo HS \nA case report of recurred hepatocellular carcinoma patient treated with radio-frequency hyperthermia in conjunction with sorafenib . J Korean Tradit Oncol . 2016 ;21 :63 -74 .\n22 \nOkusaka T Nakachi K Fukutomi A et al \nGemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan . Br J Cancer . 2010 ;103 :469 -474 .20628385 \n23 \nBruggmoser G Bauchowitz S Canters R et al \nQuality assurance for clinical studies in regional deep hyperthermia . Strahlenther Onkol . 2011 ;187 :605 -610 .21932026\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1534-7354", "issue": "17(2)", "journal": "Integrative cancer therapies", "keywords": "Klatskin tumor; chemotherapy; cholangiocarcinoma; hyperthermia; radiofrequency", "medline_ta": "Integr Cancer Ther", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001650:Bile Duct Neoplasms; D018281:Cholangiocarcinoma; D003131:Combined Modality Therapy; D005334:Fever; D006801:Humans; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "101128834", "other_id": null, "pages": "558-561", "pmc": null, "pmid": "28745084", "pubdate": "2018-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "15004818;8857851;25168575;28456089;20628385;26635802;18333200;16015690;7165009;24696835;19245868;19097774;22895392;28229077;27556507;22274918;27551529;23662149;21932026;25430985;9527064", "title": "Patient With Unresectable Cholangiocarcinoma Treated With Radiofrequency Hyperthermia in Combination With Chemotherapy: A Case Report.", "title_normalized": "patient with unresectable cholangiocarcinoma treated with radiofrequency hyperthermia in combination with chemotherapy a case report" }	[ { "companynumb": "KR-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-147520", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, FIRST AND EIGHTH DAYS OF A 21-DAY CYCLE FOR 6 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOLANGIOCARCINOMA", "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": "4", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "78433", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, FIRST AND EIGHTH DAYS OF A 21-DAY CYCLE FOR 6 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOLANGIOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYU J, LEE K, JOE C, JOO J, LEE N, YOO HS. 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{ "abstract": "Blockade of the cyclin-dependent kinase 4 and 6 pathway has been shown to be effective in the treatment of hormone receptor-positive advanced breast cancer (ABC). We report the interim results of DAWNA-1 ( NCT03927456 ), a double-blind, randomized, phase 3 trial of dalpiciclib (a new cyclin-dependent kinase 4 and 6 inhibitor) plus fulvestrant in hormone receptor-positive, HER2-negative ABC with disease progression after endocrine therapy. A total of 361 patients were randomized 2:1 to receive dalpiciclib plus fulvestrant or placebo plus fulvestrant. The study met the primary end point, showing significantly prolonged investigator-assessed progression-free survival with dalpiciclib plus fulvestrant versus placebo plus fulvestrant (median = 15.7, 95% confidence interval (CI) = 11.1-not reached versus 7.2, 95% CI = 5.6-9.2 months; hazard ratio = 0.42, 95% CI = 0.31-0.58; one-sided P < 0.0001 (boundary was P ≤ 0.008)). The most common grade 3 or 4 adverse events with dalpiciclib plus fulvestrant were neutropenia (84.2%) and leukopenia (62.1%). The incidence of serious adverse events was 5.8% with dalpiciclib plus fulvestrant versus 6.7% with placebo plus fulvestrant. Our findings support dalpiciclib plus fulvestrant as a new treatment option for pretreated hormone receptor-positive, HER2-negative ABC.", "affiliations": "Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].;Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.;Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, Fudan University Cancer Hospital, Shanghai, China.;Department of Medical Oncology, The First Hospital of Jilin University, Changchun, China.;Department of Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.;Department of Medical Oncology, Cancer Hospital of China Medical University/Liaoning Cancer Hospital, Shenyang, China.;Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China.;Department of Breast Oncology, Hubei Cancer Hospital, Wuhan, China.;Department of Medical Oncology, Hunan Cancer Hospital, Changsha, China.;Department of Head and Neck Cancer, West China Hospital, Sichuan University, Chengdu, China.;Department of Breast Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.;Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.;Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, China.;Department of Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences/Zhejiang Cancer Hospital, Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, China.;Department of Oncology, Jiangsu Province Hospital, Nanjing, China.;Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.;Department of Medical Oncology/Chemotherapy, Anhui Provincial Hospital, Hefei, China.;Breast Cancer Center, Shandong Cancer Hospital, Jinan, China.;Department of Breast, Bone & Soft Tissue Oncology, Guangxi Medical University Cancer Hospital, Nanning, China.;Department of Breast Disease, Henan Breast Cancer Center/The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.;Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.;Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.;Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.;Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.", "authors": "Xu\|Binghe\|B\|http://orcid.org/0000-0003-4195-337X;Zhang\|Qingyuan\|Q\|;Zhang\|Pin\|P\|;Hu\|Xichun\|X\|;Li\|Wei\|W\|;Tong\|Zhongsheng\|Z\|;Sun\|Tao\|T\|;Teng\|Yuee\|Y\|;Wu\|Xinhong\|X\|;Ouyang\|Quchang\|Q\|;Yan\|Xi\|X\|;Cheng\|Jing\|J\|;Liu\|Qiang\|Q\|;Feng\|Jifeng\|J\|;Wang\|Xiaojia\|X\|;Yin\|Yongmei\|Y\|;Shi\|Yanxia\|Y\|;Pan\|Yueyin\|Y\|;Wang\|Yongsheng\|Y\|;Xie\|Weimin\|W\|;Yan\|Min\|M\|;Liu\|Yunjiang\|Y\|;Yan\|Ping\|P\|;Wu\|Fei\|F\|;Zhu\|Xiaoyu\|X\|;Zou\|Jianjun\|J\|;\|\|\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1038/s41591-021-01562-9", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-8956", "issue": "27(11)", "journal": "Nature medicine", "keywords": null, "medline_ta": "Nat Med", "mesh_terms": null, "nlm_unique_id": "9502015", "other_id": null, "pages": "1904-1909", "pmc": null, "pmid": "34737452", "pubdate": "2021-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial.", "title_normalized": "dalpiciclib or placebo plus fulvestrant in hormone receptor positive and her2 negative advanced breast cancer a randomized phase 3 trial" }	[ { "companynumb": "2021A858254", "fulfillexpeditecriteria": "1", "occurcountry": null, "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FULVESTRANT" }, "drugadditional": "3", "drugadministrationroute": "030", "drugauthorizationnumb": "021344", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HER2 positive breast cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FULVESTRANT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Binghe Xu. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial. Nature Medicine 2021;27:1904-1909.", "literaturereference_normalized": "dalpiciclib or placebo plus fulvestrant in hormone receptor positive and her2 negative advanced breast cancer a randomized phase 3 trial", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20211207", "receivedate": "20211207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20157223, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "OBJECTIVE\nMycophenolate mofetil (MMF) is mainly used in conjunction with calcineurin inhibitors as an additional immunosuppressive for renal sparing after liver transplantation. However, few reports about MMF use in infants after living donor liver transplantation (LDLT) are available. The purpose of this study was to examine the efficacy and safety of MMF in infants.\n\n\nMETHODS\nThis study enrolled infants younger than 1 year of age who received LDLT at our institution. Patients received oral MMF twice daily. The initial dose was 40 to 50 mg/kg/d, which was increased to a target mycophenolic acid (MPA) trough level of 2 mg/L. Body weight, height, MMF dose, MPA trough level, acute cellular rejection (ACR) episodes, pathologic findings, and adverse effects were analyzed. Allograft fibrosis was graded using the Meta-analysis of Histological Data in Viral Hepatitis score.\n\n\nRESULTS\nPatients received MMF for refractory ACR (n = 2), fulminant hepatitis (n = 2), and pre-existing antibodies (n = 1). Original diseases were biliary atresia (n = 3) and fulminant hepatitis (n = 2). Mean age at transplant was 8 months (range 3-10 months). The last available mean trough level was 2.7 mg/L. The mean dose was 66 mg/kg/d or 1429 mg/m2/d at the time of the last available through level. The regression line for MMF dose and MPA trough level was y = 1.8 × 10-3x. The correlation coefficient was 0.65. All allografts showed F1 to F2 fibrosis. Two patients discontinued MMF because of infection and bone marrow suppression, respectively. Two patients converted to everolimus. One patient continued on MMF.\n\n\nCONCLUSIONS\nAfter LDLT, infants require a higher MMF dose than older patients based on trough levels, but allograft fibrosis can progress.", "affiliations": "Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. Electronic address: [email protected].;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.", "authors": "Ueno\|Takehisa\|T\|;Kodama\|Tasuku\|T\|;Noguchi\|Yuki\|Y\|;Deguchi\|Koichi\|K\|;Nomura\|Motonari\|M\|;Saka\|Ryuta\|R\|;Watanabe\|Miho\|M\|;Tazuke\|Yuko\|Y\|;Bessho\|Kazuhiko\|K\|;Okuyama\|Hiroomi\|H\|", "chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid", "country": "United States", "delete": false, "doi": "10.1016/j.transproceed.2020.01.160", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1345", "issue": "52(6)", "journal": "Transplantation proceedings", "keywords": null, "medline_ta": "Transplant Proc", "mesh_terms": "D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D009173:Mycophenolic Acid; D013997:Time Factors", "nlm_unique_id": "0243532", "other_id": null, "pages": "1855-1857", "pmc": null, "pmid": "32571709", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": null, "title": "Serum Trough Concentration and Effects of Mycophenolate Mofetil Based on Pathologic Findings in Infants After Liver Transplantation.", "title_normalized": "serum trough concentration and effects of mycophenolate mofetil based on pathologic findings in infants after liver transplantation" }	[ { "companynumb": "JP-ACCORD-198183", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 TO 50 MG/KG/D, TWICE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UENO T, KODAMA T, NOGUCHI Y, DEGUCHI K, NOMURA M, SAKA R ET AL. SERUM TROUGH CONCENTRATION AND EFFECTS OF MYCOPHENOLATE MOFETIL BASED ON PATHOLOGIC FINDINGS IN INFANTS AFTER LIVER TRANSPLANTATION. TRANSPLANT PROC. 2020 JUN 19:S0041?1345(19)31830?5.", "literaturereference_normalized": "serum trough concentration and effects of mycophenolate mofetil based on pathologic findings in infants after liver transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200902", "receivedate": "20200902", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18222324, "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-TEVA-2020-JP-1829559", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TAPERED FROM TACROLIMUS BASED IMMUNOSUPPRESSION ACCORDING TO OUR PROTOCOL", "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": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SEE NARRATIVE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "UENO T, KODAMA T, NOGUCHI Y, DEGUCHI K, NOMURA M, SAKA R, ET AL. SERUM TROUGH CONCENTRATION AND EFFECTS OF MYCOPHENOLATE MOFETIL BASED ON PATHOLOGIC FINDINGS IN INFANTS AFTER LIVER TRANSPLANTATION. TRANSPLANT?PROC 2020?52(6):1855?1857.", "literaturereference_normalized": "serum trough concentration and effects of mycophenolate mofetil based on pathologic findings in infants after liver transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200929", "receivedate": "20200929", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18321391, "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\nThere is a significant prevalence of new onset neuropsychiatric symptoms (NPS), some severe and persistent, in patients with coronavirus disease 2019 (COVID-19).\n\n\nOBJECTIVE\nThis study reports on the use of electroconvulsive therapy (ECT) to treat NPS associated with COVID-19.\n\n\nMETHODS\nA review of the literature pertaining to the use of ECT in patients with COVID-19 and NPS was performed through PubMed, PsycINFO, and MEDLINE. Search terms included \"Electroconvulsive Therapy\" and \"ECT,\" combined with \"COVID-19\" and \"Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2).\" In addition, we present a case in which ECT was used to achieve complete remission in a patient who developed new onset, treatment-resistant depression, psychosis, and catatonia, associated with COVID-19.\n\n\nRESULTS\nA total of 67 articles were reviewed with 3 selected for inclusion. These articles detailed 3 case reports of patients with new onset NPS (mania, psychosis and suicidality, and catatonia) that developed in the context of active COVID-19 and were treated successfully with ECT.\n\n\nCONCLUSIONS\nECT, a broad-spectrum treatment that has been found to be effective in various NPS (independent of etiology), is shown in our case report and others, to be safe and effective for NPS associated with COVID-19. Although we identified only 3 other cases in the literature, we believe that the probable antiinflammatory mechanism of ECT, its safety and tolerability, and the faster time to symptom remission support the need for more research and increased clinician awareness about this life-saving procedure.", "affiliations": "The Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX. Electronic address: [email protected].;The Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.;The Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.;The Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.", "authors": "Austgen\|Gabriela\|G\|;Meyers\|Matthew S\|MS\|;Gordon\|Mollie\|M\|;Livingston\|Robin\|R\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jaclp.2021.07.010", "fulltext": null, "fulltext_license": null, "issn_linking": "2667-2960", "issue": null, "journal": "Journal of the Academy of Consultation-Liaison Psychiatry", "keywords": "COVID-19; catatonia; electroconvulsive therapy; neuropsychiatric; psychiatric; psychosis", "medline_ta": "J Acad Consult Liaison Psychiatry", "mesh_terms": null, "nlm_unique_id": "101775059", "other_id": null, "pages": null, "pmc": null, "pmid": "34358726", "pubdate": "2021-08-04", "publication_types": "D016428:Journal Article; D016454:Review", "references": "32433118;26844966;33315969;21030090;33223217;32298803;32593479;31764451;27574610;29697715;33268001;31861926;31196793;15486852;32593341;33992595;33376990;32437679;32791211;32345550;33220366;19491313;29776679;29287239;28783929;32422545;32561222;32740329;33015547", "title": "The Use of Electroconvulsive Therapy in Neuropsychiatric Complications of Coronavirus Disease 2019: A Systematic Literature Review and Case Report.", "title_normalized": "the use of electroconvulsive therapy in neuropsychiatric complications of coronavirus disease 2019 a systematic literature review and case report" }	[ { "companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-06022", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZITHROMYCIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "065398", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "4", "drugadministrationroute": "042", "drugauthorizationnumb": "209097", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Neuropsychiatric symptoms", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": "5", "drugtreatmentdurationunit": "804", "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "078169", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Neuropsychiatric symptoms", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "3", "drugtreatmentdurationunit": "804", "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "077670", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Neuropsychiatric symptoms", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": "5", "drugtreatmentdurationunit": "804", "medicinalproduct": "SERTRALINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Neuropsychiatric symptoms", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": "10", "drugtreatmentdurationunit": "804", "medicinalproduct": "ARIPIPRAZOLE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Neuropsychiatric symptoms", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": "10", "drugtreatmentdurationunit": "804", "medicinalproduct": "OLANZAPINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Neuropsychiatric symptoms", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": "8", "drugtreatmentdurationunit": "804", "medicinalproduct": "RISPERIDONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, (2 DOSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Respiratory symptom", "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": "52", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Austgen G, Meyers MS, Gordon M, Livingston R. The use of electroconvulsive therapy in neuropsychiatric complications of coronavirus disease 2019: a systematic literature review and case report. Journal of the Academy of Consultation-Liaison Psychiatry. 2022;63(1):86-93", "literaturereference_normalized": "the use of electroconvulsive therapy in neuropsychiatric complications of coronavirus disease 2019 a systematic literature review and case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220423", "receivedate": "20220423", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20742064, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220720" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-333820", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91038", "drugbatchnumb": null, "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": "OLANZAPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "91038", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Psychotic disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "SERTRALINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Psychotic disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE" } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Austgen G, Meyers MS, Gordon M, Livingston R. The Use of Electroconvulsive Therapy in Neuropsychiatric Complications of Coronavirus Disease 2019: A Systematic Literature Review and Case Report. J Acad Consult Liaison Psychiatry. 2022;63(1):86-93", "literaturereference_normalized": "the use of electroconvulsive therapy in neuropsychiatric complications of coronavirus disease 2019 a systematic literature review and case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220426", "receivedate": "20220426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20748686, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]
{ "abstract": "Progressive outer retinal necrosis is a necrotizing herpetic retinopathy usually seen in immunocompromised patients. The authors describe two patients with this disease who initially had findings suggestive of an optic neuropathy. Vision declined after treatment with methylprednisolone, after which fundus examination became consistent with progressive outer retinal necrosis. These cases underscore the importance of careful examination of the retinal periphery before management of any presumed optic neuropathy with steroids.", "affiliations": "Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA.", "authors": "Nakamoto\|B K\|BK\|;Dorotheo\|E U\|EU\|;Biousse\|V\|V\|;Tang\|R A\|RA\|;Schiffman\|J S\|JS\|;Newman\|N J\|NJ\|", "chemical_list": "D000998:Antiviral Agents; D017245:Foscarnet; D011241:Prednisone; D000212:Acyclovir; D008775:Methylprednisolone", "country": "United States", "delete": false, "doi": "10.1212/01.wnl.0000147263.89255.b8", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-3878", "issue": "63(12)", "journal": "Neurology", "keywords": null, "medline_ta": "Neurology", "mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000212:Acyclovir; D000328:Adult; D000998:Antiviral Agents; D003586:Cytomegalovirus Infections; D017726:Cytomegalovirus Retinitis; D003951:Diagnostic Errors; D004172:Diplopia; D018450:Disease Progression; D018792:Encephalitis, Viral; D005260:Female; D017245:Foscarnet; D006562:Herpes Zoster; D006801:Humans; D008279:Magnetic Resonance Imaging; D008775:Methylprednisolone; D008875:Middle Aged; D009336:Necrosis; D009902:Optic Neuritis; D010291:Paresis; D011241:Prednisone; D012160:Retina", "nlm_unique_id": "0401060", "other_id": null, "pages": "2423-5", "pmc": null, "pmid": "15623719", "pubdate": "2004-12-28", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.; D016454:Review", "references": null, "title": "Progressive outer retinal necrosis presenting with isolated optic neuropathy.", "title_normalized": "progressive outer retinal necrosis presenting with isolated optic neuropathy" }	[ { "companynumb": "US-ACTAVIS-2016-00671", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OPTIC NEUROPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE ACETATE (WATSON LABORATORIES)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "080356", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OPTIC NEUROPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE (WATSON LABORATORIES)" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Necrotising herpetic retinopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NAKAMOTO BK, DOROTHEO EU, BIOUSSE V, TANG RA, SCHIFFMAN JS, NEWMAN NJ. PROGRESSIVE OUTER RETINAL NECROSIS PRESENTING WITH ISOLATED OPTIC NEUROPATHY. NEUROLOGY. 2004?63(12):2423-5.", "literaturereference_normalized": "progressive outer retinal necrosis presenting with isolated optic neuropathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160119", "receivedate": "20160119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11926568, "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": "US-ACTAVIS-2016-00670", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTABLE SUSPENSION", "drugdosagetext": "1 G, DAILY( 2 COURSES OF 3 DAYS EACH)", "drugenddate": null, "drugenddateformat": null, "drugindication": "OPTIC NEUROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE ACETATE (WATSON LABORATORIES)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "080356", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "70 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "OPTIC NEUROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE (WATSON LABORATORIES)" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Necrotising herpetic retinopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NAKAMOTO BK, DOROTHEO EU, BIOUSSE V, TANG RA, SCHIFFMAN JS, NEWMAN NJ. PROGRESSIVE OUTER RETINAL NECROSIS PRESENTING WITH ISOLATED OPTIC NEUROPATHY. NEUROLOGY. 2004?63(12):2423-5.", "literaturereference_normalized": "progressive outer retinal necrosis presenting with isolated optic neuropathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160119", "receivedate": "20160119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11926586, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]
{ "abstract": "Since the introduction of targeted therapies, prognosis in human epidermal growth factor receptor (HER) 2-positive metastatic breast cancer (MBC) has radically changed. The addition of Pertuzumab to Trastuzumab and standard chemotherapy has further increased patients' overall survival (OS). However, there is no agreement regarding the optimal duration of trastuzumab therapy in selected patients achieving long-term complete remission. In addition, no potential factors of long-term benefit have been identified yet. In the present study, we report the case of a MBC woman who was successfully treated with trastuzumab for over 10 years. At the time of diagnosis (February 2005), she revealed lung, nodal and bone metastases. Therefore, a first-line chemotherapy with Epirubicine and Docetaxel was administered for 6 cycles and then the patient started Trastuzumab plus hormonal therapy until reaching a sensible reduction of mammary lump and disappearance of distant metastases. Following a multidisciplinary evaluation, in November 2006, the patient underwent radical mastectomy and axillary dissection, achieving a complete remission. She continued Trastuzumab until September 2015 (for a total of 156 cycles) when a pleural diffusion was demonstrated. Long-term survival during anti-HER2 treatment remains a rare and optimal situation. Currently, no data exist to support trastuzumab interruption in this setting and collaborative efforts to better analyze the characteristics of long-responder patients are needed. Data regarding prognostic factors in this setting are relatively confusing. Our review reveals that hormonal receptor (HR)-positive disease is associated with a better prognosis, whereas the role of visceral spread differs by single or dual target anti HER2-inhibition. The introduction of Pertuzumab is raising concerns in terms of toxicity and its cost effectiveness. While waiting for novel molecular data and randomized trials, available evidence advocates continuous use of anti-HER2 therapies until disease progression or development of side effects.", "affiliations": "Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.", "authors": "Cantini\|Luca\|L\|;Pistelli\|Mirco\|M\|;Savini\|Agnese\|A\|;Bastianelli\|Lucia\|L\|;Della Mora\|Arianna\|A\|;Merloni\|Filippo\|F\|;Burattini\|Michela\|M\|;Berardi\|Rossana\|R\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3892/mco.2017.1495", "fulltext": null, "fulltext_license": null, "issn_linking": "2049-9450", "issue": "8(1)", "journal": "Molecular and clinical oncology", "keywords": "HER2; breast cancer; long-term survival; maintenance; pertuzumab; trastuzumab", "medline_ta": "Mol Clin Oncol", "mesh_terms": null, "nlm_unique_id": "101613422", "other_id": null, "pages": "147-152", "pmc": null, "pmid": "29387408", "pubdate": "2018-01", "publication_types": "D016428:Journal Article", "references": "24743708;18038883;27964843;23072512;26456898;25511015;24368024;23602601;27522517;25378932;22149875;24104881;23676508;22767587;17074677;11248153;22997442;24799465;26040825;21143954;26875184;25371387;25693012;28327998", "title": "Long-responders to anti-HER2 therapies: A case report and review of the literature.", "title_normalized": "long responders to anti her2 therapies a case report and review of the literature" }	[ { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-160572", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FEMARA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/KG EVERY 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/KG, EVERY 3 WEEKS, GLOBALLY 156 CYCLES FOR MORE THAN 10 YEARS", "drugenddate": "201509", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADO-TRASTUZUMAB EMTANSINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TDM-1" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG/KG FIRST DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200606", "drugstartdateformat": "610", "drugstructuredosagenumb": "8", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug effect incomplete", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CANTINI L, PISTELLI M, SAVINI A, BASTIANELLI L, MORA AD, MERLONI F, ET AL. LONG-RESPONDERS TO ANTI-HER2 THERAPIES: A CASE REPORT AND REVIEW OF THE LITERATURE. MOL-CLIN-ONCOL. 2018?8:147-152", "literaturereference_normalized": "long responders to anti her2 therapies a case report and review of the literature", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180206", "receivedate": "20180120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14414313, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]
{ "abstract": "Patients with advanced and/or metastatic solid tumors have limited treatment options. Mutations that serve as biomarkers of carcinogenesis can be found in cell-free DNA of patients' plasma. Analysis of circulating tumor DNA (ctDNA) was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is not technically feasible or it is associated with high risk for complications. The role of ctDNA in precision oncology is promising but its clinical significance across tumor types remains to be validated. We report a case series of three heavily pretreated patients with advanced solid tumors who received matched targeted therapy based on ctDNA analysis and/or tumor molecular profiling.\nThree patients with advanced, metastatic cancer and the following characteristics are presented: a 71-year-old woman with ovarian cancer and BRCA2 mutation identified in ctDNA and tumor tissue was treated with a PARP inhibitor and achieved partial response by RECIST (Response Evaluation Criteria in Solid Tumors) for 22.6+ months; a 40-year-old woman with adenoid cystic carcinoma of the parotid gland was treated with a MEK/RAF pathway inhibitor on the basis of RAF1 amplification on ctDNA analysis and had stable disease for 20.2 months; and a 56-year-old woman with breast cancer and a BRCA1 mutation identified by ctDNA analysis was treated with a PARP inhibitor and achieved stable disease for 9.1 months. All three patients are alive at the time of this report.\nThese results suggest that ctDNA analysis can contribute to selection of targeted therapy in patients with advanced, metastatic cancer. Prospective clinical trials to evaluate and optimize ctDNA biomarkers, as well as the integration of novel and/or alternative targeted therapies, are warranted to fully assess the role of ctDNA analysis in cancer therapy.\nwww.clinicaltrials.gov (NCT02152254). Registered May 28, 2014. https://www.clinicaltrials.gov/ct2/show/NCT02152254. MD Anderson protocol # PA12-1161 (approval ID IRB1 FWA00000121) and # PA11-0377 (approval ID IRB4 FWA00005015).", "affiliations": "Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Abdominal Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030, USA.", "authors": "Naqvi\|Mohammad Faraz\|MF\|;Vo\|Henry Hiep\|HH\|;Vining\|David\|D\|;Tsimberidou\|Apostolia-Maria\|AM\|https://orcid.org/0000-0003-2713-233X", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/17588359211001538", "fulltext": "\n==== Front\nTher Adv Med Oncol\nTher Adv Med Oncol\nTAM\nsptam\nTherapeutic Advances in Medical Oncology\n1758-8340\n1758-8359\nSAGE Publications Sage UK: London, England\n\n10.1177/17588359211001538\n10.1177_17588359211001538\nCase Series\nProlonged response to treatment based on cell-free DNA analysis and molecular profiling in three patients with metastatic cancer: a case series\nNaqvi Mohammad Faraz Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\n\nVo Henry Hiep Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\n\nVining David Department of Abdominal Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\n\nhttps://orcid.org/0000-0003-2713-233X\nTsimberidou Apostolia-Maria Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030, USA\n\[email protected]\n* These authors contributed equally to this work.\n\n24 3 2021\n2021\n13 1758835921100153819 1 2021\n10 2 2021\n© The Author(s), 2021\n2021\nSAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nBackground:\n\nPatients with advanced and/or metastatic solid tumors have limited treatment options. Mutations that serve as biomarkers of carcinogenesis can be found in cell-free DNA of patients’ plasma. Analysis of circulating tumor DNA (ctDNA) was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is not technically feasible or it is associated with high risk for complications. The role of ctDNA in precision oncology is promising but its clinical significance across tumor types remains to be validated. We report a case series of three heavily pretreated patients with advanced solid tumors who received matched targeted therapy based on ctDNA analysis and/or tumor molecular profiling.\n\nCase presentation:\n\nThree patients with advanced, metastatic cancer and the following characteristics are presented: a 71-year-old woman with ovarian cancer and BRCA2 mutation identified in ctDNA and tumor tissue was treated with a PARP inhibitor and achieved partial response by RECIST (Response Evaluation Criteria in Solid Tumors) for 22.6+ months; a 40-year-old woman with adenoid cystic carcinoma of the parotid gland was treated with a MEK/RAF pathway inhibitor on the basis of RAF1 amplification on ctDNA analysis and had stable disease for 20.2 months; and a 56-year-old woman with breast cancer and a BRCA1 mutation identified by ctDNA analysis was treated with a PARP inhibitor and achieved stable disease for 9.1 months. All three patients are alive at the time of this report.\n\nConclusions:\n\nThese results suggest that ctDNA analysis can contribute to selection of targeted therapy in patients with advanced, metastatic cancer. Prospective clinical trials to evaluate and optimize ctDNA biomarkers, as well as the integration of novel and/or alternative targeted therapies, are warranted to fully assess the role of ctDNA analysis in cancer therapy.\n\nTrial registration:\n\nwww.clinicaltrials.gov (NCT02152254). Registered May 28, 2014. https://www.clinicaltrials.gov/ct2/show/NCT02152254. MD Anderson protocol # PA12-1161 (approval ID IRB1 FWA00000121) and # PA11-0377 (approval ID IRB4 FWA00005015).\n\ncell-free DNA\ncirculating tumor DNA\ngenomic profiling\npersonalized therapy\nprecision medicine\ntargeted therapy\nnational institutes of health https://doi.org/10.13039/100000002 P30 CA016672 Donor funds from Jamie’s Hope, Mr. and Mrs. Zane W. Arrott, and Mr. and Mrs. Steven McKenzie for Dr. Tsimberidou’s Personalized Medicine Program cover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nGenomic alterations play an important role in carcinogenesis, disease progression, resistance and response to targeted therapy. The genetic heterogeneity across tumor types complicates the management of these diseases. Using the genomic profiles of individual patient tumors, precision medicine helps optimize treatment selection to improve clinical outcomes for patients with cancer.1 Mutations that serve as biomarkers of tumor progression and response can be found in cell-free DNA collected from the plasma of individual patients. Analysis of this circulating tumor DNA (ctDNA), therefore, offers a promising, non-invasive, and personalized diagnostic approach to selecting treatment and patients for enrollment in clinical trials.\n\nTumor biopsy samples are typically analyzed to determine the tumor characteristics, but biopsy is not feasible for some patients because their tumors are not easily accessible or because the biopsy procedure is associated with significant risk. Also, samples obtained from biopsies can be insufficient for tumor analysis. The proportion of patients who are ineligible for molecular screening due to inaccessibility or high risk of tumor biopsy, and therefore are excluded from certain clinical trials offering targeted treatment based on molecular alterations, has not been systematically analyzed. In the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) study, it was estimated that 10% to 15% of patients with lung cancer did not have sufficient material for next-generation molecular testing.2 In an interim analysis of IMPACT2, an ongoing randomized study evaluating genomic profiling and targeted agents in metastatic cancer, of 391 patients who were enrolled in the first part of the study, 19 (4.86%) patients had inadequate tumor cells for analysis and biopsy was not feasible or tumor was not accessible in 15 (3.84%) patients. Overall, 213 (54.48%) of 391 received anticancer therapy (Tsimberidou et al., Npj Precision Oncology, in Press).\n\nCtDNA analysis was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is associated with significant risk, when tumor tissue is insufficient or inaccessible, and/or when repeated assessment of tumor molecular abnormalities is needed to optimize treatment.3\n\nWe previously reviewed the role of ctDNA in guiding targeted therapy in clinical trials that involved ctDNA analysis of specific tumors and across tumor types.3 CtDNA analysis based on epidermal growth factor receptor (EGFR) and v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) has been well established for selecting treatment for patients with advanced non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), respectively.4,5 However, the assessment of ctDNA and clinical trials that involve ctDNA analysis in other tumor types are still needed. Herein, we describe encouraging clinical outcomes of three patients with advanced metastatic cancer who received matched targeted therapy based on the results of ctDNA analysis.\n\nCase presentation\n\nCase presentation 1: Patient (ID 001)\n\nA 71-year-old woman was diagnosed with metastatic ovarian cancer in October 2010. She had been experiencing symptoms of vaginal dryness, dyspareunia, and abdominal and lower back pain. Magnetic resonance imaging (MRI) of the pelvis demonstrated a complex adnexal mass and computed tomography (CT) imaging studies demonstrated a lesion in the upper lobe of the left lung, and an adenoma of the left adrenal gland. Transvaginal ultrasonography confirmed a multilocular mass (6.0 × 5.0 × 5.6 cm) centered in the right adnexal region. The mass had multiple irregular thick septa and a soft tissue component with definite vascular flow in the regions of echogenic soft tissue and was highly suggestive of cystadenocarcinoma. The patient underwent a laparoscopic bilateral salpingo-oophorectomy, and the surgical pathology report demonstrated ovarian high-grade serous carcinoma with extension to the fallopian tube surface and fimbrial end in the right ovary and tube, and metastatic to the omentum. In November 2010, the patient was treated with six cycles of carboplatin and paclitaxel followed by 11 cycles of paclitaxel consolidation therapy. CT imaging studies demonstrated no evidence of disease at 5 months after treatment and annually for 3 years. Three years after treatment, she presented to the clinic with increasing pain and pressure in the lower abdomen, including pain with urination. CT scans demonstrated diffuse peritoneal carcinomatosis, evidenced by multiple nodular masses noted within the peritoneum and the supracolic omentum, and small volume ascites. She was retreated with six cycles of carboplatin and paclitaxel, and restaging scans demonstrated improvement in the peritoneal carcinomatosis and no gross CT evidence of residual disease. She had no evidence of disease for 17 months, and then CT scans showed interval development of a heterogeneous soft tissue lesion in the pelvis compatible with recurrent disease. She underwent tumor reductive surgery followed by six cycles of carboplatin and paclitaxel. Molecular analysis using formalin-fixed paraffin-embedded (FFPE) tissue of the most recently resected pelvic mass demonstrated tumor protein p53 (TP53) mutation and breast cancer type 2 (BRCA2) somatic mutation (Table 1). The disease responded to treatment with carboplatin and paclitaxel but recurred after 20 months and the patient was referred to the Department of Investigational Cancer Therapeutics in July 2017. She was enrolled on a clinical trial that included carboplatin, paclitaxel and immunotherapy. Her best response was immune-related partial response (PR). On cycle 19, day 22, CT images demonstrated increasing size and number of nodules within the peritoneum consistent with increasing metastatic disease; a growing metastasis was also noted in segment five of the liver. ctDNA analysis performed 13 months prior to disease progression demonstrated the following alterations: neurofibromin 1 (NF1), splice site SNV 1.9, TP53 V157F 0.2, guanine nucleotide binding protein, alpha stimulating activity polypeptide (GNAS) R201H 0.2, BRCA2 R3052W 0.1 (Table 1). On the basis of this information and evidence of a BRCA2 somatic mutation in the pelvic mass, the patient was enrolled on a clinical trial of a poly (ADP-ribose) polymerase (PARP) inhibitor administered daily. She underwent genetic counseling, and testing for germline BRCA1 and BRCA2 mutations was negative. Thus far, she has received 21 cycles of the PARP inhibitor, and her best RECIST response was PR (76% decrease from baseline per RECIST 1.1) (Figure 1). Her treatment is ongoing [progression-free survival (PFS) = 22.6+ months] (Table 2). The patient experienced grade 3 anemia that started during cycle 3 and was treated with transfusion of red blood cells (average, 2 units monthly). On cycle 7, day 1, she required a dose adjustment consisting of a 25% reduction in the PARP inhibitor dose and a decrease of days of treatment to 3 weeks on, 1 week off, after which she tolerated the treatment without the need for transfusion.\n\nTable 1. Genomic analysis using tissue and ctDNA samples.\n\nPt. ID\tCollection date\tSample source\tGenomic alterations\tPanel, no. of clinically relevant genes\t\n001\t16 June 2015\tPelvic mass\tTP53 V157F\tSolid tumor genomic assay V2, 146 genes\t\n\t\t\tBRCA2 R3052W\t\t\n\t20 July 2017\tBlood\tBRCA2 R3052W\tGuardant360, 73 genes\t\n\t\t\tNF1 splice site\t\t\n\t\t\tTP53 V157F\t\t\n\t\t\tGNAS R201H\t\t\n002\t21 July 2017\tBlood\tRAF1 amplification\tGuardant360, 73 genes\t\n\t25 September 2017\tLiver\tNone\tSolid tumor genomic assay V1, 134 genes\t\n\t22 November 2019\tLiver\tBRAF V600dup\tTempus × T assay, 596 genes\t\n\t\t\tMYB-NFIB chromosomal rearrangement\t\t\n\t\t\tKMT2D Q2696 Stop gain – LOF\t\t\n003\t29 January 2015\tLung\tATM loss exons 57–63\tFoundationOne, 315 genes\t\n\t\t\tNOTCH2 A3F\t\t\n\t\t\tESR1 Y537S\t\t\n\t\t\tCCND1 amplification\t\t\n\t\t\tEMSY amplification\t\t\n\t\t\tFGF19 amplification\t\t\n\t\t\tFGF3 amplification\t\t\n\t\t\tFGF4 amplification\t\t\n\t\t\tMCL1 amplification - equivocal\t\t\n\t15 October 2018\tBlood\tATM M3011T\tLiquid biopsy panel, 70 genes\t\n\t\t\tBRCA1 Q356\t\t\n\t\t\tESR1 Y537S\t\t\n\t\t\tTP53 A159V\t\t\n\t\t\tTP53 P152L\t\t\nATM, ATM serine/threonine kinase; BRAF, rapidly accelerated fibrosarcoma homolog B; BRCA1, breast cancer type 1; BRCA2, breast cancer type 2; CCND1, Cyclin D1; EMSY, BRCA2 interacting transcriptional repressor; ESR1, estrogen receptor 1; FGF, fibroblast growth factor; GNAS, guanine nucleotide binding protein, alpha stimulating activity polypeptide; KMT2D, histone-lysine N-methyltransferase 2D; LOF, loss of function; MCL1, myeloid cell leukemia 1; MYB-NFIB, myeloblastosis virus oncogene – nuclear factor 1 B-type; NF1, neurofibromatosis type 1; NOTCH2, notch receptor 2; RAF1, rapidly accelerated fibrosarcoma 1; TP53, tumor protein p53.\n\nMolecular alterations identified by ctDNA analysis and used to select matched therapy are presented in bold text.\n\nTable 2. Clinical outcomes of three patients with advanced solid tumors who received matched therapy based on ctDNA analysis.\n\nPt. ID\tctDNA biomarker\tMatched therapy\tBest RECIST response\tPFS, months\tProgr.status\tSubsequent Rx\tSurvival status\tOS†, months\t\n001\tBRCA2 R3052W\tPARP inhibitor\tPR\t22.6+\tN/A\tN/A\tAlive\t22.6+\t\n002\tRAF1 amplification\tMEK/RAF pathway inhibitor\tSD\t20.2\tPD\tInvestigational\tAlive\t28.4+\t\n003\tBRCA1 Q356\tPARP inhibitor\tSD\t9.1\tPD\tDoxorubicin; radiotherapy\tAlive\t14.8+\t\nN/A, non-applicable; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; Progr., progression; Rx, therapy; SD, stable disease.\n\nBRAC1, breast cancer type 1; BRAC2, breast cancer type 2; MEK, mitogen-activated protein kinase kinase; PARP, poly (ADP-ribose) polymerase; RAF1, rapidly accelerated fibrosarcoma 1.\n\n Progression-free survival is measured in months from cycle 1, day 1 to time of radiologic scan showing progressive disease.\n\n† Overall survival is measured in months from cycle 1, day 1 to the most recent time of this report.\n\nFigure 1. Changes in tumor measurement from baseline in patient 001, who underwent treatment with PARP inhibitor on the basis of ctDNA analysis showing BRCA2 R3052W mutation. (a) Scatter plot illustrates changes in lesion tumor burden. Computed tomography (CT) scan data at the most recent time prior to cycle 1, day 1 is chosen as baseline (time 0). The horizontal (x) axis shows time at restaging CT scans as months from baseline. The vertical (y) axis shows percentage of change in tumor measurement from baseline. Each dot represents a data point collected at each restaging CT scan. The blue line represents PR (⩾30% decrease in tumor measurements from baseline, based on RECIST 1.1). (b) Scatter plot illustrates changes in tumor marker levels over time. (c) Representative CT images from the patient at baseline. (d) Representative CT images from the patient after 20.6 months of targeted therapy with PARP inhibitor.\n\nRed arrows indicate target lesions.\n\nCase presentation 2: Patient (ID 002)\n\nA 40-year-old woman was first diagnosed in 2007 with adenoid cystic carcinoma of the left parotid gland and bone metastases. She was a non-smoker and had a pertinent family history of multiple cancers, notably of the brain, stomach, and skin. The patient underwent superficial parotidectomy with apparently negative margins followed by post-operative adjuvant radiotherapy. Subsequent imaging revealed a lytic lesion at the L3 vertebral body; biopsy did not demonstrate metastatic tumor. She had no evidence of disease until 2013, when a positron emission tomography (PET)/CT revealed increased activity in the L3 vertebra. The patient experienced back pain while lifting heavy objects or when the lesion was percussed, post-operative paresthesia in the lobule and tragus of the left ear and stiffening of the left neck. In October 2013, she received stereotactic radiation therapy to the L3 vertebra (24 Gy to the gross tumor volume and 16 Gy to the clinical target volume). Three months later, PET/CT imaging studies demonstrated no evidence of FDG-avid metastasis.\n\nShe had no evidence of active disease for 33 months, until October 2016, when MRI and PET/CT imaging studies demonstrated left pulmonary metastasis, an enlarging lesion at L3–L4 consistent with progressive disease. She was referred to the Department of Investigational Cancer Therapeutics in February 2017. She was treated with an investigational combination therapy comprising a STAT3 inhibitor and nivolumab for eight cycles. Her best RECIST response was stable disease (SD), with a 13% decrease in tumor measurements from baseline to cycle 3, day 26 (RECIST 1.1). She was taken off protocol in July 2017 owing to disease progression that included liver metastases. Possibly related adverse events included grade 1 diarrhea and abdominal cramps.\n\nMolecular diagnostic solid tumor genomic assay using FFPE slides from a liver biopsy performed in September 2017 did not identify any somatic mutations (Table 1). However, ctDNA analysis using the patient’s blood sample demonstrated a strongly positive rapidly accelerated fibrosarcoma 1 (RAF1) amplification, with a magnitude in the 50th to 90th percentile (Table 1). On the basis of this finding, the patient was started on a clinical trial with a mitogen-activated protein kinase kinase/ rapidly accelerated fibrosarcoma (MEK/RAF) pathway inhibitor in January 2018. Her best RECIST response was SD with an 18% decrease in tumor measurements (RECIST 1.1) after 10 cycles (Figure 2). She received 29 cycles of the study drug and was taken off study owing to progressive disease confirmed by CT imaging studies. PFS duration was 20.2 months and overall survival duration was 28.4+ months. Adverse events possibly associated with MEK/RAF pathway inhibitor were all grade 1 and included intermittent diarrhea and vomiting; maculopapular and acneiform rash; neutropenia; blurry vision; and hair thinning.\n\nFigure 2. Changes in tumor measurement from baseline in patient 002, who underwent treatment with MEK/RAF pathway inhibitor on the basis of ctDNA analysis showing RAF1 amplification. (a) Representative computed tomography (CT) images from the patient at baseline. (b) Representative CT images from the patient after 6.8 months of treatment with MEK/RAF pathway inhibitor.\n\nRed arrows indicate target lesions.\n\nIn November 2019, the patient underwent a core needle biopsy of the liver for completion of molecular profiling, which demonstrated rapidly accelerated fibrosarcoma homolog B (BRAF) V600dup and myeloblastosis virus oncogene – nuclear factor 1 B-type (MYB-NFIB) chromosomal rearrangement, biologically relevant histone-lysine n-methyltransferase 2D (KMT2D) genomic variant, negative programmed death-ligand 1 (PDL1) expression, normal DNA mismatch repair protein expression, and RNA sequencing demonstrating fibroblast growth factor receptor 2 (FGFR2) and fibroblast growth factor receptor 1 (FGFR1) overexpression (Table 1). Two months later, she underwent transcatheter arterial hepatic embolization of the larger liver metastases. The patient was alive at the time of this report (Table 2). She did not experience any serious adverse events and did not require any blood transfusions.\n\nCase presentation 3: Patient (ID 003)\n\nA 56-year-old woman with a history of breast cancer was referred to the Department of Investigational Cancer Therapeutics in January 2015. She had no pertinent medical history and was in good health until early 2005, when she felt a mass in her left breast. She was a non-smoker and had a family history of breast cancer and prostate cancer. Physical examination demonstrated a 3 × 3 cm mass in the 10 to 11-o’clock position in the superior aspect of the left breast and a 2 cm lymph node in the left axilla. Ultrasound-guided core needle biopsy performed in February 2005 demonstrated an estrogen receptor- and progesterone receptor-positive, human epidermal growth factor receptor 2 (HER-2/neu)-negative invasive mammary carcinoma of the left breast [modified Black’s nuclear grade 1 (well differentiated)], carcinoma in situ, low grade, solid type, without necrosis). CT scans indicated no evidence of metastasis; however, fine-needle aspiration of the left axilla lymph nodes demonstrated metastatic carcinoma consistent with the primary breast tumor.\n\nIn March 2005, the patient was enrolled on a clinical trial that included weekly paclitaxel chemotherapy for 12 cycles followed by six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide. Four months later, imaging studies indicated a reduction in tumor size. In September 2005, she underwent a left skin-sparing total mastectomy with axillary lymph node dissection followed by delayed reconstruction using a submuscular tissue expander. Then, from October to December 2005, she underwent post-operative adjuvant radiation therapy (50 Gy in 25 fractions to the left central chest and left lateral chest wall with an additional 10 Gy boost to the tumor bed). She also intermittently received Tamoxifen between 2005 and 2008. In December 2006, imagining studies demonstrated bone metastasis and the patient was treated with radiation therapy and anastrozole plus fulvestrant from December 2006 to March 2014. The bone disease stabilized, but she had disease progression in her lungs and lymph nodes. Although her tumor did not harbor an alteration in the PI3K/Akt/mTOR pathway, she was treated with the standard-of-care exemestane and everolimus from March 2014 to January 2015.\n\nIn January 2015, CT scans demonstrated increasing thoracic lymphadenopathy and pulmonary metastatic disease, and a nuclear medicine bone scan demonstrated bone metastasis involving the left ilium, acetabulum, and ischium. The patient was referred to the Department of Investigational Cancer Therapeutics in January 2015 and underwent biopsy of a lung tumor. Molecular profiling of the tumor demonstrated the following genomic alterations: ATM serine/threonine kinase (ATM) loss in exons 57 to 63, notch receptor 2 (NOTCH2) A3F, estrogen receptor 1 (ESR1) Y537S, and amplification of the following genes: cyclin D1 (CCND1), myeloid cell leukemia 1 (MCL1), BRCA2 interacting transcriptional repressor (EMSY), fibroblast growth factor 19 (FGF19), fibroblast growth factor 3 (FGF3), and fibroblast growth factor 4 (FGF4) (Table 1). Early assessments suggested that preclinical models with increased cyclin D1 or cyclin-CDK-Rb pathway activation may have increased sensitivity to CDK4/6 inhibitors.6,7 However, the patient did not receive a CDK4/6 inhibitor because clinical trials were not available at that time. She was presented at the multidisciplinary conference for optimization of treatment selection. On the basis of tumor molecular profiling demonstrating multiple mutations in FGF (FGF19, FGF3, and FGF4), the patient was offered an investigational therapy comprising FGFR inhibitor, but she pursued treatment with eribulin; after four cycles she developed disease progression. Subsequently, she was treated with 11 cycles of fulvestrant and palbociclib and was taken off study owing to progressive disease in August 2017.\n\nOn the basis of her tumor’s NOTCH2 A3F alteration, in October 2017, the patient was enrolled on a clinical trial consisting of a NOTCH inhibitor, cisplatin, and gemcitabine. Her best RECIST response was PR per RECIST 1.1 criteria on cycle 12, day 19. She received 22 cycles of the investigational drug combination for 19 months and was taken off study owing to disease progression. Adverse events included impaired hearing and thrombocytopenia.\n\nThe patient underwent genetic counseling, and testing for germline BRCA1 and BRCA2 mutations was negative. CtDNA analysis in October 2018 demonstrated multiple somatic mutations which included a breast cancer type 1 (BRCA1) nonsense mutation on exon 10 (Table 1). On the basis of these findings, the patient was enrolled on a clinical trial with a PARP inhibitor. Her best RECIST response was SD with a 14% decrease in tumor measurement from baseline per RECIST 1.1, and the PFS duration was 9.1 months (Figure 3 and Table 2). Imaging studies in January 2020 demonstrated evidence of progressive disease and she was taken off study. Subsequently, she received radiotherapy and doxorubicin. At the time of this report, the patient was still alive, and the overall survival duration was 14.8+ months (Table 2).\n\nFigure 3. Changes in tumor measurement from baseline in patient 003, who underwent treatment with PARP inhibitor on the basis of ctDNA analysis showing BRCA1 Q356* mutation. (a) Representative computed tomography (CT) images from the patient at baseline. (b) Representative CT images from the patient after 6.5 months of treatment with PARP inhibitor. (c) Representative positron emission tomography (PET) overview image from the patient at baseline. (d) Representative PET overview image from the patient after 6.5 months of treatment with PARP inhibitor.\n\nRed arrows indicate target lesions.\n\nDiscussion and conclusions\n\nThe clinical significance of ctDNA analysis is evolving. The FDA has approved the use of next-generation sequencing (NGS) analysis as a companion diagnostic device for multiple biomarkers detected by ctDNA analysis using plasma specimens of patients with NSCLC (EGFR mutations for the use of gefitinib, osimertinib and erlotinib; and ALK rearrangements for treatment with alectinib), prostate (BRCA1 and BRCA2 alterations for the use of rucaparib and olaparib; and ATM alterations for the use of olaparib), ovarian (BRCA1 and BRCA2 alterations for the use of rucaparib), and breast cancer (PI3K mutations for the use of alpelisib). CtDNA analysis is also used for KRAS in CRC5 and in the management of resistance to ALK inhibitors in lung cancer.8 However, ctDNA analysis has not been systematically validated for patients with other tumor types. If the specific genomic alterations associated with these FDA-approved drugs are not detected in the blood, then tumor biopsies should be performed to identify these alterations.\n\nIn this case series, the use of ctDNA analysis alone or in combination with tumor molecular profiling was associated with encouraging clinical outcomes in three patients with advanced, metastatic cancer treated with targeted therapy. One patient had a durable PR of 22.6+ months as evidenced by CT imaging and tumor marker monitoring (Figure 1); the other two patients had SD lasting for 20.2 months and 9.1 months, respectively (Table 2). Our data demonstrate that in heavily pretreated patients with advanced, metastatic cancer, targeted therapy selected on the basis of ctDNA and/or tumor genomic analysis was associated with encouraging results. Our observation emphasizes the need to systematically analyze ctDNA in correlation with tumor genomic analysis. Further, the role of ctDNA analysis should be assessed in prospective clinical trials for selection of personalized therapy in individual patients.\n\nIn our study, patient ID 002, who received MEK/RAF pathway inhibitor on the basis of ctDNA analysis demonstrating a strongly positive RAF1 amplification, had disease stabilization for 20.2 months and overall survival (OS) >28.4+ months. Genomic analysis using tumor biopsy also demonstrated BRAF_V600dup alteration. Tumor harboring both RAF amplification and BRAF V600dup may have sensitivity to treatment with MEK/RAF inhibitors, and our results warrant further investigation. There is minimal evidence on RAF1 amplification and enhanced tumor response to targeted therapies. Overexpression of RAF1 promotes c-Raf signaling in vitro, and preclinical studies have suggested that tumors with activating c-Raf signaling may be more sensitive to MEK inhibition.9–11 Tumors with RAF1 amplification therefore might benefit from MEK inhibitor therapy. Studies conducted by other investigators in a phase III, randomized clinical trial demonstrated that patients with melanoma harboring either RAF1, KRAS or CCND1 amplification who received carboplatin, paclitaxel, and sorafenib, had a longer OS and PFS compared with only carboplatin and paclitaxel.12 The outcomes were attributed to targeting of RAF1 by sorafenib. Hence, it is possible that RAF1 amplification in this tumor type might sensitize cells to sorafenib and other multi-tyrosine kinase inhibitors.\n\nBRAF_V600dup has been reported to be an activating alteration. This alteration is a duplication of codon V600, a “hotspot” codon located within the BRAF kinase domain (amino acids 457–717), which is commonly mutated in cancer. Codon V600 is important for maintaining the Asp-Phe-Gly (DFG) motif of BRAF in an inactive state.13 Alterations at codon V600 increase BRAF activity by stabilizing the active conformation of BRAF. Several studies conducted by other investigators demonstrated that multiple missense mutations at V600 promote constitutive activation of BRAF and alterations at K601 and T599I promote BRAF kinase activity.13–17 These alterations and other overlapping deletion and/or insertion events have been reported to be activating in vitro as evidenced by the activation of BRAF kinase activity, increase in MEK and ERK signaling, and transformation in NIH-3T3 cells.18\n\nThe effect of BRAF inhibitors on tumors harboring activating non-BRAF V600 mutations is unclear. Limited preclinical data suggest that the majority of non-BRAF V600 mutations are associated with decreased response or resistance to BRAF inhibitors, vemurafenib and dabrafenib.19,20 In contrast, other investigators reported that activating non-V600 variants may retain some sensitivity to dabrafenib.21 Some preclinical data indicate that MEK and ERK inhibitors may be effective for tumors harboring non-BRAF V600 mutations.21–23\n\nPlasma ctDNA analysis may address tissue heterogeneity by capturing somatic alterations that represent multiple metastatic sites; therefore, it may be more informative than tissue molecular profiling. These alterations may indicate tumor sensitivity to targeted therapies or resistance to treatment. ctDNA analysis is associated with a shorter turnaround time compared with tumor tissue molecular analysis and eliminates the risks associated with invasive biopsies. Identification of tumor genomic alterations using ctDNA analysis also may help select patients for enrollment in clinical trials.\n\nThe use of different panels and genomic assays in our study may contribute to the differences in molecular alterations found in tumor biopsy versus ctDNA. Other factors may include the methodology used for genomic assays, tumor heterogeneity, and tumor burden at the time of diagnosis and at the time of disease progression. Notably, in patient ID 002, RAF1 amplification detected using ctDNA analysis was not found in tumor analysis (Table 1). The results are consistent with the concept that ctDNA analysis may be more representative of the overall tumor molecular profiling, regardless of the location of the tumor.\n\nThe practice of ordering ctDNA analysis when response to ongoing therapy starts to wane may allow for optimized treatment selection without delay at the time of disease progression. Patients with advanced, metastatic cancer typically have a higher total systemic tumor burden compared with that of patients with early stage disease and, therefore, higher ctDNA levels.24 For instance, in CRC, the ctDNA levels decreased after tumor resection and generally increased with the presentation of new lesions evidenced by imaging scans.24\n\nCtDNA analysis and selected targeted treatments have been well established4,5,25,26 in CRC and NSCLC, and the concordant rates between ctDNA and matched tissue biopsies across other advanced/metastatic solid tumors range from 48% to 100%. The respective published data include patients with breast cancer,27 castration-resistant prostate cancer,28 pancreatic cancer,29 neuroblastoma,30 and melanoma.31\n\nAnalysis of ctDNA and tumor tissue samples in patients with metastatic breast cancer using droplet digital polymerase chain reaction analysis reported an overall concordance rate of 74.3% in ESR1 mutation status,27 indicating acquired resistance to endocrine therapy.27 In patients with metastatic, castration-resistant prostate cancer, the concordance between ctDNA and matched metastatic tissue biopsies was 100% in somatic mutations and 88.9% for individual copy number calls of the driver genes androgen receptor (AR), BRCA2, ATM, phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), TP53, and RB transcriptional corepressor 1 (RB1).28 In patients with advanced pancreatic ductal adenocarcinoma, the concordance rates between ctDNA and tumor tissue DNA alterations were 61% for TP53 and 52% for KRAS mutations.29 For KRAS alterations, concordance between ctDNA and tumor tissue DNA was significantly higher for metastatic than for primary tumors.29\n\nOne 83-year-old male patient with advanced pancreatic ductal adenocarcinoma (PDAC) treated with trametinib based on evidence of MEK pathway (GNAS, KRAS, and NF1) mutations, remained on treatment for 6+ months; although he was unable to undergo CT due to renal insufficiency, the levels of total ctDNA and CA19-9 significantly decreased.29\n\nIn patients with neuroblastoma, the concordance rate between ctDNA and tumor tissue for one of three anaplastic lymphoma kinase (ALK) mutational hotspots, the ALK F1174L mutation, was 100%.30 In patients with metastatic melanoma, the concordance rate between ctDNA from plasma compared with tumor tissue ranged from 75% to 100% (average, 89%).31\n\nSerial monitoring of ctDNA can be used to assess clonal evolution, predict progressive disease, and identify resistant clones. Other investigators have reported on ctDNA analysis in diverse solid tumors including advanced breast, ovarian, lung, and colorectal cancers.32–35 CtDNA clonal mutations were assessed to monitor tumor burden and disease progression in patients with advanced gastric cancer.36 For instance, serial monitoring of ctDNA samples from patients with gastric cancer and evaluation of the molecular tumor burden index (mTBI) identified progressive disease a mean of 18 weeks before it was seen on radiographic results. In patients who received anti-HER2 therapy, ctDNA analysis identified 32 expanding mutations potentially related to trastuzumab resistance. In patients who received chemotherapy, prediction of progressive disease using mTBI was validated with 94% sensitivity. Higher mTBI (⩾1%) in pre-treatment ctDNA was associated with shorter PFS.36\n\nMicrosatellite instability (MSI) and high tumor mutation burden (TMB-High) are promising pan-tumor biomarkers for the selection of patients to receive checkpoint blockade immunotherapy. Studies conducted by other investigators demonstrated the feasibility of using ctDNA analysis to assess MSI and TMB-high status.37,38 However, sensitive detection of MSI using ctDNA is still in early phases of development owing to technical and bioinformatics challenges including efficient molecular capture, sequencing, mapping, variant calling, error correction at microsatellite loci, the highly repetitive genomic context and low tumor fraction in circulation, high level of normal cell contamination, and technical noise due to polymerase slippage. Other factors affecting the accuracy of MSI detection using ctDNA and associated with discrepancies between studies include the number and type of microsatellite markers used, tumor cell fraction, and intratumor and intertumor heterogeneity.39 In patients with gastric cancer, high MSI status, as assessed by ctDNA analysis, was associated with favorable clinical response to immunotherapy.38 MSI detection using ctDNA sequencing demonstrated high specificity, precision, and sensitivity up to a limit of 0.1% tumor content. CtDNA analysis detected 87% of tissue with high MSI and 99.5% of microsatellite stable tissue, with an overall accuracy of 98.4% and a 95% positive predictive value. Objective responses were noted in 63% of these patients.38 Ongoing studies are investigating the role of ctDNA in assessment of MSI and TMB-high status as predictive biomarkers for the selection of checkpoint inhibitors.\n\nEncouraging results have been reported using ctDNA analysis to select targeted therapy across tumor types. The TARGET (Tumour chARacterisation to Guide Experimental Targeted therapy) study, which was initiated in 2015, matches patients with diverse advanced tumors to early-phase clinical trials based on the tumor molecular abnormalities identified by ctDNA analysis.40 In 100 patients (Part A) with advanced colorectal cancer, breast cancer, NSCLC, small-cell lung carcinoma, sarcoma, prostate cancer, cholangiocarcinoma, small bowel cancer, melanoma, adrenal cancer, solitary fibrous tumor, cancer of unknown primary, or other cancers, the concordance rate between mutations identified in ctDNA and in the tumor tissue was 70%. Genomic profiling of ctDNA using NGS identified actionable mutations in 41 patients, of whom 11 patients received a matched therapy and 17 patients received a non-matched therapy.40 Four of the 11 patients treated with targeted therapy had a PR lasting for 8, 12, 18, and 20 months, respectively; and four of the 17 patients treated with non-matched therapy had SD (no objective response was noted). The study is accruing patients in Part B with a planned enrollment of 450 patients over 3 years to compare clinical outcomes between matched and non-matched therapies.40 The TARGET study indicates the feasibility of using ctDNA analysis to guide targeted therapy in early-phase clinical trials. Notably, in August 2020, the FDA approved Guardant360 CDx, the first liquid biopsy companion diagnostic approved to provide information on multiple solid tumor biomarkers.41 In October and November 2020, the FDA also approved FoundationOne Liquid CDx test (Foundation Medicine, Inc.) as a companion diagnostic device for multiple additional biomarkers detected in cell-free DNA isolated from plasma specimens.42\n\nClinical trials that allow ctDNA analysis for selection of targeted therapy are in development, including the TAPUR (Targeted Agent and Profiling Utilization Registry) study, a non-randomized, open-label, multi-basket, pragmatic phase II precision oncology trial that integrates tumor genomic profiling using tumor biopsy and/or liquid biopsy to match patients with diverse advanced cancers to targeted anticancer agents outside of their FDA-approved indications (NCT02693535).43 The NEXT-2 [Next Generation pErsonalized tX (Therapy) with plasma DNA] trial is another ongoing prospective study being conducted in Korea that evaluates the role of ctDNA in refractory solid tumors (NCT02140463).44 The investigators reported that 30 (15.5%) of 195 patients who underwent comprehensive ctDNA genomic profiling were enrolled on clinical trials with matched therapy and noted objective responses in six of nine patients with gastric cancer, 13 of 15 patients with NSCLC, one of two patients with melanoma, and zero of one patient in the other tumor types category.44\n\nLimitations to ctDNA analysis are associated with discordance between ctDNA and tumor tissue genomic analysis due to biologic and technical differences (sensitivity and specificity), metastatic sites, histology, time of treatment administration prior to blood/plasma collection, low tumor burden, and absence of a primary tumor.25,45–47 CtDNA is secreted by tumor cells, phagocyte-engulfed tumor cells, and necrotic or apoptotic tumor cells, and therefore reflects tumor from all sites of disease.3 In addition, genomic analysis using only ctDNA may exclude other biomarkers. Analysis of circulating RNAs, circulating tumor cells, and exosomes may overcome this challenge.45\n\nIn conclusion, ctDNA and tumor profiling for treatment optimization for patients with advanced solid tumors requires greater precision. Although the role of ctDNA in guiding targeted treatments is well established in NSCLC and in CRC,4,5 the assessment of ctDNA and its clinical significance in other tumor types remains to be validated, despite some encouraging results. Prospective clinical trials involving ctDNA analysis and targeted agents are ongoing and/or awaiting results. ctDNA analysis at the time of diagnosis, or early evidence of progressive disease during ongoing treatment, will yield significant insights into the evolution of the patient’s tumor biology, accelerate drug development, and contribute to the implementation of precision medicine to improve clinical outcomes.\n\nWe thank the patients, their families, and caregivers for participating in the study.\n\nAuthors’ contributions: MFN and HHC contributed to literature search, data acquisition, data analysis, data interpretation and writing the manuscript. DV contributed to data acquisition, data analysis, data interpretation, and review of the manuscript. AMT (corresponding author) conceptualized the manuscript, contributed to patient enrollment, patient treatment and assessment, data analysis, data interpretation and writing the manuscript. All authors read and approved the final manuscript.\n\nFunding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by donor funds from Jamie’s Hope, Mr. and Mrs. Zane W. Arrott, and Mr. and Mrs. Steven McKenzie for Dr. Tsimberidou’s Personalized Medicine Program. This work was also supported in part by the National Institutes of Health/National Cancer Institute award number P30 CA016672 (University of Texas MD Anderson Cancer Center).\n\nConflict of interest statement: Apostolia M. Tsimberidou: Clinical Trial Research Funding/Grant Support: IMMATICS, Parker Institute for Cancer Immunotherapy, Tempus, OBI Pharma, EMD Serono, Baxalta, ONYX, Bayer, Boston Biomedical, Placon Therapeutics, Karus Therapeutics, Tvardi, CPRIT; Travel: ASCO, Japanese Society of Medical Oncology.\n\nConsulting or Advisory Role: Covance, Genentech, Tempus\n\nDavid J. Vining: Other ownership interests: VisionSR, Majority owner and CEO, multimedia structured reporting for use in advancing medical research; Bracco Diagnostics, Inventor, virtual colonoscopy-related products for colorectal cancer imaging.\n\nThe remaining authors have no competing interests.\n\nEthics approval and consent to participate: The protocol was approved by the FDA and the Institutional Review Board at The University of Texas MD Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All the study participants provided written informed consent before enrollment on the individual clinical trials in which they participated.\n\nConsent for publication: Patient consent for publication is not required. Patients consented to participate in the study.\n\nORCID iD: Apostolia-Maria Tsimberidou https://orcid.org/0000-0003-2713-233X\n\nAvailability of data and material: Data are available upon reasonable request. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request and approval from study sponsor and institution according to available guidelines at time of request.\n==== Refs\nReferences\n\n1 Said R Tsimberidou AM . Basket trials and the MD Anderson precision medicine clinical trials platform. Cancer J 2019; 25 : 282–286.31335392\n2 Tam AL Papadimitrakopoulou V Wistuba II , et al . The value of interventional radiology in clinical trial teams: experience from the BATTLE lung cancer trials. Clin Radiol 2021; 76 : 155.e25-155.e34.\n3 Said R Guibert N Oxnard GR , et al . Circulating tumor DNA analysis in the era of precision oncology. Oncotarget 2020; 11 : 188–211.32010431\n4 Oxnard GR Thress KS Alden RS , et al . 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RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study. Ann Oncol 2018; 29 : 1211–1219.29438522\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1758-8340", "issue": "13()", "journal": "Therapeutic advances in medical oncology", "keywords": "cell-free DNA; circulating tumor DNA; genomic profiling; personalized therapy; precision medicine; targeted therapy", "medline_ta": "Ther Adv Med Oncol", "mesh_terms": null, "nlm_unique_id": "101510808", "other_id": null, "pages": "17588359211001538", "pmc": null, "pmid": "33995588", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "31011204;19376813;31358542;26644315;26560360;22508966;26307133;31335392;20551065;31383735;10684259;19874578;23563269;29438522;19010912;33268083;31506389;29206995;27354477;32010431;22752848;10764150;21388974;28419195;31031019;28778025;25706985;28947956;15035987;25934077;31015557;30312528;31527165;25653133;24569458;32913970;18670422;16144912;21190184;29700206;24658074;28368441;31801585;15046639", "title": "Prolonged response to treatment based on cell-free DNA analysis and molecular profiling in three patients with metastatic cancer: a case series.", "title_normalized": "prolonged response to treatment based on cell free dna analysis and molecular profiling in three patients with metastatic cancer a case series" }	[ { "companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2021-00659", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201710", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "207575", "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": "201710", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE, UNKNOWN" } ], "patientagegroup": "5", "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoacusis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NAQVI M, VO H, VINING D. PROLONGED RESPONSE TO TREATMENT BASED ON CELL?FREE DNA ANALYSIS AND MOLECULAR PROFILING IN THREE PATIENTS WITH METASTATIC CANCER: A CASE SERIES. THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY. 2021 FEB 10?13:1?13. 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PROLONGED RESPONSE TO TREATMENT BASED ON CELL?FREE DNA ANALYSIS AND MOLECULAR PROFILING IN THREE PATIENTS WITH METASTATIC CANCER: A CASE SERIES. 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"drugdosageform": "UNKNOWN", "drugdosagetext": "11 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FULVESTRANT." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoacusis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NAQVI M, VO H, VINING D, TSIMBERIDOU A. PROLONGED RESPONSE TO TREATMENT BASED ON CELL FREE DNA ANALYSIS AND MOLECULAR PROFILING IN THREE PATIENTS WITH METASTATIC CANCER: A CASE SERIES. THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY. 2021 MAR 24?13:.", "literaturereference_normalized": "prolonged response to treatment based on cell free dna analysis and molecular profiling in three patients with metastatic cancer a case series", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210520", "receivedate": "20210520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19280580, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "Carfilzomib is a second-generation proteasome inhibitor that irreversibly inhibits chymotrypsin-like (CT-L) activities of the proteasome, and is indicated for relapsed or refractory multiple myeloma. Cardiotoxicity is a well-established adverse effect of carfilzomib. The extent of cardiac toxicity in the literature spans anywhere from palpitations to cardiac arrest, with the most commonly reported manifestation being new-onset or worsening heart failure. A pre-clinical study of the pharmacokinetics and pharmacodynamics of carfilzomib given via intravenous bolus or 30-minute infusion in rats showed that carfilzomib can strongly induce apoptosis and potently damage cardiac myocytes at clinically relevant concentrations. Moreover, the mortality rate with the bolus administration was 44% whereas the same dose administered as a 30-minute infusion did not result in mortality. There remains limited clinical data regarding the safety of carfilzomib at doses of 27-56 mg/m2 based on infusion times as these doses have not been well studied. This retrospective review was conducted to evaluate the safety of carfilzomib at doses >27 mg/m2 at all infusion times.", "affiliations": "Department of Pharmacy, 12297 New York University Langone Medical Center , New York, NY.;Department of Pharmacy, 12297 New York University Langone Medical Center , New York, NY.;Department of Pharmacy, 12297 New York University Langone Medical Center , New York, NY.;Department of Pharmacy, 12297 New York University Langone Medical Center , New York, NY.", "authors": "Kim\|Gee Youn\|GY\|;Ahuja\|Tania\|T\|;Papadopoulos\|John\|J\|;Cirrone\|Frank\|F\|", "chemical_list": "D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib", "country": "England", "delete": false, "doi": "10.1177/1078155217729564", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "25(1)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Carfilzomib; cancer; cardiotoxicity; infusion time; multiple myeloma", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066126:Cardiotoxicity; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D012189:Retrospective Studies", "nlm_unique_id": "9511372", "other_id": null, "pages": "229-233", "pmc": null, "pmid": "28914153", "pubdate": "2019-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Cardiotoxicity with carfilzomib at doses greater than 27 mg/m2: A case series.", "title_normalized": "cardiotoxicity with carfilzomib at doses greater than 27 mg m2 a case series" }	[ { "companynumb": "US-AMGEN-USASP2018173195", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, 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{ "abstract": "BACKGROUND Giant carotid intracavernous aneurysm refers to those lesions larger than 2.5 cm and derived from a cavernous segment, accounting for about 30% of all intracranial tumors. Dynamic CT perfusion imaging (PCT) is a common method recently employed to evaluate cerebral perfusion. This study investigated the efficacy and clinical application of intraoperative CT in the surgery for giant symptomatic carotid intracavernous aneurysm. MATERIAL AND METHODS A retrospective analysis was performed on 23 cases with giant symptomatic carotid intracavernous aneurysm. BTO testing was performed before surgery. Differential treatments were performed based on the condition of aneurysm, and some patients received intraoperative PCT. Postoperative anti-coagulation was given with DSA or CTA follow-up examinations at 3-6 months, 1 year, and 2 years after surgery. RESULTS A total of 17 patients received aneurysm isolation coupled with high-flow bypass surgery. Among those, 9 developed early-onset neurological function after surgery, with gradual recover within 6 months. One coma patient died 25 months after discharge. One patient had aneurysm isolation with clapping of anterior communicating artery, and the other 5 cases received artery clapping only. In those patients, 4 had improvement at early phase, while 1 patient had numbness of the oculomotor nerve. Six patients received surgery in the CT room, including 5 cases with single proximal ligation of the internal carotid artery plus 1 aneurysm isolation combined with high-flow bypass surgery. CONCLUSIONS Intraoperative PCT can provide objective evidence and effective evaluation of cerebral perfusion.", "affiliations": "Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).", "authors": "Xue\|Zhe\|Z\|;Wang\|Fuyu\|F\|;Sun\|Zhenghui\|Z\|;Zhang\|Hui\|H\|;Wu\|Chen\|C\|;Kong\|Dongsheng\|D\|;Xu\|Bainan\|B\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.12659/msm.902225", "fulltext": "\n==== Front\nMed Sci MonitMed. Sci. MonitMedical Science MonitorMedical Science Monitor : International Medical Journal of Experimental and Clinical Research1234-10101643-3750International Scientific Literature, Inc. 2864079310.12659/MSM.902225902225Clinical ResearchIntraoperative Computed Tomography (CT) for Treating Giant Carotid Intracavernous Aneurysms Xue Zhe ACEWang Fuyu AGSun Zhenghui BCEZhang Hui BDWu Chen BDKong Dongsheng CEFXu Bainan BDFDepartment of Neurosurgery, General Hospital of PLA, Beijing, P.R. ChinaCorresponding Authors: Bainan Xu, e-mail: [email protected], Zhenghui Sun, e-mail: [email protected] 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\n2017 22 6 2017 23 3054 3063 03 11 2016 01 12 2016 © Med Sci Monit, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Background\nGiant carotid intracavernous aneurysm refers to those lesions larger than 2.5 cm and derived from a cavernous segment, accounting for about 30% of all intracranial tumors. Dynamic CT perfusion imaging (PCT) is a common method recently employed to evaluate cerebral perfusion. This study investigated the efficacy and clinical application of intraoperative CT in the surgery for giant symptomatic carotid intracavernous aneurysm.\n\nMaterial/Methods\nA retrospective analysis was performed on 23 cases with giant symptomatic carotid intracavernous aneurysm. BTO testing was performed before surgery. Differential treatments were performed based on the condition of aneurysm, and some patients received intraoperative PCT. Postoperative anti-coagulation was given with DSA or CTA follow-up examinations at 3–6 months, 1 year, and 2 years after surgery.\n\nResults\nA total of 17 patients received aneurysm isolation coupled with high-flow bypass surgery. Among those, 9 developed early-onset neurological function after surgery, with gradual recover within 6 months. One coma patient died 25 months after discharge. One patient had aneurysm isolation with clapping of anterior communicating artery, and the other 5 cases received artery clapping only. In those patients, 4 had improvement at early phase, while 1 patient had numbness of the oculomotor nerve. Six patients received surgery in the CT room, including 5 cases with single proximal ligation of the internal carotid artery plus 1 aneurysm isolation combined with high-flow bypass surgery.\n\nConclusions\nIntraoperative PCT can provide objective evidence and effective evaluation of cerebral perfusion.\n\nMeSH Keywords\nAcidosis, Renal TubularAneurysmCavernous SinusGastric BypassIntracranial Aneurysm\n==== Body\nBackground\nGiant carotid intracavernous aneurysm refers to those lesions larger than 2.5 cm, which are derived from the cavernous segment. They account for about 30% of all giant intracranial tumors [1], with more female patients [2]. Clinically, it is manifested as headache and compression of cranial nerve III to VI, with less subarachnoid hemorrhage. Current curative indication mainly includes symptomatic aneurysm, and regular follow-ups are required for asymptomatic lesions until manifestation [2–4]. Giant symptomatic internal carotid intracavernous aneurysm can be treated by proximal blockade [5], vascular bypass conjunction with proximal blockade or aneurysm isolation [6,7], direct surgical clapping [8], or interventional therapy [9–11]. Due to the wide neck and huge volume of these aneurysms, and the protection of the cranial nerve inside the cavernous area, direct clapping is very difficult and not suitable for all patients. For giant or large intracavernous aneurysms, intervention and embolization have unsatisfactory efficacy [12]. Single proximal blockade can benefit patients and vascular bypass in conjunction with proximal blockade or aneurysm isolation is also a common treatment strategy. In recent years, flow-diverting stents (FDSs) have been developed and especially designed to reduce the flow velocity vortex within the aneurysm and can improve the laminar flow in the main artery and surrounding branches [13]. Computation hemodynamics suggests that a stent with an overall porosity of 50% to 70% (30–50% metallic coverage) will significantly reduce the inflow rate into an aneurysm [14]. In theory, FDSs could treat aneurysms no regardless of location and could be deployed covering collateral vessels that are not occluded. Initial clinical experiences with the use of FDSs in the treatment of visceral and peripheral aneurysms have yielded satisfactory results in technical success, aneurysm thrombosis and shrinkage, and branch vessel patency. Better results are achieved 12 months after the procedure rather than at 6 months in aortic aneurysms. Importantly, there have been no aneurysm ruptures reported after treatment with an FDS [13].\n\nIt is critical to evaluate the compensation of lateral circulation, regardless of the treatment strategy. Balloon test occlusion (BTO) is a safe and effective way to evaluate cerebral resistance after tumor-bearing artery blockade [15]. The combination of BTO assay with semi-quantitative/quantitative evaluation for focal cerebral blood flow, such as SPECT [16–18], xenon CT [19, 20], and PET scan [21], can further lower the false-negative rate. Dynamic CT perfusion imaging (PCT) is a common method recently used to evaluate cerebral perfusion. The direct application of PCT in surgery can provide objective evidence of cerebral blood perfusion, and can work as an effective monitoring approach [22]. Our group has used PCT in aneurysm surgery.\n\nMaterial and Methods\nGeneral information\nWe recruited a total of 23 patients with giant symptomatic carotid intracavernous aneurysm in the General Hospital of the PLA from February 2007 to March 2013, including 3 males and 20 females, ages 24–68 years (average age=54.7 years). Major manifestations of aneurysm included headache and compression of cranial nerves, including 6 cases with optical nerve affected, 12 cases with oculomotor nerve, 4 cases with trigeminal nerve, and 1 patient with abducent nerve injury. There were 8, 1, and 1 patients having headache, dizziness, and vertigo, respectively. All patients had confirmed diagnosis by DSA, showing 12 and 11 lesions at left and right hemisphere, respectively. Diameters of all lesions were larger than 2.5 cm. This study was approved by the Medical Ethics Committee of General Hospital of PLA. Informed consents were obtained from all patients prior to the study.\n\nPre-operative evaluation\nBTO assay was performed 30 min before surgery to observe compensation of anterior/posterior circulation, coupled with neurological function evaluation. If compensation showed no symptom, blood pressure was further lowered by 20% to observe the existence of neurological dysfunction.\n\nAneurysm isolation coupled with high-flow bypass\nSurgical indications included those with unsatisfactory compensation before surgery or those with neurological dysfunction. Using the great saphenous vein as the transplant vessel, external carotid and M2 segment of cerebral middle brain were ligated, followed by isolation of the aneurysm. During the surgery, microvascular Doppler was used to quantify blood flow velocity of recipient and implanted vessels. Neurological function was monitored by electrophysiology approach. Some patients further received ICG testing for measuring flow of transplanted vessels, while some patients were evaluated for perfusion via intraoperative PCT.\n\nAneurysm isolation or blockade of internal carotid artery starting point\nSurgical indications included satisfactory compensation before surgery or with neurological symptoms. We performed 2–3 weeks of neck compression training before surgery with preparation for bypass surgery. The inner carotid artery was first exposed during the surgery, along with exposure of the external and common carotid arteries. The inner carotid artery was temporarily clamped for observing neurological-pathology conditions. Some patients underwent intraoperative PCT for monitoring ischemia condition. The absence of ischemia manifestation indicated aneurysm isolation or proximal blockade; otherwise, the surgery was combined with bypass. After finishing isolation or proximal blockade operations, patients were awakened and underwent intubation for another 30-min observation to evaluate neurological function. No abnormality signalled the end of surgery; otherwise, combined bypass surgery was performed.\n\nPCT imaging during surgery\nImaging was performed in the CT room during surgery. CT perfusion was first carried out before surgery. Re-scanning of perfusion and CTA examination were performed after temporary blockade. Areas of interests were the blood supply region from the cerebral middle artery and anterior artery closest to the basal ganglia layer. Cerebral blood flow (CBF), cerebral blood volume (CBV), and time to peak (TTP) were obtained from all areas of interests, along with relative perfusion indexes, including rCBV, rCBV, and rTTP. Perfusion indexes were compared between surgical and intact hemispheres, and relative perfusion indexes were compared before and after surgery.\n\nPostoperative treatment and follow-ups\nAll patients received heparin as anti-coagulation treatment for 24 h, followed by oral ingestion of anti-platelet drugs. Bedside ultrasound was employed to test the flow of transplanted vessels. CT or MRI was used to observe the occurrence of thrombosis or hemorrhage. Before discharge, DSA or CTA was used for re-check. Patients were asked to return for re-examination by DSA or CTA at 3–6 month after discharge. Further follow-ups were performed at 1 year and 2 years. Patients who could not attend follow-ups in person were told by telephone to go to a nearby hospital for re-examination.\n\nResults\nAneurysm isolation coupled with high-flow bypass surgery\nA total of 17 patients (3 males and 14 females) presented improvements of symptoms early after surgery, including 1 case with oculomotor nerve affected, 1 patient with optic nerve dysfunction, and 1 patient with headache. Newly-formed neurological dysfunction after surgery included 1 optic nerve injury, 3 patients with oculomotor nerve injury, 1 headache, and 1 dazzle case, plus 1 transient aphasia, 1 patient having tracheotomy due to cough and fatigue (patient had choking before surgery, with bilateral spinal artery occlusion on DSA), and 1 coma patient due to occlusion of the transplanted artery (Table 1). All these cranial nerve symptoms gradually resolved by 2–6 month after surgery. The middle-to-long-term result showed scores of 5 in GOS in 13 patients within 3 months to 6 years and at 3-month follow-up. The patient with tracheotomy had the tube removed 1 month later, followed by rehabilitation; this patient still required daily care at the time of follow-up. The coma patient received treatment in a local hospital and died 25 months later. Two patients were lost to follow-up.\n\nAneurysm isolation or blockade of internal carotid artery starting point\nA total of 6 patients (all females) received such treatment. Among these, 1 patient had clapping of the anterior communicating artery coupled with isolation of the internal carotid artery aneurysm. This patient presented transient indifference, which was improved after elevating blood pressure and vasodilation. All 5 patients received single blockade, and symptom improvements were observed, including 2 cases with optic nerve injury, 1 case with oculomotor nerve affected, and 1 headache case (Table 1). Newly-formed neurological dysfunction occurred after surgery, including 1 patient with oculomotor nerve injury, which gradually recovered after 2 months, and 1 patient with headache improved by vasodilation. Long-term, all 6 patients had GOS scores of 5 within the follow-up period (9–15 months).\n\nPCT imaging results\nSix patients received PCT during the surgery. Among these, 5 had proximal ligation of the internal carotid artery, and 1 had aneurysm isolation coupled with high-flow vessel bypass surgery. One patient had an approximately 50% decrease in somatosensory-induced potential after temporary blockade of the proximal internal carotid artery, and PCT showed improved perfusion after surgery, indicating direct proximal blockade. One case showed a minor (less than 50%) decrease in somatosensory-induced potential after temporary blockade of the proximal internal carotid artery, and PCT showed no change in perfusion after surgery, indicating direct proximal blockade.\n\nReport of typical cases\nCase 1\nFemale, 65 years old, admitted as “Intermittent headache and double vision for 1 year”. Physical exam showed blepharoptosis of the right upper eyelid. Head MRI indicated a round-shaped parasellar lesion on the right hemisphere, and DSA suggested a giant aneurysm in the cavernous segment of the right internal carotid artery. Isolation of the aneurysm combined with high-flow bypass surgery was performed. During the surgery, the internal carotid artery was exposed, along with external and common carotid arteries. A front temporal approach was used. Using the great saphenous vein as the transplant vessel, the external carotid and M2 segment of cerebral middle brain were ligated, followed by isolation of the aneurysm. After surgery, headache was improved, along with recovered numbness of the oculomotor nerve. No sign of aneurysm was found in postoperative DSA, indicating satisfactory hemodynamics of the transplanted vessel. Imagining of the right cerebral middle artery and anterior artery showed no abnormalities (Figure 1).\n\nCase 2\nFemale, 63 years old, admitted as “Blepharoptosis of right upper eyelid for 3 months”. Physical exam showed blepharoptosis of the right upper eyelid. Head CT and MRI indicated a round parasellar lesion on the right hemisphere, and DSA suggested a giant aneurysm in the cavernous segment of the right internal carotid artery. After 1-week neck compression training, blockade of the right internal carotid artery was chosen for surgery. Pre-operative PCT indicated a large hypo-perfusion area in the right temporal lobe. After temporary blocking of the right internal carotid artery, intraoperative PCT indicated significantly improved right temporal perfusion. Intraoperative CTA showed no image of right inner carotid artery from the starting points, plus satisfactory imaging of right cerebral middle/anterior arteries. Blockade of the right inner carotid artery was thus performed. No postoperative complications occurred, and there was gradual recovery of oculomotor nerve numbness (Figures 2, 3).\n\nCase 3\nFemale, 29 years old, admitted as “Blurred vision in left eye for 4 years, plus headache for 2 months”. Physical exam showed normal right eye vision. Head CT and MRI indicated a round lesion in the left parasellar region, accompanied by calcification. CTA and DSA suggested a giant aneurysm of the intracavernous segment of the left inner carotid artery. Surgery was performed using isolation of the left inner carotid artery intracavernous aneurysm accompanied by high-flow bypass by the great saphenous vein. Pre-operative PCT showed worse perfusion in the left cerebral hemisphere. Intraoperative PCT suggested similar results. Re-examination after bypass surgery via CTA showed good hemodynamics in bridge vessels, and imaging of left cerebral middle/anterior artery revealed good recovery after surgery (Figure 4).\n\nDiscussion\nClinical symptoms of intracavernous aneurysm include headache or compression of cranial nerves, and most cases have benign history with few suffering subarachnoid hemorrhage [2,21]. Therefore, current indications of surgery mainly refer to large or giant symptomatic aneurysm [2–4]. In our department, the choice of aneurysm treatment was stipulated by the surgical team and intervention clinicians, in consideration of the patient’s opinion and economic conditions, thus benefiting patient care via individualized treatment.\n\nBTO assay can be used before treating intracavernous aneurysm of the carotid artery. This assay is an effective and safe method for evaluating ischemia resistance of a tumor-bearing artery after blockade [15]. Combined treatment with bypass surgery is required when BTO assay indicates unsatisfactory hemodynamic compensation or symptoms. Even in BTO-negative patients, there was a 5–20% chance of cerebral infarction after blocking the artery. Therefore, BTO results alone are not completely reliable [23]. Currently, multiple methods, including SPECT [14–16], xenon CT [19,20], PET [21], and TCD [24], can evaluate focal cerebral blood flow volume quantitatively or semi-quantitatively. The combination of BTO with these assays thus can improve accuracy of quantification of cerebral tissue ischemia, but requires multiple procedures [7,24]. In this study, we used depressurization assay with 15-min observation for neurological function evaluation and monitoring after depressing blood pressure by 20~30%. The combination with BOT can help to improve predicative value of the assay. In this study, all 17 patients had unsatisfactory blood flow compensation via pre-operative BTO assay, or had good compensation but with symptoms, or the presentation of symptoms after managing hypotension. After high-flow bypass surgery, most patients had certain levels of improvements.\n\nIn recent years, intraoperative PCT has been widely used to evaluate resistance to ischemia of brain tissues [22], with satisfactory effects. A total of 6 patients received perfusion PCT imaging after surgery. Among those, 2 patients had clear depression of somatosensory-induced potential after blockading the proximal inner carotid artery, and PCT showed no change in blood supply, leading to the direct blockade of proximal vessels. Therefore, intraoperative PCT is an effective approach.\n\nMost common approaches for treating intracavernous aneurysm include proximal blockade or aneurysm isolation coupled with vascular bypass surgery. In this study, 17 patients received aneurysm isolation plus high-flow bypass surgery using the giant saphenous vein as the bridging vessel, which was further ligated onto the descending branch of the external carotid artery and cerebral middle artery. By this approach, no clapping of the inner carotid artery is required when clapping, thus reducing the incidence of ischemia. During the preparation of the subcutaneous tunnel and skull window, it is necessary to keep transplanted vessels from being compressed. One patient developed cerebral ischemia and coma due to blockade of the transplanted vessel and died 2 years later, suggesting that transplanted vessel blockade is a major factor causing ischemic stroke after surgery. This is related to multiple factors, including the selection of transplanted vessels, matching of vessels, ligation technique, postoperative blood pressure management, and anti-coagulation and anti-platelet drugs. One patient had onset of dazzles and choking before surgery, as supported by blockade of the bilateral spinal artery. After surgery, this patient had worse coughing reflex and underwent tracheotomy. At 6-year follow-up, the patient was still in a wheelchair but has satisfactory results in general conditions, further indicating the importance of vascular condition before surgery for patient prognosis.\n\nFor those patients with satisfactory resistance for proximal blockade in BTO assay, isolation of the aneurysm or blockade of the proximal inner carotid artery might be effective and safe approaches. In all 6 patients with BTO resistance, surgery was performed after 2–3 weeks of continuous neck compression training. The preparation for bypass surgery was performed before surgery, in which temporally proximal blockade was first performed. One patient only received 30-min electrophysiological monitoring and the other 5 received simultaneous examinations including electrophysiology and intraoperative PCT, both of which had no abnormality. Proximal blockade was then performed. Two patients presented headache and dazzle after surgery, and were all discharged after treatment. Four patients showed improvement of symptoms. Blockade caused by thrombosis detachment is a common complication, with 5–10% incidence [25]. During this study, all 6 patients had no severe complication of thrombosis. Proximal clapping can be performed on either the common carotid artery or internal carotid artery. Some scholars believe that these 2 ischemia-related complications are different, while others disagree with this opinion. We chose blockade of the inner carotid artery, which is the tumor-bearing vessel. Therefore, direct blockade of the aneurysm accelerates the velocity of thrombosis formation and can improve symptoms. In this group, only 2 patients had headache or dazzle symptoms, and these were improved after treatment. Other scholars [5] utilized chronic clapping of carotid artery to treat intracavernous aneurysm, which, however, had relatively higher incidence of thrombosis, and incomplete blockade of aneurysm. The application of anti-coagulation and anti-platelet treatment can help to decrease the incidence of ischemic episodes. A previous report indicated potential decrease of thrombosis events by interventional blockade proximal to the tumor neck [6]. Other groups also found that proximal blockade of the inner carotid artery generates new aneurysms or enlarges original tumors [26]. This study, however, did not find de novo aneurysm, indicating certain preventive effects by post-op management of blood pressure.\n\nIn addition to blockade of the proximal inner carotid artery in the treatment of aneurysm, flow-diverting stents (FDSs) are a new alternative treatment approach for aneurysms that takes into account their unique characteristics. The largest published experience to date comes from use of FDSs in visceral aneurysms, and the results are very encouraging, with a significant incidence of aneurysm thrombosis and shrinkage during follow-up and without any branch vessel occlusion. In terms of peripheral aneurysms, FDSs have been widely used in the treatment of iliac, popliteal, and subclavian aneurysms. In these anatomic areas, significant collateral branches have to be preserved, including the internal iliac artery, the genicular arteries, and the vertebral arteries, respectively [13].\n\nThis study has certain limitations. Firstly, it has a relatively smaller sample size and short follow-up periods, in which loss to follow-up gradually increased. The outcome of long-term follow-up has been found to be important for the choice between proximal ligation and aneurysm isolation combined with bypass procedure [27]. Based on previous studies, the incidence of ischemia episodes is lower in the short term, but needs further long-term evaluation in the future. Secondly, the method for evaluating hemodynamic compensation needs to be elaborated, due to the occurrence of ischemia complications even after the surgical optimization based on pre-operative evaluation [28]. In early-phase cases, we preferred the aneurysm isolation combined with bypass procedure, which is mature technique with fewer complications. However, the use of bypass surgery in all cases is just based on safeguarding the blood supply, because some patients actually had satisfactory long-term outcomes without bypass. Therefore, the treatment strategy needs to be refined based on evaluation before and during surgery. Patients still need to be prepared for bypass surgery at the time of proximal ligation. However, new symptoms may develop after surgery, and long-term follow-up data are needed to evaluate the efficacy of proximal ligation. Intraoperative electrophysiology monitoring also has certain limitations, as it cannot reflect the consistency between clapping of aneurysm/adjacent vessels and cerebral perfusion, in addition to false-positive and false-negative results, which can be affected by anesthesia, electrical devices, and surgical operation, although intraoperative PCT combined with CTA provides more information. Factors during the surgery should be carefully controlled, including blood pressure, consistency between pre- and intraoperative scanning, dosage of imaging reagent, and radiation dosage. Moreover, large-cohort clinical studies are required to comprehensively analyze results of electrophysiology monitoring and PCT imaging.\n\nConclusions\nThe use of PCT during surgery can provide objective and timely evidence for cerebral blood perfusion and is an effective monitoring method.\n\nDisclosure of conflict of interest\n\nNone.\n\nSource of support: Departmental sources\n\nFigure 1 Report of patient A, with isolation of giant intracavernous aneurysm on right side plus high-flow bypass surgery. (A) Illustration of aneurysm isolation combined with high-flow bypass surgery. (B) DSA image of giant intracavernous aneurysm before surgery. (C) Postoperative DSA results showed no indication of aneurysm, good hemodynamics of transplanted vessel, and satisfactory images of right cerebral middle/anterior artery.\n\nFigure 2 Patient B undergoing blockade at starting point of right giant intracavernous aneurysm of inner carotid artery. (A) Pre-operative head CT showed high-density round lesion on right parasellar region (red arrow). (B) Head CT showed round vacuoles at right parasellar region (red arrow). (C) Pre-operative DSA indicated giant aneurysm of intracavernous segment in inner carotid artery (red arrow). (D) After blocking of inner carotid artery initiating point, intraoperative CTA showed no imaging of distal end in inner carotid artery, while right cerebral middle artery (red arrow) and anterior artery had good imaging.\n\nFigure 3 Pseudo-colored image of intraoperative PCT in patient B. (A) Lower rCBF value (0.81) of right temporal lobe before surgery. (B) Higher CBF value (1.41) in right temporal lobe during the surgery after temporal blockade of right inner carotid artery. (C) Similar rCBV value (1.01) between right and left temporal lobe before surgery. (D) Higher rCBV value (1.31) in right temporal lobe during the surgery after temporal blockade of right inner carotid artery. (E) Significantly elongated TTP in right temporal lobe compared to left hemisphere before surgery (rTTP value=1.39). (F) Similar TTP (rTTP=1.00) between right and left temporal lobe in surgery after temporal blockade of right inner carotid artery.\n\nFigure 4 Isolation of left inner carotid artery intracavernous aneurysm coupled with high-flow vessel bypass surgery using giant saphenous vein. (A) Pre-operative head CT showed a round high-density region in the left parasellar area, accompanied with calcification (red arrow). (B) Head MRI indicated a round vacuole in the left parasellar region, accompanied with thrombosis formation (red arrow). (C) CTA indicated a giant aneurysm within the intracavernous segment of the left inner carotid artery (maximal diameter, 25.9 mm). (D) Pre-operative DSA indicated a giant aneurysm in the intracavernous segment of the left inner carotid artery. (E) Intraoperative CTA showed good hemodynamics of bridge vessels (read arrow), and no image at initiating point of left inner carotid artery. (F) Intraoperative CTA showed good imaging of left cerebral artery (red arrow) and anterior artery after bypass surgery.\n\nTable 1 Outcomes of patients after surgery.\n\nTreatments\tn\t\nAneurysm isolation coupled with high flow bypass surgery\t17\t\n Optic nerve injury\t1\t\n Oculomotor nerve injury\t3\t\n Headache\t1\t\n Dazzle\t1\t\n Transient aphasia\t1\t\n Tracheotomy\t1\t\n Coma\t1\t\nAneurysm isolation or blockade of internal carotid artery starting point\t6\t\n Clapping of anterior communicating artery coupled with isolation of internal carotid artery aneurysm\t1\t\n Single blockade\t5\t\n Optic nerve injury\t2\t\n Oculomotor nerve\t1\t\n Headache\t1\n==== Refs\nReferences\n1 Dengler J Maldaner N Bijlenga P Quantifying unruptured giant intracranial aneurysms by measuring diameter and volume – a comparative analysis of 69 cases Acta Neurochir (Wien) 2015 157 361 68 discussion 368 25502806 \n2 Stiebel-Kalish H Kalish Y Bar-On RH Presentation, natural history, and management of carotid cavernous aneurysms Neurosurgery 2005 57 850 57 discussion 857 16284555 \n3 Eddleman CS Hurley MC Bendok BR Batjer HH Cavernous carotid aneurysms: to treat or not to treat? Neurosurg Focus 2009 26 E4 \n4 ter Brugge KG Cavernous sinus segment internal carotid artery aneurysms: Whether and how to treat Am J Neuroradiol 2012 33 327 28 22300929 \n5 Niiro M Shimozuru T Nakamura K Long-term follow-up study of patients with cavernous sinus aneurysm treated by proximal occlusion Neurol Med Chir (Tokyo) 2000 40 88 96 discussion 97 10786096 \n6 Field M Jungreis CA Chengelis NL Symptomatic cavernous sinus aneurysms: Management and outcome after carotid occlusion and selective cerebral revascularization Am J Neuroradiol 2003 24 1200 7 12812955 \n7 Tacconi L Extracranial-intracranial bypass for the treatment of cavernous sinus aneurysms J Clin Neurosci 2006 13 1001 5 17070053 \n8 Dolenc V Direct microsurgical repair of intracavernous vascular lesions J Neurosurg 2009 58 824 31 \n9 van Rooij WJ Endovascular treatment of cavernous sinus aneurysms Am J Neuroradiol 2012 33 323 26 22033713 \n10 Starke RM Chalouhi N Ali MS Endovascular treatment of carotid cavernous aneurysms: Complications, outcomes and comparison of interventional strategies J Clin Neurosci 2014 21 40 46 23972560 \n11 Puffer RC Piano M Lanzino G Treatment of cavernous sinus aneurysms with flow diversion: Results in 44 patients Am J Neuroradiol 2014 35 948 51 24356675 \n12 Morita K Sorimachi T Ito Y Intra-aneurysmal coil embolization for large or giant carotid artery aneurysms in the cavernous sinus Neurol Med Chir (Tokyo) 2011 51 762 66 22123478 \n13 Sfyroeras GS Dalainas I Giannakopoulos TG Flow-diverting stents for the treatment of arterial aneurysms J Vasc Surg 2012 56 839 46 22840737 \n14 Liou TM Li YC Effects of stent porosity on hemodynamics in a sidewall aneurysm model J Biomech 2008 41 1174 83 18377914 \n15 Lesley WS Rangaswamy R Balloon test occlusion and endosurgical parent artery sacrifice for the evaluation and management of complex intracranial aneurysmal disease J Neurointerv Surg 2009 1 112 20 21994280 \n16 Sugawara Y Kikuchi T Ueda T Usefulness of brain SPECT to evaluate brain tolerance and hemodynamic changes during temporary balloon occlusion test and after permanent carotid occlusion J Nucl Med 2002 43 1616 23 12468510 \n17 Tomura N Omachi K Takahashi S Comparison of technetium Tc 99m hexamethylpropyleneamine oxime single-photon emission tomograph with stump pressure during the balloon occlusion test of the internal carotid artery Am J Neuroradiol 2005 26 1937 42 16155138 \n18 Shimizu H Matsumoto Y Tominaga T Parent artery occlusion with bypass surgery for the treatment of internal carotid artery aneurysms: Clinical and hemodynamic results Clin Neurol Neurosurg 2010 112 32 39 19875229 \n19 Gupta DK Young WL Hashimoto T Characterization of the cerebral blood flow response to balloon deflation after temporary internal carotid artery test occlusion J Neurosurg Anesthesiol 2002 14 2 123 29 11907392 \n20 Marshall RS Young WL Solomon RA Clinical utility of quantitative cerebral blood flow measurements during internal carotid artery test occlusions Neurosurgery 2002 50 5 996 1004 discussion 1004–5 11950402 \n21 Brunberg JA Horton JA Deveikis JP [15O]H2O positron emission tomography determination of cerebral blood flow during balloon test occlusion of the internal carotid artery Am J Neuroradiol 1994 15 725 32 8010276 \n22 Schichor C Rachinger W Zausinger S Intraoperative computed tomography angiography with computed tomography perfusion imaging in vascular neurosurgery: Feasibility of a new concept J Neurosurg 2010 112 722 28 19817544 \n23 Linskey ME Jungreis CA Yonas H Stroke risk after abrupt internal carotid artery sacrifice: Accuracy of preoperative assessment with balloon test occlusion and stable xenon-enhanced CT Am J Neuroradiol 1994 15 829 43 8059649 \n24 Bakke SJ Sorteberg W Angiographic balloon test occlusion and therapeutic sacrifice of major arteries to the brain Neurosurgery 2008 63 651 60 18824944 \n25 Hauck EF Welch BG White JA Stent/coil treatment of very large and giant unruptured ophthalmic and cavernous aneurysms Surg Neurol 2009 71 1 19 24 discussion 24 18423540 \n26 Fujiwara S Fujii K Fukui M De novo aneurysm formation and aneurysm growth following therapeutic carotid occlusion for intracranial internal carotid artery (ICA) aneurysms Acta Neurochir (Wien) 1993 120 20 25 8434512 \n27 Date I Ohmoto T Long-term outcome of surgical treatment of intracavernous giant aneurysms Neurol Med Chir (Tokyo) 1998 38 62 69 10234980 \n28 Souto AAD Domingues F Espinosa G Complex paraclinoidal and giant cavernous aneurysms: importance of preoperative evaluation with temporary balloon occlusion test and SPECT Arq Neuropsiquiatr 2006 64 768 73 17057883\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1234-1010", "issue": "23()", "journal": "Medical science monitor : international medical journal of experimental and clinical research", "keywords": null, "medline_ta": "Med Sci Monit", "mesh_terms": "D000328:Adult; D000368:Aged; D002343:Carotid Artery, Internal; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D007430:Intraoperative Care; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "9609063", "other_id": null, "pages": "3054-3063", "pmc": null, "pmid": "28640793", "pubdate": "2017-06-22", "publication_types": "D016428:Journal Article", "references": "18824944;12468510;17057883;22300929;16284555;11907392;22123478;22033713;24356675;8059649;21994280;8010276;6854374;19875229;22840737;10234980;18377914;25502806;12812955;10786096;18423540;16155138;11950402;19817544;17070053;19409005;8434512;23972560", "title": "Intraoperative Computed Tomography (CT) for Treating Giant Carotid Intracavernous Aneurysms.", "title_normalized": "intraoperative computed tomography ct for treating giant carotid intracavernous aneurysms" }	[ { "companynumb": "CN-FRESENIUS KABI-FK201707120", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "017029", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "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": "HEPARIN (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral ischaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arterial occlusive disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "XUE Z,WANG F,SUN Z,ZHANG H,WU C,KONG ET AL.. INTRAOPERATIVE COMPUTED TOMOGRAPHY (CT) FOR TREATING GIANT CAROTID INTRACAVERNOUS ANEURYSMS. MEDICAL SCIENCE MONITOR 2017;3054-3063.", "literaturereference_normalized": "intraoperative computed tomography ct for treating giant carotid intracavernous aneurysms", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20170823", "receivedate": "20170823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13897427, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "CN-SHENZHEN TECHDOW PHARMACEUTICAL CO. LTD-CN-2017TEC0000054", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "202732", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, RECEIVED FOR 24 HRS POST SURGERY", "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": "HEPARIN SODIUM INJECTION USP, PRESERVATIVE FREE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral ischaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venous occlusion", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "XUE Z, WANG F, SUN Z, ZHANG H, WU C, KONG D, ET AL.. INTRAOPERATIVE COMPUTED TOMOGRAPHY (CT) FOR TREATING GIANT CAROTID INTRACAVERNOUS ANEURYSMS. MEDICAL SCIENCE MONITOR. 2017;23:3054-3063", "literaturereference_normalized": "intraoperative computed tomography ct for treating giant carotid intracavernous aneurysms", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20170928", "receivedate": "20170926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14013012, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171128" } ]
{ "abstract": "The case report of botulinum toxin treatment of gastroparesis in a patient following allogenic bone marrow transplantation is described. The causes of gastroparesis and methods of prevention and treatment are discussed. It was noted that pyloric injection of botulinum toxin can improve symptoms and gastric emptying.", "affiliations": "National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.", "authors": "Galstyan\|G M\|GM\|;Pashkova\|M V\|MV\|;Popova\|O Y\|OY\|;Makarova\|P M\|PM\|;Dubnyak\|D S\|DS\|;Kuzmina\|L A\|LA\|;Parovichnikova\|E N\|EN\|", "chemical_list": "D001905:Botulinum Toxins", "country": "Russia (Federation)", "delete": false, "doi": "10.26442/terarkh201890160-64", "fulltext": null, "fulltext_license": null, "issn_linking": "0040-3660", "issue": "90(1)", "journal": "Terapevticheskii arkhiv", "keywords": "bone marrow transplantation; botulinum toxin; cyclosporine A; cytomegalovirus infection; foscarnet; ganciclovir; gastroparesis; immunosuppressive therapy; pyloric injection; tacrolimus; «graft-versus-host disease", "medline_ta": "Ter Arkh", "mesh_terms": "D001853:Bone Marrow; D016026:Bone Marrow Transplantation; D001905:Botulinum Toxins; D005746:Gastric Emptying; D018589:Gastroparesis; D006801:Humans", "nlm_unique_id": "2984818R", "other_id": null, "pages": "60-64", "pmc": null, "pmid": "30701760", "pubdate": "2018-02-14", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation.", "title_normalized": "treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation" }	[ { "companynumb": "RU-ROCHE-2266221", "fulfillexpeditecriteria": "1", "occurcountry": "RU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSEUDOMONAS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFREQUENT BOWEL MOVEMENTS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORIN A" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "POLYMYXIN B" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSEUDOMONAS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POLYMYXIN B." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMPAIRED GASTRIC EMPTYING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RUXOLITINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACTERIAL SEPSIS", "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": "5", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACTERIAL SEPSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "COLISTIMETHATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACTERIAL SEPSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLISTIMETHATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FOSCARNET" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSCARNET" } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired gastric emptying", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute graft versus host disease in intestine", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GALSTYAN G, PASHKOVA M, POPOVA O, MAKAROVA P, DUBNYAK D AND KUZMINA LA, ET AL. TREATMENT OF GASTROPARESIS WITH BOTULINUM TOXIN IN PATIENT AFTER ALLOGENIC BONE MARROW TRANSPLANTATION. TERAPEVTICHESKII ARKHIV 2018?90 (1):60-64.", "literaturereference_normalized": "treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation", "qualification": "3", "reportercountry": "RU" }, "primarysourcecountry": "RU", "receiptdate": "20190218", "receivedate": "20190218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15975197, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "RU-BAUSCH-BL-2019-005046", "fulfillexpeditecriteria": "1", "occurcountry": "RU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022246", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMPAIRED GASTRIC EMPTYING", "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": "ERYTHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PERISTALSIS VISIBLE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORIPENEM." }, { "actiondrug": "5", "activesubstance": null, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": "50", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEOCYTOTECT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONTINUED FOR 12 DAYS", "drugenddate": "2016", "drugenddateformat": "602", "drugindication": "IMPAIRED GASTRIC EMPTYING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20161026", "drugstartdateformat": "102", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ANIDULAFUNGIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANIDULAFUNGIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022246", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONTINUED FOR 12 DAYS", "drugenddate": "2016", "drugenddateformat": "602", "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022246", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PERISTALSIS VISIBLE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "POLYMYXIN B" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POLYMYXIN B." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201611" } }, "primarysource": { "literaturereference": "GALSTYAN G, PASHKOVA M, POPOVA O, MAKAROVA P, DUBNYAK D, KUZMINA L. TREATMENT OF GASTROPARESIS WITH BOTULINUM TOXIN IN PATIENT AFTER ALLOGENIC BONE MARROW TRANSPLANTATION. THERAPEUTIC ARCHIVE. 2018?90(1):60-64.", "literaturereference_normalized": "treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation", "qualification": "3", "reportercountry": "RU" }, "primarysourcecountry": "RU", "receiptdate": "20190228", "receivedate": "20190221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15990208, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "PHHY2019RU037021", "fulfillexpeditecriteria": "1", "occurcountry": "RU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": "3", "drugadministrationroute": 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"drugdosagetext": "3 COURSES OF 5-AZATHIOPRINE THERAPY", "drugenddate": "201606", "drugenddateformat": "610", "drugindication": "MYELODYSPLASTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201603", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GRAFT VERSUS HOST DISEASE IN 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLISTIMETHATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE AND TRIMETHOPRIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ANIDULAFUNGIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANIDULAFUNGIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050574", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MOXIFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MOXIFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORIPENEM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTAZIDIME" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTAZIDIME." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Impaired gastric emptying", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood pressure decreased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201611" } }, "primarysource": { "literaturereference": "GALSTYAN GM, PASHKOVA MV, POPOVA OY, MAKAROVA PM, DUBNYAK DS, KUZMINA LA ET AL. TREATMENT OF GASTROPARESIS WITH BOTULINUM TOXIN IN PATIENT AFTER ALLOGENIC BONE MARROW TRANSPLANTATION. TERAPEVTICHESKII ARKHIV. 2018?90(1):60-4", "literaturereference_normalized": "treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation", "qualification": "3", "reportercountry": "RU" }, "primarysourcecountry": "RU", "receiptdate": "20190218", "receivedate": "20190218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15977189, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "RU-PFIZER INC-2019072731", "fulfillexpeditecriteria": "1", "occurcountry": "RU", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORIPENEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.05 MG/KG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ANIDULAFUNGIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANIDULAFUNGIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTAZIDIME" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTAZIDIME." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG/KG, UNK", "drugenddate": "201611", "drugenddateformat": "610", "drugindication": "GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20161026", "drugstartdateformat": "102", "drugstructuredosagenumb": "3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "COLISTIMETHATE SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLISTIMETHATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE, TRIMETHOPRIM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MOXIFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MOXIFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "011153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG/KG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20161026", "drugstartdateformat": "102", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (3 COURSES OF 5-AZATHIOPRINE THERAPY)", "drugenddate": "201606", "drugenddateformat": "610", "drugindication": "MYELODYSPLASTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201603", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired gastric emptying", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood pressure decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201611" } }, "primarysource": { "literaturereference": "GALSTYAN, GM.. TREATMENT OF GASTROPARESIS WITH BOTULINUM TOXIN IN PATIENT AFTER ALLOGENIC BONE MARROW TRANSPLANTATION. TERAPEVTICHESKII ARKHIV. 2018?90(1):DOI:10.26442/TERARKH201890160-", "literaturereference_normalized": "treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation", "qualification": "3", "reportercountry": "RU" }, "primarysourcecountry": "RU", "receiptdate": "20200312", "receivedate": "20190220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15987549, "safetyreportversion": 6, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "RU-ASTELLAS-2019US006111", "fulfillexpeditecriteria": "1", "occurcountry": "RU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, 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"reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pseudomonas infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastric atony", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft versus host disease in gastrointestinal tract", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erosive oesophagitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Erosive duodenitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired gastric emptying", 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TREATMENT OF GASTROPARESIS WITH BOTULINUM TOXIN IN PATIENT AFTER ALLOGENIC BONE MARROW TRANSPLANTATION. TERAPEVTICHESKII ARKHIV. 2018?90 (1):60-4", "literaturereference_normalized": "treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation", "qualification": "3", "reportercountry": "RU" }, "primarysourcecountry": "RU", "receiptdate": "20190322", "receivedate": "20190221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15988820, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]
{ "abstract": "Various factors may be responsible for blood pressure alterations during perioperative care. When these physiologic alterations require treatment, several therapeutic options are available. Clevidipine is an ultrashort-acting, intravenous L-type calcium channel antagonist of the dihydropyridine class. Anecdotal experience has demonstrated its efficacy in various clinical scenarios in the pediatric population. We report apparent resistance to the vasodilatory effects of clevidipine in a 13-year-old girl who presented for anesthetic care during posterior spinal fusion for neuromuscular scoliosis whose chronic medication regimen included aripiprazole and methylphenidate for the treatment of depression and attention-deficit/hyperactivity disorder. We discuss the potential interaction of aripiprazole and methylphenidate with the calcium channel antagonists and cellular mechanisms responsible for the resistance to the vasodilatory effects of clevidipine.", "affiliations": "The Ohio State University College of Medicine, Columbus, OH, USA.;Neuro and Critical Care, The Medicines Company, Parsippany, NJ, USA.;Department of Anesthesiology and Pain Medicine, The Ohio State University, Columbus, OH, USA; Department of Anesthesiology and Pain Medicine, Nationwide Children's Hospital, Columbus, OH, USA.", "authors": "Jacklen\|M Alysse\|MA\|;Campagna\|Jason A\|JA\|;Tobias\|Joseph D\|JD\|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/JEP.S71914", "fulltext": "\n==== Front\nJ Exp PharmacolJ Exp PharmacolJournal of Experimental PharmacologyJournal of Experimental Pharmacology1179-1454Dove Medical Press 10.2147/JEP.S71914jep-6-011Case ReportClevidipine resistance in a patient taking aripiprazole and methylphenidate Jacklen M Alysse 1Campagna Jason A 2Tobias Joseph D 341 The Ohio State University College of Medicine, Columbus, OH, USA2 Neuro and Critical Care, The Medicines Company, Parsippany, NJ, USA3 Department of Anesthesiology and Pain Medicine, The Ohio State University, Columbus, OH, USA4 Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, OH, USACorrespondence: Joseph D Tobias, Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA, Tel +1 614 722 4200, Fax +1 614 722 4203, Email [email protected] 17 10 2014 6 11 14 © 2014 Jacklen et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The 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 Limited, provided the work is properly attributed.Various factors may be responsible for blood pressure alterations during perioperative care. When these physiologic alterations require treatment, several therapeutic options are available. Clevidipine is an ultrashort-acting, intravenous L-type calcium channel antagonist of the dihydropyridine class. Anecdotal experience has demonstrated its efficacy in various clinical scenarios in the pediatric population. We report apparent resistance to the vasodilatory effects of clevidipine in a 13-year-old girl who presented for anesthetic care during posterior spinal fusion for neuromuscular scoliosis whose chronic medication regimen included aripiprazole and methylphenidate for the treatment of depression and attention-deficit/hyperactivity disorder. We discuss the potential interaction of aripiprazole and methylphenidate with the calcium channel antagonists and cellular mechanisms responsible for the resistance to the vasodilatory effects of clevidipine.\n\nKeywords\nclevidipineblood pressurecalcium channel antagonistcontrolled hypotensionaripiprazoleposterior spinal fusionlabetalol\n==== Body\nIntroduction\nClevidipine (Cleviprex®, The Medicines Company, Parsippany, NJ, USA) is an ultrashort-acting, intravenous calcium channel antagonist approved for the control of blood pressure (BP) in adult patients when oral therapy is neither feasible nor desirable. Like nicardipine, it is a member of the dihydropyridine class. Clevidipine undergoes rapid metabolism by nonspecific blood and tissue esterases, resulting in a context-insensitive half-life of approximately 1 minute. Clinical trials in adult surgical and nonsurgical populations have demonstrated its efficacy in rapidly controlling BP in various clinical scenarios with a favorable adverse effect profile.1–3 Anecdotal experience in the pediatric population has further demonstrated its efficacy in various clinical scenarios.4–6 We report a 13-year-old girl with neuromuscular scoliosis who presented for anesthetic care during posterior spinal fusion with the plan to use clevidipine for controlled hypotension to limit intraoperative blood loss. Her chronic medication regimen included aripiprazole (Abilify®, Bristol-Myers Squibb, New York, NY, USA) and methylphenidate (Concerta®, Janssen Pharmaceuticals, Titusville, NJ, USA) for the treatment of depression and attention-deficit/hyperactivity disorder (ADHD). Despite increasing the infusion rate to a maximum of 5 µg/kg/min, no response was noted. We discuss the potential interactions of aripiprazole and methylphenidate with the calcium channel antagonists and cellular mechanisms responsible for the resistance to the vasodilatory effects of clevidipine.\n\nCase report\nInstitutional Review Board approval is not required for single case reports at Nationwide Children’s Hospital (Columbus, OH, USA). The patient was a 13-year-old, 51.3 kg female who presented for posterior spinal fusion for correction of neuromuscular scoliosis. Her past medical history was significant for progressive scoliosis unresponsive to conservative treatment, including bracing. Additional comorbid conditions included ADHD and depression. Pertinent past surgical history included laminectomy with release of a tethered spinal cord at age 11 years. Current medications included methylphenidate (36 mg once a day) and aripiprazole (10 mg once a day). Preoperative laboratory data including complete blood count, platelet count, and coagulation function were within normal limits. The patient was held nil per os for solids for 8 hours and clear liquids for 2 hours. In the perioperative surgical unit her BP was 123/69 mmHg, heart rate was 120 beats/minute, oxygen saturation was 99% while breathing room air, and body temperature was 36.6°C. The patient was brought to the operating room and standard American Society of Anesthesiologists monitors were placed. Anesthesia was induced via inhalation of sevoflurane in oxygen/nitrous oxide, and peripheral intravenous access was achieved. Fentanyl (100 µg) and propofol (1 mg/kg) were then administered and neuromuscular blockade was provided by rocuronium (0.6 mg/kg). Direct laryngoscopy was performed and a 6.0 mm cuffed endotracheal tube was placed. After anesthetic induction, a second large bore peripheral intravenous cannula and a radial arterial catheter were placed. Maintenance anesthesia consisted of desflurane in air/oxygen titrated to maintain the bispectral index at 40–60 and a remifentanil infusion adjusted from 0.05 µg/kg/min up to 0.3 µg/kg/min to maintain the mean arterial pressure (MAP) at 55–65 mmHg. The patient was positioned prone on a Jackson table. Normothermia was maintained using forced air warming. Per our usual routine, controlled hypotension using clevidipine was planned as part of the anesthetic technique to limit blood loss and the need for allogeneic blood products. The clevidipine infusion is initiated if the MAP cannot be maintained at <65 mmHg despite a remifentanil infusion of 0.3 µg/kg/min. Additional techniques to limit intraoperative blood loss and the need for allogeneic transfusions included the administration of tranexamic acid and intraoperative cell salvage. Motor and somatosensory evoked potentials were monitored intraoperatively throughout the surgery. During the procedure, despite a remifentanil infusion at 0.3 µg/kg/min, the MAP was ≥65 mmHg and clevidipine was added in an attempt to further decrease the MAP to 55–65 mmHg. The infusion was started at 1 µg/kg/min and increased every 2 minutes by 1 µg/kg/min. Despite the maximum suggested labeled clevidipine infusion of 5 µg/kg/min, the MAP remained at 70–75 mmHg. While continuing the clevidipine infusion, labetalol (incremental doses of 0.1 mg/kg) were required to achieve the target MAP of 55–65 mmHg. Following the second dose of labetalol (total of 0.2 mg/kg), the MAP decreased from 75–80 mmHg to 60–65 mmHg. Three more doses of labetalol (0.1 mg/kg) were administered over the next 75 minutes to maintain the MAP at 55–65 mmHg. Following completion of the surgical procedure, the patient’s trachea was extubated and she was transferred to the postanesthesia care unit in a stable condition. Postoperative analgesia was provided by hydromorphone administered by a patient-controlled analgesia device. She was admitted to the inpatient ward. The remainder of her postoperative course was unremarkable and she was discharged home on postoperative day 4.\n\nDiscussion\nThe administration of allogeneic blood products has been shown to have a negative impact on postoperative outcome following major surgical procedures.7 Given these concerns, several techniques are generally employed to limit intraoperative blood loss and therefore the need for allogeneic blood products. These techniques include appropriate positioning on the Jackson table to limit pressure on the abdomen and the engorgement of epidural veins, maintenance of normothermia, controlled hypotension, the administration of antifibrinolytic agents, and intraoperative cell salvage.7 Controlled hypotension, a technique commonly employed during major orthopedic surgery, involves the deliberate lowering of the MAP to 55–65 mmHg. Although several pharmacologic agents may be used for this purpose, our current clinical preference is the ultrashort-acting calcium channel antagonist clevidipine.8,9 In a previous retrospective report, clevidipine was shown to effectively provide controlled hypotension during spinal fusion in a cohort of 20 adolescents ranging in age from 14 years to 18 years and in weight from 46 kg to 96 kg.6 To maintain the MAP at 55–65 mmHg, the maintenance infusion rate of clevidipine varied from 1 µg/kg/min to 5 µg/kg/min, with an average infusion rate of 2.9±0.7 µg/kg/min. According to the clevidipine package insert, this dose is in the middle of the linear dose response range for the drug in adult patients. In this retrospective review and a more recent prospective trial, the patient in this report represents the only failure in a pediatric population.6,9 The patient whom we report was enrolled in an open-label, observational study focusing on the use of clevidipine for controlled hypotension during posterior spinal fusion for neuromuscular scoliosis. The outcome of that trial has been published previously, including mention of this patient who represented the only failure of clevidipine in that cohort of 50 patients.9 As noted in the current case report, there was no change in our patient’s MAP despite a clevidipine infusion that had been increased up to 5 µg/kg/min. The MAP remained at 70–75 mmHg. Control of the MAP was eventually achieved with the intermittent administration of labetalol during the remainder of the procedure. This being the only case to date representing a clinical failure of clevidipine in our clinical experience of approximately 200 patients over a 10-year period, it led us to consider possible drug–drug interactions with the patient’s current medications, including aripiprazole and methylphenidate.\n\nClevidipine is an intravenous ultrashort-acting, L-type calcium channel antagonist that directly and selectively acts on peripheral vascular smooth muscle to dilate resistance arterioles. As a third-generation dihydropyridine calcium channel antagonist, it acts to rapidly decrease and stabilize BP. Although it has no direct effects on cardiac function, its vasodilatory properties may lead to reflex tachycardia and, potentially, stimulation of the sympathetic nervous system. These effects, although present, have been shown to be less with the dihydropyridine calcium channel antagonists (nicardipine and clevidipine) than with other direct-acting vasodilators such as sodium nitroprusside.1–3 However, our clinical experience has suggested that reflex tachycardia may be more common with clevidipine than with nicardipine.4–6,9–11\n\nL-type calcium channel antagonists work at the terminal effect site for the sympathetic nervous system. Elevated sympathetic outflow eventually results in the release of norepinephrine, which binds to α-adrenergic receptors on vascular smooth muscle, resulting in membrane depolarization and opening of voltage gated L-type calcium channels. These channels allow calcium to enter the muscle cell, eventually resulting in vascular smooth muscle contraction. The dose response curves for clevidipine (and other L-type dihydropyridine calcium channel antagonists) depend on the level of sympathetic tone.12 In adults with severe intracranial hemorrhage or subarachnoid bleeding, significant rightward shifts in the dose response relationship for clevidipine have been noted (The Medicines Company, data on file). These patients are experiencing a powerful neutrally mediated vasopressor response and have elevated levels of plasma catecholamines.13 We postulate that chronic stimulation of the sympathetic nervous system in a patient taking medications such as aripiprazole and methylphenidate may be one plausible mechanism for the resistance to clevidipine that we observed in our patient.\n\nAripiprazole is an atypical quinolinone antipsychotic with approved use in the treatment of major depressive and psychotic disorders. It is a partial agonist at dopamine receptors (D2/D3) and a partial agonist at serotonin receptors (5-HT1A), thereby making it an aminergic agonist.14 Furthermore, aripiprazole has moderate affinity at other sites, including dopamine (D4), serotonin (5-HT2C, 5-HT7), α1-adrenergic, and H1 receptors. Previous anecdotal reports have documented the occurrence of hypertension during therapy with aripiprazole and resolution following its discontinuation.15–18 While none of these reports has conclusively demonstrated the mechanism for this hypertension, Borras and Constant18 noted successful treatment with propranolol, suggesting that the sympathetic nervous system with adrenergic hyperactivity was the primary mechanism for the alterations in BP.\n\nOur patient was also receiving methylphenidate as part of her chronic medication regimen. Alterations in BP have also been noted with methylphenidate, with the primary mechanism postulated to be the result of increased central and peripheral concentrations of dopamine, norepinephrine, and epinephrine.19 We would postulate that the combined effects of these two medications (aripiprazole and methylphenidate) may augment the normal surgical stress response that is mediated by the sympathetic nervous system. This sympathetic release of endogenous catecholamines, including norepinephrine and epinephrine, modulates perioperative alterations in BP, an effect appreciated even in patients without a prior history of hypertension.20 While an exact mechanism cannot be determined for the resistance to clevidipine noted in our patient, we would postulate that the combination of medications either increased the normal sympathetic response to surgery or potentiated the response at the level of the vascular smooth muscle. The involvement of the sympathetic nervous system is further supported by our patient’s response to labetalol, a mixed α- and β-adrenergic antagonist.\n\nIn summary, we present anecdotal evidence for resistance to the direct vasodilatory effects of clevidipine in a patient chronically receiving methylphenidate and aripiprazole. We would postulate that the mechanism involves the sympathetic nervous system with either increased release of endogenous catecholamines or an augmented effect of these agents on the smooth muscle of the vasculature. In such clinical scenarios, medications that act primarily through blocking the sympathetic nervous system or its peripheral effects, such as with labetalol, appear to be a logical choice for BP control.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1 Levy JH Mancao MY Gitter R Clevidipine effectively and rapidly controls blood pressure preoperatively in cardiac surgery patients: the results of the randomized, placebo-controlled efficacy study of clevidipine assessing its preoperative antihypertensive effect in cardiac surgery Anesth Analg 2007 105 918 925 17898366 \n2 Singla N Warltier DC Gandhi SD Treatment of acute postoperative hypertension in cardiac surgery patients: an efficacy study of clevidipine assessing its postoperative antihypertensive effect in cardiac surgery-2 (ESCAPE-2), a randomized, double-blind, placebo-controlled trial Anesth Analg 2008 107 59 67 18635468 \n3 Aronson S Dyke CM Stierer KA The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients Anesth Analg 2008 107 1110 1121 18806012 \n4 Towe E Tobias JD Preliminary experience with clevidipine in the pediatric population J Intensive Care Med 2010 25 349 352 20837631 \n5 Tobias JD Schechter WS Phillips A Clevidipine for perioperative blood pressure control in infants and children undergoing cardiac surgery for congenital heart disease J Pediatr Pharmacol Ther 2011 16 55 60 22477825 \n6 Tobias JD Hoernschemeyer DG Clevidipine for controlled hypotension during spinal surgery in adolescents J Neurosurg Anesthesiol 2011 23 347 351 21623231 \n7 Tobias JD Strategies for minimizing blood loss in orthopedic surgery Semin Hematol 2004 41 145 156 14872436 \n8 Tobias JD Controlled hypotension in children: a critical review of available agents Paediatr Drugs 2002 4 439 453 12083972 \n9 Kako H Gable A Martin D A prospective, open-label trial of clevidipine for controlled hypotension during posterior spinal fusion in adolescents J Pediatr Pharm Therap \n10 Tobias JD Hersey S Mencio GA Green NE Nicardipine for controlled hypotension during spinal surgery J Pediatr Orthop 1996 16 370 373 8728640 \n11 Tobias JD Nicardipine to control mean arterial pressure after cardiothoracic surgery in infants and children Am J Ther 2001 8 3 6 11304651 \n12 Pedrinelli R Tarazi RC Interference of calcium entry blockade in vivo with pressor responses to alpha-adrenergic stimulation: effects of two unrelated blockers on responses to both exogenous and endogenously released norepinephrine Circulation 1984 69 1171 1176 6143626 \n13 Myers MG Norris JW Hachniski VC Sole MJ Plasma norepinephrine in stroke Stroke 1981 12 200 204 7233464 \n14 Chen TY Tzeng NS Aripiprazole: a dopamine modulator that mimics methylphenidate in producing faster antidepressant effects Med Hypotheses 2013 81 183 185 23751312 \n15 Hsiao YL Chen SJ Shen TW Chang CH Chen ST Aripiprazole augmentation induced hypertension in major depressive disorder: a case report Prog Neuropsychopharmacol Biol Psychiatry 2011 35 305 306 21111018 \n16 Bat-Pitault F Delorme R Aripiprazole and hypertension in adolescents J Child Adolesc Psychopharmacol 2009 19 601 602 19877990 \n17 Yasui-Furukori N Fujii A Worsened hypertension control induced by aripiprazole Neuropsychiatr Dis Treat 2013 9 505 507 23723701 \n18 Borras L Constant EL Hypertension and aripiprazole Am J Psych 2005 162 12 \n19 Volkow ND Wang GJ Fowler JS Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma Psychopharmacology 2003 166 264 270 12589522 \n20 Nordlander M Pfaffendorf M van Wezel HB Calcium channel antagonists for perioperative blood pressure control Semin Cardiothor Vasc Anesth 1998 2 231 242\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1179-1454", "issue": "6()", "journal": "Journal of experimental pharmacology", "keywords": "aripiprazole; blood pressure; calcium channel antagonist; clevidipine; controlled hypotension; labetalol; posterior spinal fusion", "medline_ta": "J Exp Pharmacol", "mesh_terms": null, "nlm_unique_id": "101530345", "other_id": null, "pages": "11-4", "pmc": null, "pmid": "27186138", "pubdate": "2014", "publication_types": "D002363:Case Reports", "references": "25859171;11304651;22477825;7233464;21111018;14872436;12589522;16330611;12083972;21623231;19877990;18806012;6143626;17898366;18635468;8728640;23723701;23751312;20837631", "title": "Clevidipine resistance in a patient taking aripiprazole and methylphenidate.", "title_normalized": "clevidipine resistance in a patient taking aripiprazole and methylphenidate" }	[ { "companynumb": "US-JNJFOC-20141117721", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021121", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUSTAINED RELEASE TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATTENTION DEFICIT/HYPERACTIVITY DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "36", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPHENIDATE HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUSTAINED RELEASE TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "36", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPHENIDATE HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLEVIDIPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLEVIDIPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARIPIPRAZOLE." } ], "patientagegroup": "3", "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "51.3", "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood pressure decreased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Heart rate increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JACKLEN MA, CAMPAGNA JA, TOBIAS JD. CLEVIDIPINE RESISTANCE IN A PATIENT TAKING ARIPIPRAZOLE AND METHYLPHENIDATE. JOURNAL OF EXPERIMENTAL PHARMACOLOGY 2014;6:11-14.", "literaturereference_normalized": "clevidipine resistance in a patient taking aripiprazole and methylphenidate", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150524", "receivedate": "20150319", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10928678, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]
{ "abstract": "BACKGROUND\nThere have been several reports of bupropion insufflation since 2002 and 2 cases of intravenous bupropion use disorder since 2013. There are no documented cases of bupropion injection associated with tissue necrosis or psychosis.\n\n\nMETHODS\nWe report 2 cases of habitual intravenous bupropion injection by individuals with polysubstance use disorder and comorbid mental illness. The patients obtained bupropion as a result of physician deception, diversion or crime, and injected it to achieve a high. Both individuals experienced tissue and vascular complications, including tissue necrosis, cellulitis, and compartment syndrome in 1 patient. The other patient reported visual hallucinations and persecutory ideation that persisted for 3 days after his last use of the drug.\n\n\nCONCLUSIONS\nBupropion seems to have addictive effects, particularly when administered intravenously or intranasally. Individuals who inject high doses of bupropion may be at risk of tissue necrosis, seizures, or psychosis. Prescribers should be aware of uncontrolled medications with emerging potential for abuse and popularity among recreational drug users. We identify a need for policy on clinical strategies to minimize the abuse and diversion of bupropion and other uncontrolled prescription drugs.", "affiliations": "From the Department of Psychiatry (MS, SH), University of Ottawa, ON, Canada; and Department of Psychological Medicine (SH), University of Auckland, Auckland, New Zealand.", "authors": "Strike\|Melanie\|M\|;Hatcher\|Simon\|S\|", "chemical_list": "D018765:Dopamine Uptake Inhibitors; D016642:Bupropion", "country": "United States", "delete": false, "doi": "10.1097/ADM.0000000000000114", "fulltext": null, "fulltext_license": null, "issn_linking": "1932-0620", "issue": "9(3)", "journal": "Journal of addiction medicine", "keywords": null, "medline_ta": "J Addict Med", "mesh_terms": "D016642:Bupropion; D018765:Dopamine Uptake Inhibitors; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009336:Necrosis; D011605:Psychoses, Substance-Induced; D015819:Substance Abuse, Intravenous; D055815:Young Adult", "nlm_unique_id": "101306759", "other_id": null, "pages": "246-50", "pmc": null, "pmid": "25822212", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Bupropion injection resulting in tissue necrosis and psychosis: previously undocumented complications of intravenous bupropion use disorder.", "title_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder" }	[ { "companynumb": "PHHY2015CA134561", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "75932", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "EXTENDED RELEASE TABLET", "drugdosagetext": "300 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug administration error", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral swelling", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persecutory delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Injection site pain", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S.. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER.. J-ADDICT-MED. 2015?9(3):246-50.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151021", "receivedate": "20151021", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11649594, "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": "CA-TEVA-605130USA", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "045", "drugauthorizationnumb": "75310", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "75310", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG 4 TIMES DAILY AS REQUIRED FOR ANXIETY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "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": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG AT BEDTIME", "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": "QUETIAPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG AT BEDTIME", "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": "TRAZODONE" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Persecutory delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Injection site pain", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J-ADDICT-MED 2015? 9(3):246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151102", "receivedate": "20151102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11690644, "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" }, { "companynumb": "CA-IMPAX LABORATORIES, INC-2015-IPXL-01033", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "NICOTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICOTINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 3 /DAY (TAKING UP TO 10 MG DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "075913", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "300 MG, EVERY 1 TO 2 HOURS (1500 TO 3000 MG DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE SR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. INDICA TOP" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE ABUSE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANNABIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAFFEINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAFFEINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "075913", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "7 INJECTIONS OF 300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE SR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood pressure increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Heart rate increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arterial occlusive disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S.. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. JOURNAL OF ADDICTION MEDICINE. 2015?9:3:246-50", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151027", "receivedate": "20151027", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11668537, "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": "CA-WATSON-2016-10109", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, QHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "077715", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET (EXTENDED RELEASE)", "drugdosagetext": "4500 MG, DAILY( 30 TABLETS OVER 48 HOURS WITH AN AVERAGE OF 1 TABLET PER HOUR)", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE XL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "045", "drugauthorizationnumb": "077715", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET (EXTENDED RELEASE)", "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": "BUPROPION HYDROCHLORIDE XL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, QID, AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Injection site pain", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Substance-induced psychotic disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug diversion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED. 2015;9(3):246-50.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160516", "receivedate": "20160516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12372257, "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": "CA-EDGEMONT-2015EDG00043", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 4X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "022497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "4500 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE EXTENDED RELEASE (XL)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "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": "BUPROPION HYDROCHLORIDE EXTENDED RELEASE (XL)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" } ], "patientagegroup": "5", "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peripheral swelling", "reactionmeddraversionpt": "18.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED (DOI: 10.1097/ADM.0000000000000114). 2015?9(3):246-250", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11705977, "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": "CA-PRINSTON PHARMACEUTICAL INC.-2015PRN00101", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "202304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "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": "BUPROPION HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "202304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "4500 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 4X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED (DOI: 10.1097/ADM.0000000000000114). 2015?9(3):246-250", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151109", "receivedate": "20151109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11714448, "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": "CA-EDGEMONT-2015EDG00044", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 3X/DAY (UP TO 10 MG/DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAFFEINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "CAFFEINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "022497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "300 MG EVERY 1 TO 2 HOURS (1500 TO 3000 MG DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE EXTENDED RELEASE (XL)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NICOTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "NICOTINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, 1X/DAY", "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": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. INDICA TOP" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "CANNABIS" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Arterial occlusive disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2011" } }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED (DOI: 10.1097/ADM.0000000000000114). 2015?9(3):246-250", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11705988, "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" }, { "companynumb": "CA-TEVA-605131USA", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UP TO 10MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "75310", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 INJECTIONS AT RATE OF 300MG/H (TOTAL 2100MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1MG 3 TIMES DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "75310", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Arterial occlusive disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J-ADDICT-MED 2015? 9(3):246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151102", "receivedate": "20151102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11690648, "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" }, { "companynumb": "CA-BAUSCH-BL-2015-026277", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021515", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "USING ALTERNATING FOREARMS, CONSUMED AN AVERAGE OF 1 TABLET PER HOUR, INJECTED 30 TABLETS OVER 48 HO", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSIVE SYMPTOM", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION XL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIACETYLMORPHINE" }, "drugadditional": null, "drugadministrationroute": "042", "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": "HEROIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS REQUIRED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYCODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "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": "OXYCONTIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": null, "drugadministrationroute": "042", "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": "HYDROMORPHONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "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": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": 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": "COCAINE" }, "drugadditional": null, "drugadministrationroute": "042", "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": "COCAINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": null, "drugadministrationroute": "042", "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": "MORPHINE" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persecutory delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral swelling", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vascular wall hypertrophy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. JOURNAL OF ADDICTION MEDICINE. 2015?9:246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151111", "receivedate": "20151111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11723099, "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": "CA-WATSON-2016-10122", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET (EXTENDED RELEASE)", "drugdosagetext": "THE 7TH INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE SR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET (EXTENDED RELEASE)", "drugdosagetext": "1800 MG, TOTAL( 6 INJECTIONS AT A RATE OF 300 MG PER HOUR)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE SR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74869", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UP TO 10 MG DAILY", "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": "CLONAZEPAM (UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74869", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "1 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacillus infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug diversion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry gangrene", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED. 2015;9(3):246-50.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160516", "receivedate": "20160516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12372549, "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" }, { "companynumb": "CA-IMPAX LABORATORIES, INC-2015-IPXL-01032", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYCODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCONTIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "COCAINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COCAINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "4500 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION XL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION XL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIACETYLMORPHINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEROIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "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": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG 4 TIMES DAILY AS REQUIRED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Euphoric mood", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug tolerance increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persecutory delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S.. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. JOURNAL OF ADDICTION MEDICINE. 2015?9:3:246-50", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151026", "receivedate": "20151026", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11661182, "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" }, { "companynumb": "CA-MYLANLABS-2015M1036172", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "045", "drugauthorizationnumb": "075491", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG 4 TIMES DAILY AS REQUIRED FOR ANXIETY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "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": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG AT BEDTIME", "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": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "075491", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "30 TABLETS (4500MG DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG AT BEDTIME", "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": "QUETIAPINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Injection site pain", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persecutory delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J-ADDICT-MED 2015? 9(3):246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151026", "receivedate": "20151026", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11662030, "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": "CA-PRINSTON PHARMACEUTICAL INC.-2015PRN00102", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "NICOTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "NICOTINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "202304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "300 MG EVERY 1 TO 2 HOURS (1500 TO 3000 MG DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. INDICA TOP" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "CANNABIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAFFEINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "CAFFEINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, 1X/DAY", "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": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 3X/DAY (UP TO 10 MG/DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacillus infection", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2011" } }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED (DOI: 10.1097/ADM.0000000000000114). 2015?9(3):246-250", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151109", "receivedate": "20151109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11714450, "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" }, { "companynumb": "PHHY2015CA134563", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "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": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "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": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPHENIDATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021278", "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": "METHYLPHENIDATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. INDICA TOP" }, "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": "CANNABIS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NICOTINE" }, "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": "NICOTINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALERT//CAFFEINE" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S.. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER.. J-ADDICT-MED. 2015?9(3):246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151020", "receivedate": "20151020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11645305, "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": "CA-MYLANLABS-2015M1036173", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "075491", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 INJECTIONS AT RATE OF 300MG/H (TOTAL 2100MG)", "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": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, TID", 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"drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UP TO 10MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arterial occlusive disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J-ADDICT-MED 2015? 9(3):246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151026", "receivedate": "20151026", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11662031, "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" }, { "companynumb": "PHHY2015CA134562", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "75932", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "EXTENDED RELEASE TABLET", "drugdosagetext": "300 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SMOKING CESSATION THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug administration error", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S.. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER.. J-ADDICT-MED. 2015?9(3):246-50.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151021", "receivedate": "20151021", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11649593, "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": "We describe a 51-year-old man who developed renal and neural toxicity after the administration of colistin. He developed respiratory apnoea, neuromuscular blockade and severe comatose encephalopathy with the lack of brainstem reflexes. After discontinuation of the antibiotic, he made a prompt recovery to his baseline neurological function. The case illustrates the importance of recognising the toxicities associated with colistin. Although recent literature details its nephrotoxicity, current data have been discordant with the rare cases of respiratory apnoea or neuromuscular blockade once cited over 30 years ago. Additionally, no cases have ever described the profound encephalopathy with lack of brainstem function described here. The awareness of colistin's potentially fatal effects must be kept in mind when administering this antibiotic. Vigilance of the encephalopathic picture can also facilitate the diagnosis of colistin-mediated neurotoxicity in a patient with altered mental status of otherwise unknown aetiology.", "affiliations": "Rush University Medical Center, Chicago, Illinois, USA.;Department of Pulmonary and Critical Care, Rush University Medical Center, Chicago, Illinois, USA.", "authors": "Wadia\|Subeer\|S\|;Tran\|Betty\|B\|", "chemical_list": "D000900:Anti-Bacterial Agents; D003091:Colistin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2014()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000900:Anti-Bacterial Agents; D001049:Apnea; D001933:Brain Stem; D003091:Colistin; D003128:Coma; D006801:Humans; D007674:Kidney Diseases; D008297:Male; D008875:Middle Aged; D009468:Neuromuscular Diseases; D020258:Neurotoxicity Syndromes", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "25199193", "pubdate": "2014-09-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "16507149;21906345;21906382;4306125", "title": "Colistin-mediated neurotoxicity.", "title_normalized": "colistin mediated neurotoxicity" }	[ { "companynumb": "US-PAR PHARMACEUTICAL, INC-2014SCPR009508", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORIPENEM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TIGECYCLINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIGECYCLINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "COLISTIMETHATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "050108", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "275 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "275", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLY-MYCIN M" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neuromuscular blockade", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal tubular necrosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Apnoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "WADIA S., TRAN B.. COLISTIN-MEDIATED NEUROTOXICITY. 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"INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROTEUS TEST POSITIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLISTIMETHATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TIGECYCLINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIGECYCLINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORIPENEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORIPENEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACINETOBACTER INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORIPENEM." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neuromuscular blockade", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal tubular necrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Apnoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WADIA S, TRAN B.. COLISTIN-MEDIATED NEUROTOXICITY.. BMJ CASE REP.. 2014?2014:PII: BCR-2014-205332", "literaturereference_normalized": "colistin mediated neurotoxicity", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200212", "receivedate": "20200212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17406116, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200409" } ]
{ "abstract": "Rivaroxaban is a factor-Xa-inhibitor which has been shown to be non-inferior to the vitamin-K-antagonist (VKA) warfarin in atrial fibrillation patients. In the manufacturer-sponsored trial, the rate of intracranial hemorrhage in rivaroxaban-treated patients was lower than in VKA-treated. It is unknown if this advantage of rivaroxaban is also present outside clinical trials. We report a patient with fatal cerebral bleeding 4months after initiation of rivaroxaban. Bleeding might be favored by hypertension, hypoalbuminemia, renal impairment, hepatopathy and drug-drug interactions of rivaroxaban with amiodarone and bisoprolol. Patients have to be monitored closely after initiation of rivaroxaban, especially if they are treated with possibly interacting drugs. Additionally, hepatic function, albumin level, and renal function have to be closely monitored. Therapy with VKA seems more convenient, safer and more favorable for the patient than rivaroxaban with its associated uncertainties concerning metabolization and drug-drug interactions and no possibility to reverse its activity in emergency situations.", "affiliations": "Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Austria. Electronic address: [email protected].;Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Austria. Electronic address: [email protected].;Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Austria. Electronic address: [email protected].", "authors": "Stöllberger\|Claudia\|C\|;Bastovansky\|Adam\|A\|;Finsterer\|Josef\|J\|", "chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0167-5273", "issue": "201()", "journal": "International journal of cardiology", "keywords": "Atrial fibrillation; Cerebral bleeding; Rivaroxaban", "medline_ta": "Int J Cardiol", "mesh_terms": "D000368:Aged; D002543:Cerebral Hemorrhage; D065427:Factor Xa Inhibitors; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D000069552:Rivaroxaban", "nlm_unique_id": "8200291", "other_id": null, "pages": "110-2", "pmc": null, "pmid": "26296048", "pubdate": "2015-12-15", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Fatal intracerebral bleeding under rivaroxaban.", "title_normalized": "fatal intracerebral bleeding under rivaroxaban" }	[ { "companynumb": "US-UNICHEM LABORATORIES LIMITED-UCM201510-000856", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BISOPROLOL FUMARATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078635", "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": "BISOPROLOL FUMARATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": null, "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": "AMIODARONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "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": "RIVAROXABAN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STOLLBERGER C,BASTOVANSKY A,FINSTERER J. FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. INTERNATIONAL JOURNAL OF CARDIOLOGY 2015 OCT 10?201:110-2.", "literaturereference_normalized": "fatal intracerebral bleeding under rivaroxaban", "qualification": "3", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20151102", "receivedate": "20151102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11691034, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "AT-PFIZER INC-2015352153", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONIDINE" }, "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": "CLONIDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIODARONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "018972", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201411", "drugstartdateformat": "610", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BISOPROLOL FUMARATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201411", "drugstartdateformat": "610", "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL FUMARATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201411", "drugstartdateformat": "610", "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIODARONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "018972", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "URAPIDIL" }, "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": "URAPIDIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALSARTAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "160", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALSARTAN." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STOLLBERGER, C.. FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. INTERNATIONAL JOURNAL OF CARDIOLOGY. 2015;201:110-112", "literaturereference_normalized": "fatal intracerebral bleeding under rivaroxaban", "qualification": "1", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20170801", "receivedate": "20151103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11693846, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "AT-FRESENIUS KABI-FK201505802", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIODARONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075761", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALSARTAN" }, "drugadditional": null, "drugadministrationroute": "065", "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": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "160", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALSARTAN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIODARONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075761", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL" }, { "actiondrug": null, "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": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STOLLBERGER C,BASTOVANSKY A,FINSTERER J. FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. INTERNATIONAL JOURNAL OF CARDIOLOGY 2015 OCT 10?201:110-112.", "literaturereference_normalized": "fatal intracerebral bleeding under rivaroxaban", "qualification": "3", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20151116", "receivedate": "20151116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11744229, "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" }, { "companynumb": "PHHY2015AT142454", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75315", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. INT-J-CARDIOL. 2015?201110-112", "literaturereference_normalized": "fatal intracerebral bleeding under rivaroxaban", "qualification": "3", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11703282, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "AT-JNJFOC-20151118719", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202439", 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"drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALSARTAN" }, "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": "VALSARTAN." }, { "actiondrug": "5", "activesubstance": { 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"reactionoutcome": "5" }, { "reactionmeddrapt": "Hypoalbuminaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Liver disorder", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STOLLBERGER C, BASTOVANSKY A, FINSTERER J. FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. INTERNATIONAL JOURNAL OF CARDIOLOGY 2015?201:110-112.", "literaturereference_normalized": "fatal intracerebral bleeding under rivaroxaban", "qualification": "3", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20151120", "receivedate": "20151120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11760260, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "AT-UNICHEM LABORATORIES LIMITED-UCM201510-000856", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": null, "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": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "URAPIDIL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, 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FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. INTERNATIONAL JOURNAL OF CARDIOLOGY 2015?201:110-2.", "literaturereference_normalized": "fatal intracerebral bleeding under rivaroxaban", "qualification": "3", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20151217", "receivedate": "20151217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11846505, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" }, { "companynumb": "AT-MYLANLABS-2015M1038577", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076217", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200MG/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": "AMIODARONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076217", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201411", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALSARTAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160MG/DAY", "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": "VALSARTAN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STOLLBERGER C, BASTOVANSKY A, FINSTERER J. FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. INT-J-CARDIOL 2015? 201:110-112.", "literaturereference_normalized": "fatal intracerebral bleeding under rivaroxaban", "qualification": "3", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20151111", "receivedate": "20151111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11723801, "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": "The long-term safety and efficacy of filgotinib (from phase II studies), with or without methotrexate (MTX), for the treatment of patients with rheumatoid arthritis was assessed in DARWIN 3, a long-term, open-label extension study (ClinicalTrials.gov: NCT02065700).\n\n\n\nEligible patients completing the 24-week DARWIN 1 (filgotinib + MTX) and DARWIN 2 (filgotinib monotherapy) studies entered DARWIN 3, where they received filgotinib 200 mg/day, except for 15 men who received filgotinib 100 mg/day. Safety analyses were performed using the safety analysis set and the exposure-adjusted incidence rate (EAIR) of treatment-emergent adverse events (TEAEs) was calculated. Efficacy was assessed from baseline in the parent studies.\n\n\n\nOf 790 patients completing the phase II parent studies, 739 enrolled in the study. Through April 2019, 59.5% of patients had received ≥ 4 years of the study drug. Mean (SD) exposure to filgotinib was 3.55 (1.57) years in the filgotinib + MTX group and 3.38 (1.59) years in the filgotinib monotherapy group. EAIR per 100 patient-years of exposure for TEAEs was 24.6 in the filgotinib + MTX group and 25.8 in the filgotinib monotherapy group, and for serious TEAEs, the EAIR was 3.1 and 4.3, respectively. American College of Rheumatology 20/50/70 responses among patients remaining in the study could be maintained through 4 years, with 89.3%/69.6%/49.1% of the filgotinib + MTX group and 91.8%/69.4%/44.4% of the monotherapy group maintaining ACR20/50/70 responses, respectively, based on observed data.\n\n\n\nFilgotinib was well tolerated with a 4-year safety profile comparable to that of the parent trials, both in patients receiving combination therapy with MTX or as monotherapy.", "affiliations": "A. Kavanaugh, MD, University of California San Diego, La Jolla, California, USA; [email protected].;R.R. Westhovens, MD, PhD, KU Leuven, Skeletal Biology and Engineering Research Center, Leuven, Belgium.;K.L. Winthrop, MD, MPH, Oregon Health and Science University, Portland, Oregon, USA.;S.J. Lee, MD, Y. Tan, PhD, D. An, PhD, L. Ye, PhD, J.S. Sundy, MD, PhD, Gilead Sciences Inc., Foster City, California, USA.;S.J. Lee, MD, Y. Tan, PhD, D. An, PhD, L. Ye, PhD, J.S. Sundy, MD, PhD, Gilead Sciences Inc., Foster City, California, USA.;S.J. Lee, MD, Y. Tan, PhD, D. An, PhD, L. Ye, PhD, J.S. Sundy, MD, PhD, Gilead Sciences Inc., Foster City, California, USA.;S.J. Lee, MD, Y. Tan, PhD, D. An, PhD, L. Ye, PhD, J.S. Sundy, MD, PhD, Gilead Sciences Inc., Foster City, California, USA.;S.J. Lee, MD, Y. Tan, PhD, D. An, PhD, L. Ye, PhD, J.S. Sundy, MD, PhD, Gilead Sciences Inc., Foster City, California, USA.;R. Besuyen, MD, L. Meuleners, MS, Galapagos NV, Mechelen, Belgium.;R. Besuyen, MD, L. Meuleners, MS, Galapagos NV, Mechelen, Belgium.;M. Stanislavchuk, MD, National Pirogov Memorial Medical University, Vinnytsya, Ukraine.;A.J. Spindler, MD, Centro Medico Privado de Reumatologia, San Miguel de Tucuman, Argentina.;M. Greenwald, MD, Desert Medical Advances, Palm Desert, California, USA.;R. Alten, MD, Schlosspark Klinik, University Medicine Berlin, Berlin, Germany.;M.C. Genovese, MD, Stanford University School of Medicine, Division of Immunology & Rheumatology, Stanford, and Gilead Sciences Inc., Foster City, California, USA.", "authors": "Kavanaugh\|Arthur\|A\|;Westhovens\|Rene R\|RR\|;Winthrop\|Kevin L\|KL\|;Lee\|Susan J\|SJ\|;Tan\|YingMeei\|Y\|;An\|Di\|D\|;Ye\|Lei\|L\|;Sundy\|John S\|JS\|;Besuyen\|Robin\|R\|0000-0002-8699-4549;Meuleners\|Luc\|L\|;Stanislavchuk\|Mykola\|M\|;Spindler\|Alberto J\|AJ\|;Greenwald\|Maria\|M\|;Alten\|Rieke\|R\|0000-0002-3395-4412;Genovese\|Mark C\|MC\|0000-0001-5294-4503", "chemical_list": "D018501:Antirheumatic Agents; C584571:GLPG0634; D011725:Pyridines; D014230:Triazoles; D008727:Methotrexate", "country": "Canada", "delete": false, "doi": "10.3899/jrheum.201183", "fulltext": null, "fulltext_license": null, "issn_linking": "0315-162X", "issue": "48(8)", "journal": "The Journal of rheumatology", "keywords": "ACR improvement criteria; inflammation; methotrexate; rheumatoid arthritis", "medline_ta": "J Rheumatol", "mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008727:Methotrexate; D011725:Pyridines; D016896:Treatment Outcome; D014230:Triazoles", "nlm_unique_id": "7501984", "other_id": null, "pages": "1230-1238", "pmc": null, "pmid": "33526618", "pubdate": "2021-08", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Safety and Efficacy of Filgotinib: Up to 4-year Results From an Open-label Extension Study of Phase II Rheumatoid Arthritis Programs.", "title_normalized": "safety and efficacy of filgotinib up to 4 year results from an open label extension study of phase ii rheumatoid arthritis programs" }	[ { "companynumb": "US-AZURITY PHARMACEUTICALS, INC.-US-2022ARB000851", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": "208400", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15?25 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FILGOTINIB" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TOTAL 50?200 MG/DAY, GIVEN EITHER ONCE OR TWICE DAILY", "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": "FILGOTINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningitis meningococcal", "reactionmeddraversionpt": "25.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Kavanaugh A., Westhovens R.R., Winthrop K.L., Lee S.J., Tan Y., An D., et al.. Safety and efficacy of filgotinib: Up to 4-year results from an open-label extension study of phase II rheumatoid arthritis programs. Journal of Rheumatology. 2021;48:8:1230-1238", "literaturereference_normalized": "safety and efficacy of filgotinib up to 4 year results from an open label extension study of phase ii rheumatoid arthritis programs", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220405", "receivedate": "20220405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20676257, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]

{ "abstract": "Fetal supraventricular tachycardia (SVT), characterized by a fetal ventricular heart rate faster than 200 beats per minute (bpm), is often diagnosed during routine fetal heart monitoring or prenatal ultrasound examinations. Clinical guidelines for management of fetal SVT have not been determined in standardized trials, nor do we have a clear sense regarding the long-term developmental outcomes and side effects of in utero antiarrhythmic therapy. We describe our approach to the treatment of refractory SVT in a fetus with hydrops using direct umbilical vein treatment with amiodarone coupled with effusion evacuation. We successfully achieved in utero resolution of SVT. There was transient amiodarone-induced hypothyroidism, which we screened for early and treated with Synthroid. Ultimately our patient had normal long-term growth and development as measured by modified Denver office checklists and Ages and Stages questionnaires. Our experience advocates for vigilant screening and management of hypothyroidism in fetuses exposed to in utero amiodarone and suggests that it is possible to achieve good outcomes in high-acuity refractory cases of SVT.", "affiliations": "Department of Pediatrics, Division of Pediatric Cardiology, The Children's Hospital at Montefiore-Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Obstetrics, Gynecology & Women's Health, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Obstetrics, Gynecology & Women's Health, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Pediatrics, Division of Pediatric Cardiology, The Children's Hospital at Montefiore-Albert Einstein College of Medicine, Bronx, NY, USA.", "authors": "Capone|C A|CA|;Gebb|J|J|;Dar|P|P|;Shenoy|R U|RU|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone; D013974:Thyroxine", "country": "Netherlands", "delete": false, "doi": "10.3233/NPM-14814017", "fulltext": null, "fulltext_license": null, "issn_linking": "1878-4429", "issue": "7(4)", "journal": "Journal of neonatal-perinatal medicine", "keywords": "Fetal arrhythmias; amiodarone-induced hypothyroidism; cardioversion; hydrops fetalis; neurodevelopment", "medline_ta": "J Neonatal Perinatal Med", "mesh_terms": "D000328:Adult; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D005260:Female; D005315:Fetal Diseases; D006801:Humans; D015160:Hydrops Fetalis; D007037:Hypothyroidism; D007231:Infant, Newborn; D011247:Pregnancy; D013617:Tachycardia, Supraventricular; D013974:Thyroxine; D016896:Treatment Outcome; D016216:Ultrasonography, Prenatal", "nlm_unique_id": "101468335", "other_id": null, "pages": "305-9", "pmc": null, "pmid": "25468615", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Favorable neurodevelopmental outcome in a hypothyroid neonate following intracordal amiodarone for cardioversion of refractory supraventricular tachycardia in a fetus.", "title_normalized": "favorable neurodevelopmental outcome in a hypothyroid neonate following intracordal amiodarone for cardioversion of refractory supraventricular tachycardia in a fetus" }

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"reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Supraventricular tachycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hydrops foetalis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardioactive drug level below therapeutic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CAPONE C.A, GEBB J, DAR P, SHENOY RU. FAVORABLE NEURODEVELOPMENTAL OUTCOME IN A HYPOTHYROID NEONATE FOLLOWING INTRACORDAL AMIODARONE FOR CARDIOVERSION OF REFRACTORY SUPRAVENTRICULAR TACHYCARDIA IN A FETUS. 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FAVORABLE NEURODEVELOPMENTAL OUTCOME IN A HYPOTHYROID NEONATE FOLLOWING INTRACORDAL AMIODARONE FOR CARDIOVERSION OF REFRACTORY SUPRAVENTRICULAR TACHYCARDIA IN A FETUS.. 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FAVORABLE NEURODEVELOPMENTAL OUTCOME IN A HYPOTHYROID NEONATE FOLLOWING INTRACORDAL AMIODARONE FOR CARDIOVERSION OF REFRACTORY SUPRAVENTRICULAR TACHYCARDIA IN A FETUS.. JOURNAL OF NEONATAL-PERINATAL MEDICINE. 2014;7 (4):305-9", "literaturereference_normalized": "favorable neurodevelopmental outcome in a hypothyroid neonate following intracordal amiodarone for cardioversion of refractory supraventricular tachycardia in a fetus", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150128", "receivedate": "20150128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10743485, "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-SA-2015SA002670", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", 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"medicinalproduct": "GLIBENCLAMIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TACHYCARDIA FOETAL", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPRANOLOL\\PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": null, 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUPRAVENTRICULAR TACHYCARDIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLECAINIDE ACETATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "3.4", "reaction": [ { "reactionmeddrapt": "Thyroxine free decreased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood thyroid stimulating hormone increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothyroidism", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CAPONE CA, GEBB J, DAR P, SHENOY RU. FAVORABLE NEURODEVELOPMENTAL OUTCOME IN A HYPOTHYROID NEONATE FOLLOWING INTRACORDAL AMIODARONE FOR CARDIOVERSION OF REFRACTORY SUPRAVENTRICULAR TACHYCARDIA IN A FETUS. JOURNAL OF NEONATAL-PERINATAL MEDICINE 2014;7:305-9. DOI: 10.3233/NPM-14814017", "literaturereference_normalized": "favorable neurodevelopmental outcome in a hypothyroid neonate following intracordal amiodarone for cardioversion of refractory supraventricular tachycardia in a fetus", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150114", "receivedate": "20150114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10710525, "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": "Cutaneous alternariosis is an uncommon fungal infection that most commonly presents in organ transplant patients on immunosuppressive therapy. There are no clinical trials or guidelines to guide treatment of this condition, however itraconazole is the most commonly used antifungal in published cases. Here we report on a case of cutaneous alternariosis in a renal transplant recipient treated with a newer antifungal, posaconazole. A review of published reports of cutaneous alternariosis since 2008 is also discussed.", "affiliations": "Niagara Falls Memorial Medical Center, 621 10th Street, Niagara Falls, NY 14302, USA.;Niagara Falls Memorial Medical Center, 621 10th Street, Niagara Falls, NY 14302, USA; D'Youville College School of Pharmacy, 320 Porter Avenue, Buffalo, NY 14201, USA.;Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212, USA.", "authors": "Bajwa|Rajinder|R|;Wojciechowski|Amy L|AL|;Hsiao|Chiu-Bin|CB|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.mmcr.2017.01.003", "fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(17)30002-710.1016/j.mmcr.2017.01.003Case ReportCutaneous alternariosis in a renal transplant patient successfully treated with posaconazole: Case report and literature review Bajwa Rajinder aWojciechowski Amy L. [email protected]@nfmmc.orgab⁎Hsiao Chiu-Bin ca Niagara Falls Memorial Medical Center, 621 10th Street, Niagara Falls, NY 14302, USAb D’Youville College School of Pharmacy, 320 Porter Avenue, Buffalo, NY 14201, USAc Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212, USA⁎ Corresponding author at: Niagara Falls Memorial Medical Center, 621 10th Street, Niagara Falls, NY 14302, USA. [email protected]@nfmmc.org21 1 2017 3 2017 21 1 2017 15 16 20 1 12 2016 12 1 2017 17 1 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cutaneous alternariosis is an uncommon fungal infection that most commonly presents in organ transplant patients on immunosuppressive therapy. There are no clinical trials or guidelines to guide treatment of this condition, however itraconazole is the most commonly used antifungal in published cases. Here we report on a case of cutaneous alternariosis in a renal transplant recipient treated with a newer antifungal, posaconazole. A review of published reports of cutaneous alternariosis since 2008 is also discussed.\n\nKeywords\nAlternaria spp.AlternariosisFungal infectionPosaconazole\n==== Body\n1 Introduction\nSkin lesions are common in organ transplant recipients who are on immunosuppressive therapy. Almost all cases require a biopsy to confirm the etiology, as there are a variety of infectious and non-infectious causes of the skin lesions in this patient population. We recently saw a pancreatic-renal transplant patient who presented with cutaneous alternariosis. Infection with Alternaria spp. is relatively uncommon and has been primarily described in case reports and small case series, with the last major review reported in 2008 [1]. Therefore, in this report we summarize the clinical findings from reports since 2008. Further, there are no randomized trials that address treatment of cutaneous alternariosis. Although itraconazole has been used most commonly, there have been case reports of failure or relapse with that agent [2]. Newer antifungal agents have started to gain popularity in treating cutaneous alternariosis [3], [4], [5], [6], including our case which was successfully treated with posaconazole.\n\n2 Case\nA 56 year old male with end stage renal disease secondary to type 1 diabetes mellitus (DM) and history of renal and pancreatic transplant presented to the clinic (day 0) with complaints of multiple non-pruritic lesions on his lower extremities. The patient stated that he first noticed the lesion three weeks prior to presentation as a single lesion on his left ankle with then progressed and spread to both lower extremities. The patient had undergone a cadaveric renal and pancreatic transplant five months prior to presentation. The transplanted kidney underwent acute rejection and was removed four months prior to presentation, necessitating reinstitution of hemodialysis. He was continued on his immunosuppressive therapy because of well-functioning pancreatic transplant. His immunosuppressive regimen included tacrolimus 2 mg in morning and 3 mg in evening, mycophenolate mofetil 540 mg twice daily and prednisone 5 mg daily. He was also on trimethoprim-sulfamethoxazole double-strength tablet three times a week as prophylaxis against opportunistic infections. Other medications included metoprolol for hypertension and erythropoietin injections for anemia.\n\nOn the day of presentation to the clinic, the patient's physical examination was only remarkable for onychomycosis involving the toenails and multiple nodular, violaceous mildly tender skin lesions on both lower extremities up to the level of his knees. Some of these lesions had scabs associated with them (Fig. 1). Laboratory findings on day 0 revealed a white blood cell count of 3600/mm3 with a normal differential, a hemoglobin of 11.2 g/dL, a platelet count of 145,000/mm3, a creatinine of 5.4 mg/dL, a blood urea nitrogen of 21.1 mg/dL, normal liver function tests, and an erythrocyte sedimentation rate of 26 mm/h. His HIV serology was negative. A chest X-ray revealed clear lung fields.Fig. 1 Violaceous indurated nodules and ulcers on right lower extremity.\n\nFig. 1.\n\nOne of the lesions was biopsied and the histopathology revealed a few fungal hyphae. Routine, fungal and mycobacterial cultures were requested. Fungal culture grew Alternaria that was not speciated (Fig. 2, Fig. 3). As there was no evidence of systemic infection, a diagnosis of cutaneous alternariosis was made on day 14, and antifungal treatment was initiated with posaconazole 200 mg three times a day. By week 6, follow up visit revealed significant improvement, with complete resolution by week 14. The patient was continued on posaconazole due to continued immunosuppression for the functioning pancreatic graft. The patient died 18 months after the diagnosis of cutaneous alternariosis because of unrelated causes without relapse of cutaneous fungal infection.Fig. 2 Skin biopsy showing fungal hyphae with occasional branching (Gomori Methenamine stain, 200× original magnification).\n\nFig. 2.Fig. 3 Multicellular ovoid macroconidia arising on septate hyphae (Lactophenol Cotton Blue mount, 400× original magnification).\n\nFig. 3.\n\n3 Discussion\nAlternaria spp. are dematiaceous fungi, which are ubiquitous in nature. They infrequently cause human infection in immunocompetent patients [7]. However, as the number of immunocompromised patients has increased, so has the reported cases of alternariosis [8], [9]. Since the first case report in 1933 [10], over 200 cases have been reported in the literature. Cutaneous infections represent the overwhelming majority of cases [1], [11].\n\nWe have reviewed the literature published in English from 2008 to 2016 for case reports or case series on cutaneous alternariosis. Our search yielded 55 cases that are summarized in Table 1. This will supplement the comprehensive reviews of cases published by Lyke et al. in 2001 and Pastor and Guarro in 2008 [1], [2]. In our review there are 15 females and 40 males with ages ranging from 13 to 85 years. Consistent with previous reports [1], [2], cutaneous alternariosis of the extremities was the most common site of involvement.Table 1 Published cases of cutaneous Alternariosis from 2008–2016.\n\nTable 1Year\tAuthor\tSex\tAge\tUnderlying Conditiona\tSpecies\tPrimary Therapyb\tOutcome for Primary therapyc\t\n2008\tC Williams [25]\tM\t85\tNone\tAlternaria spp.\tITZ\tCure\t\n2008\tJ Brasch [26]\tM\t68\tRenal Tx\tAlternaria infectoria\tITZ\tCure\t\n2008\tL Podda [27]\tM\t24\tALL\tAlternaria infectoria\tVori\tCure\t\n2008\tG Calabro [28]\tM\t53\tRenal Tx\tAlternaria alternata\tITZ\tCure\t\n2009\tS Segner [29]\tM\t73\tRenal Tx\tAlternaria infectoria\tITZ\tImproved\t\n2010\tRD Boyce [30]\tF\t45\tCardiac Tx\tAlternaria spp.\tSx+CSP+ITZ\tFailure\t\n2010\tRD Boyce [30]\tM\t62\tCardiac Tx\tAlternaria spp.\tSx+Vori\tCure\t\n2010\tRD Boyce [30]\tM\t51\tRenal & Pancreas Tx\tAlternaria spp.\tITZ\tFailure\t\n2010\tRD Boyce [30]\tF\t60\tLung & Renal Tx\tAlternaria spp.\tSx+Vori\tImproved\t\n2010\tRD Boyce [30]\tM\t41\tRenal & Pancreas Tx\tAlternaria spp.\tSx\tFailure\t\n2010\tRD Boyce [30]\tM\t36\tRenal Tx\tAlternaria spp.\tITZ\tFailure\t\n2010\tRD Boyce [30]\tM\t40\tRenal & Pan Tx\tAlternaria spp.\tSx+ITZ\tCure\t\n2010\tRD Boyce [30]\tF\t63\tPancreas Tx\tAlternaria spp.\tSx+ITZ\tCure\t\n2010\tAM Morales [31]\tM\t63\tCardiac Tx\tAlternaria spp.\tCryotherapy+ITZ\tCure\t\n2010\tF Santiago [32]\tM\t55\tRenal Tx\tAlternaria alternata\tITZ\tFailure\t\n2010\tSEM Vermeire [21]\tF\t51\tRenal Tx\tAlternaria alternata\tSx+Vori\tCure\t\n2010\tTR Leahy [19]\tF\t14\tAML\tAlternaria infectoria\tLamB+Vori\tCure\t\n2010\tM Yasui [33]\tM\t68\tNone\tAlternaria alternata\tThermotherapy\tCure\t\n2010\tDR Matson [34]\tM\t17\tNone\tAlternaria spp.\tITZ\tImproved\t\n2011\tGW Osmond [35]\tM\t57\tCardiac Tx\tAlternaria spp.\tSx+Vori\tImproved\t\n2011\tDS Kpodzo [6]\tM\t58\tCLL\tAlternaria alternata\tSx+Posa\tCure\t\n2012\tT Robert [36]\tF\t73\tDM\tAlternaria infectoria\tITZ\tImproved\t\n2012\tT Robert [36]\tM\t54\tRenal Tx\tAlternaria infectoria\tFLU\tImproved\t\n2012\tT Robert [36]\tF\t75\tRenal Tx\tAlternaria infectoria\tVori\tDied of unrelated cause\t\n2012\tT Robert [36]\tM\t56\tCardiac & Lung Tx\tAlternaria infectoria\tSx+Vori\tImproved\t\n2012\tT Robert [36]\tM\t77\tCMML\tAlternaria infectoria\tITZ\tDied of unrelated cause\t\n2012\tT Robert [36]\tF\t41\tNone\tAlternaria infectoria\tITZ\tFailure\t\n2012\tD Cunha [37]\tM\t53\tRenal Tx\tAlternaria infectoria\tITZ\tCure\t\n2012\tB Rammaert [38]\tF\t64\tCardiac Tx\tAlternaria infectoria\tITZ\tFailure\t\n2012\tD Tambasco [39]\tF\t64\tRenal Tx\tAlternaria infectoria\tTerb\tCure\t\n2012\tRA Lavergne [40]\tM\t63\tCardiac Tx\tAlternaria alternata\tVori\tImproved\t\n2012\tL Rudnicka [41]\tM\t13\tAlopecia areata\tAlternaria chlamydospora\tUnknown\tOutcome not known\t\n2012\tVSM Saegeman [5]\tF\t52\tLung Tx\tAlternaria infectoria\tSx+Vori\tImproved\t\n2012\tF Seyfarth [42]\tF\t65\tRenal Tx\tAlternaria infectoria\tCiclo+Vori\tFailure\t\n2013\tB Sharifkashani [43]\tM\t37\tHeart Tx\tAlternaria spp.\tVori\tCure\t\n2013\tL Lopes [4]\tM\t61\tRenal Tx\tAlternaria infectoria\tITZ\tCure\t\n2013\tL Lopes [4]\tM\t63\tRenal Tx\tAlternaria infectoria\tCryotherapy+Posa\tImproved\t\n2013\tL Lopes [4]\tM\t56\tRenal Tx\tAlternaria infectoria\tSx+ITZ\tCure\t\n2013\tB Kleker [44]\tM\t55\tALL\tAlternaria alternata\tVori\tFailure\t\n2013\tN Alhmali [45]\tF\t65\tLiver Tx\tAlternaria infectoria\tCiclo+FLU\tCure\t\n2013\tC Dessinioti [46]\tM\t58\tNone\tAlternaria alternata\tBIF+ITZ\tFailure\t\n2013\tZ Secnikova [3]\tM\t60\tHeart Tx\tAlternaria alternata\tSx+Vori\tImproved\t\n2013\tMC Gonzalez-Vela [47]\tM\t60\tLung Tx\tAlternaria triticina\tITZ\tImproved\t\n2014\tN Essabbah [48]\tF\t33\tRenal Tx\tAlternaria tenuissima\tdecrease IS\tImproved\t\n2014\tM Michelon [49]\tM\t70\tRenal Tx\tAlternaria spp.\tITZ\tImproved\t\n2014\tE Coussens [50]\tM\t65\tLiver Tx\tAlternaria infectoria\tFLU\tCure\t\n2014\tD Daglar [51]\tM\t33\tRenal Tx\tAlternaria infectoria\tITZ\tFailure\t\n2014\tSH Sohng [52]\tM\t76\tNone\tAlternaria alternata\tKET\tImproved\t\n2015\tM Demirci [53]\tF\t32\tRenal Tx\tAlternaria spp.\tITZ\tCure\t\n2015\tW Hu [54]\tM\t28\tNone\tAlternaria arborescens\tITZ+LamB\tCure\t\n2015\tCC Hsu [55]\tM\t61\tRenal Tx\tAlternaria spp.\tITZ\tFailure\t\n2015\tS Bras [56]\tM\t65\tLiver Tx\tAlternaria alternata+Alternaria infectoria\tSx+ITZ\tCure\t\n2016\tCL Simpson [57]\tM\t60's\tHeart Tx\tAlternaria spp.\tITZ\tFailure\t\n2016\tRC Patel [58]\tM\t13\tNone\tAlternaria spp.\teconazole+ITZ\tCure\t\n2016\tC O'Meara [59]\tM\t80\tMDS\tAlternaria spp.\tsilver chloride gel\tCure\t\na ALL=acute lymphoblastic leukemia, AML=acute myelogenous leukemia, CLL=chronic lymphoid leukemia, CMML=chronic myelomonocytic leukemia, DM=diabetes mellitus, MDS=myelodysplastic syndrome, Tx=transplant.\n\nb BIF=bifonazole, Ciclo=ciclopiroxolamine, CSP=caspofungin, FLU=fluconazole, IS=immunosuppressive therapy, ITZ=itraconazole, KET=ketoconazole, LamB=liposomal amphotericin B, Posa=posaconazole, Sx=surgery, Terb=terbinafine, Vori=voriconazole.\n\nc Cure=complete resolution, Improved=Improvement but not complete resolution, Failure=worsening or no improvement.\n\n\n\n3.1 Agent\nThe genus Alternaria is comprised of over 80 species. A. alternata, A. infectoria, A. tenuissima and A. chartarum cause the majority of infections. Alternaria alternata (59/156, 38%) followed by A. tenuissima (23/156, 15%) were the most frequent isolates described in a previous review (Pastor, 2008), however, in 55/156 (35%) cases a speciation was not performed. In our review of 55 cases since 2008, species determination was done in 36/55 (65%) cases with Alternaria infectoria implicated in 22/55 (40%) followed by Alternaria alternata in 11/55 (20%) and Alternaria tenuissima in 1/55 (1.8%) of cases, suggesting a possible shift in prevalence of each species over the past decade.\n\n3.2 Risk factors\nMost patients with cutaneous alternariosis have an immunocompromising condition, such as transplantation [12], collagen vascular disease (e.g. systemic lupus erythematous (SLE)) [13], hematological malignancy [2], endogenous hypercortisolism and diabetes [2], [12]. Rare cases have been described in hosts with no known immunocompromising conditions [14].\n\nIn our review of cases from 2008 to present, 39/55 (71%) patients had an organ transplant and were on multiple immunosuppressive agents when lesion/lesions occurred, six (11%) patients had hematological malignancies, and several had other conditions affecting the immune system. In seven (13%) patients no obvious immunosuppression was noted. This is in contrast to cases earlier than 2008, where only 51 out of 156 (33%) cases had an organ transplant, potentially due to the increasing number of organ transplant patients living today leading to a greater percentage of infected patients falling into this category.\n\n3.3 Mode of acquisition and clinical features\nAlternaria spp. are ubiquitous in distribution and are common soil saprophytes. The mode of acquisition is not always established, although minor skin trauma and subsequent inoculation appears to be a plausible route of entry [15]. The most common presentation is skin lesions [1], [11]. Cutaneous alternariosis exists in two forms: epidermal type or dermal type depending on the depth of fungal invasion. In both types, the lesion usually appears on the exposed sites such as the dorsum of hands, forearms, knees and legs. Scaly infiltrated erythematous or ulcerative are seen with the epidermal type. The dermal type has been described as plaques with papules, pustules, crusts, and with the surface being more or less granular and atrophic. In some cases, pain is associated with the lesions [16]. Less common clinical syndromes reported with alternariosis include allergic sinusitis, hypersensitivity pneumonitis, osteomyelitis, keratitis, endophthalmitis, rhinosinusitis, onychomycosis, and peritonitis [1], [2], [7], [17].\n\n3.4 Diagnosis\nThe establishment of Alternaria spp. infection requires demonstration of fungal tissue invasion or recovery of the fungi from a sterile site. This is important, as Alternaria spp. is ubiquitously present in the environment and thereby could contaminate the culture or could be colonizing, but not infecting, superficial tissue. Alternaria spp. usually, but not always, appear dark-walled on standard histopathologic stains. Cell wall melanin may be visible as a brownish-yellow color on hematoxylin-eosin (H&E) stain. If melanin is not evident on H&E stain, it can be identified using the Fontana-Masson method. However, culture is essential for the identification of Alternaria spp., since histologic findings are not pathognonic. Morphology of the conidia is used for speciation of Alternaria spp. However clinically important species often lose their ability to sporulate and, thus, cannot be identified by microscopic examination. For this reason, molecular techniques are increasingly used to identify Alternaria spp\n[1], [18], [19].\n\n3.5 Treatment\nThere are no randomized controlled trials that have assessed the treatment of Alternaria spp. infections. In absence of any guidance from controlled data, multiple therapeutic options have been used. Review of literature has identified itraconazole as the most commonly used antimicrobial. Outcomes appear to be satisfactory. Some series report its efficacy above 90% [2], [17]. Doses ranging from 100 mg/day to 600 mg/day have been used, with the duration of therapy usually being in excess of two months. However, there have been reports of failure with itraconazole, even when in vitro data demonstrates susceptibility in vitro\n[2]. Voriconazole [19], [20], [21], fluconazole [22], Amphotericin B [16], [19], and terbinafine [22] have been used in few cases. Surgery alone has been reported to be successful in the case of localized, superficial lesions [23], [24].\n\nIn our review, itraconazole was used alone as primary therapy in 20 of 55 patients, with eight of these patients failing therapy and requiring use of additional agents. This 40% failure rate is much higher than previously reported, suggesting a possible increase in resistance to itraconazole [2], [17]. The increase in reported failures may, however, be due to a reporting bias because unexpected failures are more likely to be reported than expected cures. In our series, initial combination therapy with itraconazole plus either surgery, cryotherapy, or another antifungal agent resulted in cure in seven of nine patients (78%). Initial use of other azole antifungals, either alone or in combination with other treatment modalities, had generally positive results. Voriconazole monotherapy or in combination with surgery or topical antifungals resulted in cure or improvement in 11 of 14 patients (79%). Fluconazole monotherapy or in combination with topical ciclopiroxolamine led to improvement or cure in all three reported cases. Posaconazole use was reported in two patients, in combination with either surgery or cryotherapy, and led to cure or improvement in both cases. Additionally, in two of the cases that saw initial improvement, but not cure, with voriconazole-based therapy, a change in antifungal to posaconazole yielded improvement in the skin lesions [3], [5].\n\nCutaneous infection with Alternaria spp. is a well-described, though still relatively rare, complication in patients on immunosuppressive therapy due to solid organ transplant. Historically, itraconazole has been used most frequently to treat this infection. However it is not universally effective and it has certain disadvantages such as significant drug-drug interactions mediated by inhibition of cytochrome P450 enzymes. Posaconazole is another potential antifungal option that overcomes some of the disadvantages of itraconazole, particularly with regard to drug-drug interactions. Our case demonstrates that posaconazole can be used successfully as a first line treatment of cutaneous alternariosis, however additional clinical data are needed to determine the place in therapy for this agent.\n\nConflict of interest\nThere are none.\n\nAcknowledgements\nWe thank Dr. Thomas A. Russo for discussion and critical review of this manuscript.\n==== Refs\nReferences\n1 Pastor F.J. Guarro J. Alternaria infections: laboratory diagnosis and relevant clinical features Clin. Microbiol. Infect. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 14 8 2008 734 746 \n2 Lyke K.E. Miller N.S. Towne L. Merz W.G. 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Marques-Pinto G. Cutaneous infection by different Alternaria species in a liver transplant recipient Med. Mycol. Case Rep. 8 2015 1 4 25750855 \n57 Simpson C.L. Craig-Muller S. Sobanko J.F. Weikert B.C. Micheletti R.G. Refractory cutaneous alternariosis successfully treated with Mohs surgery and full-thickness skin grafting Dermatol. Surg. Publ. Am. Soc. Dermatol Surg. 42 3 2016 426 429 \n58 Patel R.C. Helm M. Shimizu I. Cutaneous alternariosis in an immunocompetent patient Dermatol. Online J. 22 10 2016 12 \n59 OʼMeara C. Boyanton B.L. Spurlin D. Carpenter C.F. Cutaneous fungal infection with Alternaria in a patient With myelodysplastic syndrome: successful treatment With Topical silver chloride gel Infect. Dis. Clin. Pract. 24 2 2016 112 114\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2211-7539", "issue": "15()", "journal": "Medical mycology case reports", "keywords": "Alternaria spp.; Alternariosis; Fungal infection; Posaconazole", "medline_ta": "Med Mycol Case Rep", "mesh_terms": null, "nlm_unique_id": "101598259", "other_id": null, "pages": "16-20", "pmc": null, "pmid": "28180057", "pubdate": "2017-03", "publication_types": "D016428:Journal Article", "references": "22142219;23530868;23329992;16772234;20487700;26945322;15793517;22897073;11283807;22329778;18608728;20199426;27429134;20937586;18311446;2497012;18203025;23317992;15225228;20002611;16262877;28329593;25370461;25554667;24440281;20319289;23075226;20846592;19896319;25046464;25291955;22513067;8914373;21910761;10817234;21787876;24897135;23477761;2170477;17580210;21299373;18312460;26060568;24112410;25750855;24001697;19594865;17097985;22404860;18042595;21752048;16912950;25090825;17264246;18727797;17442087", "title": "Cutaneous alternariosis in a renal transplant patient successfully treated with posaconazole: Case report and literature review.", "title_normalized": "cutaneous alternariosis in a renal transplant patient successfully treated with posaconazole case report and literature review" }

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CUTANEOUS ALTERNARIOSIS IN A RENAL TRANSPLANT PATIENT SUCCESSFULLY TREATED WITH POSACONAZOLE: CASE REPORT AND LITERATURE REVIEW. 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CUTANEOUS ALTERNARIOSIS IN A RENAL TRANSPLANT PATIENT SUCCESSFULLY TREATED WITH POSACONAZOLE: CASE REPORT AND LITERATURE REVIEW. 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{ "abstract": "OBJECTIVE\nTo evaluate the feasibility of transarterial therapy (transcatheter arterial chemoembolization and transcatheter arterial infusion) for patients with hepatocellular carcinoma and chronic kidney disease (CKD).\n\n\nMETHODS\nThe study enrolled 35 patients who received transarterial therapy. The patients were classified into a CKD group (n = 10 nondialysis chronic kidney disease [NDCKD] and n = 9 end-stage renal disease [ESRD]) or a non-CKD group (n = 16). The survival rates between the two groups were compared using two different starting points: (a) from initial diagnosis of hepatocellular carcinoma and (b) from enrollment in the study. The tolerance of transarterial therapy in patients with CKD was evaluated by comparing the incidence of major adverse events.\n\n\nRESULTS\nThe 2-year and 5-year survival rates from initial diagnosis were 83.9% and 53.8% in the CKD group and 70.1% and 40.4% in the non-CKD group (P = .478). The corresponding 3-year survival rate from enrollment in the two groups was 25.6% and 41.2%, respectively (P = .995). The 2-year and 5-year survival rates from initial diagnosis were 70.1% and 40.4% in the non-CKD group, 90.0% and 39.4% in NDCKD patients, and 76.2% and 76.2% in ESRD patients (P = .380). The corresponding 2-year survival rates from enrollment in these groups were 54.9%, 48.0%, and 48.6% (P = .943). Severe contrast-induced nephropathy (n = 3) and late-onset death caused by cholesterol crystal embolism (n = 1) were observed in the NDCKD group.\n\n\nCONCLUSIONS\nTranscatheter arterial chemoembolization is feasible in patients with CKD by instituting periprocedural hemodialysis with similar 2-year and 5-year survival compared with patients without CKD.", "affiliations": "Department of Gastroenterology, Kitasato University Medical Center, 6-100 Arai, Kitamoto, Saitama, 364-8501, Japan. Electronic address: [email protected].;Department of Risk Management and Health Care Administration, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Nephrology in Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Gastroenterology, Kitasato University East Hospital, Sagamihara, Kanagawa, Japan.", "authors": "Watanabe|Masaaki|M|;Shibuya|Akitaka|A|;Minamino|Tsutomu|T|;Murano|Junya|J|;Matsunaga|Keiji|K|;Fujii|Kaoru|K|;Ogasawara|Gou|G|;Irie|Tsugumi|T|;Woodhams|Reiko|R|;Koizumi|Wasaburo|W|", "chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D015251:Epirubicin; C406530:miriplatin; D004998:Ethiodized Oil; D002945:Cisplatin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1051-0443", "issue": "25(12)", "journal": "Journal of vascular and interventional radiology : JVIR", "keywords": null, "medline_ta": "J Vasc Interv Radiol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D002945:Cisplatin; D015331:Cohort Studies; D003131:Combined Modality Therapy; D015251:Epirubicin; D004998:Ethiodized Oil; D005240:Feasibility Studies; D005260:Female; D005781:Gelatin Sponge, Absorbable; D006801:Humans; D007676:Kidney Failure, Chronic; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D015996:Survival Rate; D016896:Treatment Outcome", "nlm_unique_id": "9203369", "other_id": null, "pages": "1947-55; quiz 1955", "pmc": null, "pmid": "25306225", "pubdate": "2014-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Benefits and problems of transarterial therapy in patients with hepatocellular carcinoma and chronic kidney disease.", "title_normalized": "benefits and problems of transarterial therapy in patients with hepatocellular carcinoma and chronic kidney disease" }

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BENEFITS AND PROBLEMS OF TRANSARTERIAL THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AND CHRONIC KIDNEY DISEASE. 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"18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WATANABE M,SHIBUYA A,MINAMINO T,MURANO J,MATSUNAGA K,FUJII K,OGASAWARA G,IRIE T,WOODHAMS R,WASABURO K. BENEFITS AND PROBLEMS OF TRANSARTERIAL THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AND CHRONIC KIDNEY DISEASE. J VASC INTERV RADIOL. 2014 JAN 01;1-9.", "literaturereference_normalized": "benefits and problems of transarterial therapy in patients with hepatocellular carcinoma and chronic kidney disease", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141030", "receivedate": "20141030", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10556086, "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" } ]

{ "abstract": "Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of medications that target the transporter that reabsorbs ~90% of glucose in the S1 segment of the proximal convoluted tubule. As a result, SGLT2 inhibition increases urinary glucose excretion, effectively lowering plasma glucose levels. In addition to reducing hemoglobin A1c levels, these drugs also lower body weight, blood pressure, and uric acid levels in Type 2 diabetes mellitus (T2DM) patients. Importantly, empagliflozin has been observed to slow progression of kidney disease and reduce dialysis requirements in T2DM patients. However, the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) has collected over 100 cases of acute kidney injury (AKI) for canagloflozin and dapagliflozin since their approval. Of the 101 patients, 96 required hospitalization, 22 required intensive care unit admission, and 15 underwent hemodialysis. The FDA now requires that AKI be listed as a potential side effect of the SGLT2 inhibitors along with cautious prescription of these drugs with other medications, such as renin-angiotensin-system antagonists, diuretics, and NSAIDs. It is unclear, however, whether this FAERS reported \"AKI\" actually represents structural kidney injury, as randomized, controlled trials of these drugs do not describe AKI as an adverse event despite coprescription with RAS blockers and diuretics. As a result of this FDA warning, diabetic patients with early-stage CKD may not be prescribed an SGLT2 inhibitor for fear of AKI. Thus, it is imperative to ascertain whether the reported AKI represents true structural kidney injury or a functional decline in glomerular filtration rate. We propose using readily available clinical tools with experimental biomarkers of kidney injury and kidney-on-a-chip technology to resolve this question and provide solid evidence about the AKI risk of these drugs for healthcare providers.", "affiliations": "Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.;Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut [email protected].", "authors": "Saly|Danielle L|DL|;Perazella|Mark A|MA|", "chemical_list": "D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors", "country": "United States", "delete": false, "doi": "10.1152/ajprenal.00250.2017", "fulltext": null, "fulltext_license": null, "issn_linking": "1522-1466", "issue": "313(4)", "journal": "American journal of physiology. Renal physiology", "keywords": "SGLT2 inhibitors; acute kidney injury; biomarkers; nephrotoxicity; urine microscopy", "medline_ta": "Am J Physiol Renal Physiol", "mesh_terms": "D058186:Acute Kidney Injury; D000818:Animals; D006801:Humans; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors", "nlm_unique_id": "100901990", "other_id": null, "pages": "F951-F954", "pmc": null, "pmid": "28637789", "pubdate": "2017-10-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Harnessing basic and clinic tools to evaluate SGLT2 inhibitor nephrotoxicity.", "title_normalized": "harnessing basic and clinic tools to evaluate sglt2 inhibitor nephrotoxicity" }

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{ "abstract": "Herein, we aimed to report a diffuse large B cell lymphoma (DLBCL) case that had extensive cutaneous relapse with no skin involvement previously. A 59-year-old man presented to hospital in April 2014 with fatigue, anorexia, fever, and anemia. Cervical lymph node biopsy revealed CD20+, BCL2+, MUM1+, BCL6+ high grade B lymphoproliferative neoplasm. After FISH investigation, he was diagnosed as DLBCL. He was given 7 cycles of R-CHOP and achieved remission. However, in November 2014, he had emerging skin lesions that cover nearly all of his body. A control PET-CT revealed diffuse cutaneous involvement. CD20+, BCL2+, MUM1+, BCL6+ high grade B cell lymphoma infiltration was detected with skin biopsy. He was diagnosed as relapse lymphoma, so 2 cycles of R-DHAP were given. There was no treatment response; therefore, R-ICE regimen was started. The patient had achieved second complete remission and his skin lesions were completely regressed. The involvement of skin with CD20+ cells after 7 cycles of rituximab therapy favors that there is a rituximab resistant disease which tends to involve the skin. To conclude, DLBCL may relapse extensively with cutaneous involvement and the best treatment option in these patients is salvage chemotherapy followed by autologous peripheral blood stem cell transplantation.", "affiliations": "Department of Hematology, School of Medicine, Hacettepe University, 0100 Ankara, Turkey.;Department of Hematology, School of Medicine, Hacettepe University, 0100 Ankara, Turkey.;Department of Hematology, School of Medicine, Hacettepe University, 0100 Ankara, Turkey.;Department of Hematology, School of Medicine, Hacettepe University, 0100 Ankara, Turkey.", "authors": "Malkan|Umit Yavuz|UY|;Gunes|Gursel|G|;Yayar|Okan|O|;Demiroglu|Haluk|H|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2015/137682", "fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2015/137682Case ReportDiffuse Large B Cell Lymphoma with Extensive Cutaneous Relapse Malkan Umit Yavuz \n*\nGunes Gursel Yayar Okan Demiroglu Haluk Department of Hematology, School of Medicine, Hacettepe University, 0100 Ankara, Turkey*Umit Yavuz Malkan: [email protected] Editor: Jeffrey M. Weinberg\n\n2015 20 9 2015 2015 1376825 7 2015 10 9 2015 Copyright © 2015 Umit Yavuz Malkan 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.Herein, we aimed to report a diffuse large B cell lymphoma (DLBCL) case that had extensive cutaneous relapse with no skin involvement previously. A 59-year-old man presented to hospital in April 2014 with fatigue, anorexia, fever, and anemia. Cervical lymph node biopsy revealed CD20+, BCL2+, MUM1+, BCL6+ high grade B lymphoproliferative neoplasm. After FISH investigation, he was diagnosed as DLBCL. He was given 7 cycles of R-CHOP and achieved remission. However, in November 2014, he had emerging skin lesions that cover nearly all of his body. A control PET-CT revealed diffuse cutaneous involvement. CD20+, BCL2+, MUM1+, BCL6+ high grade B cell lymphoma infiltration was detected with skin biopsy. He was diagnosed as relapse lymphoma, so 2 cycles of R-DHAP were given. There was no treatment response; therefore, R-ICE regimen was started. The patient had achieved second complete remission and his skin lesions were completely regressed. The involvement of skin with CD20+ cells after 7 cycles of rituximab therapy favors that there is a rituximab resistant disease which tends to involve the skin. To conclude, DLBCL may relapse extensively with cutaneous involvement and the best treatment option in these patients is salvage chemotherapy followed by autologous peripheral blood stem cell transplantation.\n==== Body\n1. Introduction\nDiffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma [1]. The majority of relapses occur during the first two years after completion of treatment [2, 3]. Relapses are usually symptomatic and rarely identified solely on the basis of routine imaging [4–6]. Extra nodal involvement of B cell lymphoma generally appears in gastrointestinal system followed by skin [7]. Skin involvement of B cell lymphomas could be either primary or secondary. Herein, we aimed to report a DLBCL case that had extensive cutaneous relapse with no skin involvement previously.\n\n2. Case Report\nA 59-year-old man presented to our clinic in April 2014 with fatigue, anorexia, fever, and anemia. Clinical examination revealed splenomegaly and cervical lymphadenopathies. Laboratory tests were reported as hemoglobin 9.1 gr/dL, white blood cell 6.1 × 103/μL, and platelets 430 × 103/μL with normal other biochemical values. HIV test was negative. Spleen size was found as 160 × 90 mm and lymphadenopathies around portal hilus were detected by abdominal USG. Cervical lymph node biopsy revealed high grade B lymphoproliferative neoplasm. Conventional cytogenetic analysis was performed; however it resulted in no metaphases. The FISH investigation has resulted in BCL2−, BCL6−, and MYC−. Immunohistochemical study has resulted in CD20+, BCL2+, MUM1+, BCL6+, and Tdt−. Ki-67 proliferation index of the patient was 90%. No disease involvement was detected in the bone marrow biopsy investigation. PET-CT was performed for disease staging. Involvement in spleen, bone marrow, cervical lymph nodes, bilateral axillary lymph nodes, thoracal lymph nodes, portal, para-aortic, paracaval, and bilateral inguinal lymph nodes, sternum, C2 vertebra, clavicula, acromion, and left humerus was detected, with SUV max value above 4. The patient was diagnosed as stage 4 diffuse large B cell lymphoma and 4 cycles of R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone) regimen were given. In August 2014, cervical, thoracal, and abdominal CT revealed regression. R-CHOP regimen was given for 3 more cycles. The patient responded to the treatment well with complete resolution of all lymphadenopathies. However, 2 months after the completion of chemotherapy cycles in November 2014, the patient had emerging skin lesions that cover nearly all of his body. The lesions were painless and different in diameter with the biggest lesion reaching 5-6 cm (Figure 1). A control PET-CT revealed diffuse cutaneous involvement (SUV max 18.3) with axillary lymph node involvement (SUV max 14.8). Interestingly this time, spleen, inguinal nodes, and bone marrow involvement could not be detected. Biopsy was performed from skin lesion which was reported as CD20+, BCL2+, MUM1+, BCL6+ high grade B cell lymphoma infiltration. The patient also had foot drop which was considered to be secondary to vincristine. Electromyography revealed diffuse and severe axonal polyneuropathy and active myopathy in distal muscles. There was no involvement in cranial MR. He was diagnosed as relapsed lymphoma, so R-DHAP (rituximab, cisplatin, cytosine arabinoside, and dexamethasone) chemotherapy regimen was started. There was no treatment response after 2 cycles of R-DHAP; therefore, chemotherapy regimen has changed to R-ICE (rituximab, etoposide, carboplatin, and ifosfamide). With R-ICE treatment, the patient achieved second complete remission and his skin lesions were completely regressed (Figure 2). Autologous peripheral blood stem cell transplantation (PBSCT) was planned for our patient.\n\n3. Discussion\nPrimary cutaneous lymphomas have better clinical course and prognosis [8, 9]. However, extensive secondary cutaneous involvement in systemic B cell lymphomas has been also reported in the literature [10, 11]. Very significant improvements were recorded in the management of DLBCL; however, it is still not usual to achieve cure with conventional treatment. The outcome of relapsed DLBCL largely depends on several factors such as fitness and chemosensitivity of the patient, eligibility for stem cell transplantation (SCT), IPI score at relapse, and time interval from previous chemotherapy. In the literature, it was stated that after the relapse of DLBCL the response rate following second line therapy (R-ICE or R-DHAP) was 63% [12]. Disease-free survival is very low in cases who reach second remission [13]. However, performing SCT in these patients would extend treatment response to two years [14]. Non-Hodgkin lymphomas generally relapse in the same involvement sites. In the literature, there are reports of cases who relapsed with CD20− skin involvement after rituximab therapy [15, 16]. Our case differs from these reports with CD20+ relapse after 7 cycles treatment with R-CHOP regimen. At the beginning of the treatment, our patient did not have skin involvement that excludes the diagnosis of primary cutaneous lymphoma. The involvement of skin with CD20+ after 7 cycles of rituximab therapy suggests that there is a resistant disease to rituximab which tends to involve the skin. Interestingly, disease relapse was not present in our patients' primary involvement sites, except axillary region. Moreover, disease relapse occurred in cutaneous region which did not have disease involvement primarily. To conclude, diffuse large B cell lymphomas may relapse extensively with cutaneous involvement and the best treatment option in these patients is salvage chemotherapy followed by autologous PBSCT.\n\nConflict of Interests\nThe authors of this paper have no conflict of interests, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.\n\nFigure 1 Prior to salvage treatment.\n\nFigure 2 After salvage treatment.\n==== Refs\n1 Morton L. M. Wang S. S. Devesa S. S. Hartge P. Weisenburger D. D. Linet M. S. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001 Blood 2006 107 1 265 276 10.1182/blood-2005-06-2508 2-s2.0-30144443996 16150940 \n2 Larouche J.-F. Berger F. Chassagne-Clément C. Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome Journal of Clinical Oncology 2010 28 12 2094 2100 10.1200/jco.2009.24.5860 2-s2.0-77951629048 20308668 \n3 Maurer M. J. Ghesquières H. Jais J.-P. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy Journal of Clinical Oncology 2014 32 10 1066 1073 10.1200/JCO.2013.51.5866 2-s2.0-84901700388 24550425 \n4 Weeks J. C. Yeap B. Y. Canellos G. P. Shipp M. A. Value of follow-up procedures in patients with large-cell lymphoma who achieve a complete remission Journal of Clinical Oncology 1991 9 7 1196 1203 2-s2.0-0025736610 1710656 \n5 Liedtke M. Hamlin P. A. Moskowitz C. H. Zelenetz A. D. Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population Annals of Oncology 2006 17 6 909 913 10.1093/annonc/mdl049 2-s2.0-33646860107 16672295 \n6 El-Galaly T. Mylam K. J. Bøgsted M. Role of routine imaging in detecting recurrent lymphoma: a review of 258 patients with relapsed aggressive non-Hodgkin and Hodgkin lymphoma American Journal of Hematology 2014 89 6 575 580 10.1002/ajh.23688 2-s2.0-84900844110 24493389 \n7 Santucci M. Pimpinelli N. Primary cutaneous B-cell lymphomas. Current concepts. I Haematologica 2004 89 11 1360 1371 2-s2.0-9144226809 15531459 \n8 Kerl H. Fink-Puches R. Cerroni L. Diagnostic criteria of primary cutaneous B-cell lymphomas and pseudolymphomas The Keio Journal of Medicine 2001 50 4 269 273 10.2302/kjm.50.269 2-s2.0-0035751482 11806505 \n9 Thomas V. Dobson R. Mennel R. Primary cutaneous large B-cell lymphoma, leg type Proceedings of the Baylor University Medical Center 2011 24 350 353 \n10 Amo Y. Tanei R. Yonemoto K. Katsuoka K. Mori M. Diffuse large B-cell lymphoma associated with skin, muscle and cranial nerve involvement European Journal of Dermatology 2000 10 4 306 308 2-s2.0-0034032694 10846261 \n11 Shamsudin N. Chang C. C. Diffuse large B-cell lymphoma presenting with extensive cutaneous infiltration Singapore Medical Journal 2012 53 9 e198 e200 2-s2.0-84870048315 23023915 \n12 Gisselbrecht C. Glass B. Mounier N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era Journal of Clinical Oncology 2010 28 27 4184 4190 10.1200/jco.2010.28.1618 2-s2.0-77957965500 20660832 \n13 Singer C. R. J. Goldstone A. H. Clinical studies of ABMT in non-Hodgkin's lymphoma Clinics in Haematology 1986 15 1 105 150 10.1016/s0308-2261(86)80008-x 2-s2.0-0023039567 3516486 \n14 Cortelazzo S. Rambaldi A. Rossi A. Intensification of salvage treatment with high-dose sequential chemotherapy improves the outcome of patients with refractory or relapsed aggressive non-Hodgkin's lymphoma British Journal of Haematology 2001 114 2 333 341 10.1046/j.1365-2141.2001.02955.x 2-s2.0-0034882693 11529852 \n15 Iguchi T. Miyazawa K. Okabe S. Relapse of diffuse large B cell lymphoma to CD20-negative multiple cutaneous tumors immediately after anti-CD20 monoclonal antibody (rituximab) therapy Rinshō Ketsueki 2004 45 10 1129 1134 2-s2.0-16644363199 15553050 \n16 Massengale W. T. McBurney E. Gurtler J. CD20-negative relapse of cutaneous B-cell lymphoma after anti-CD20 monoclonal antibody therapy Journal of the American Academy of Dermatology 2002 46 3 441 443 10.1067/mjd.2002.108490 2-s2.0-0036123109 11862185\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "2015()", "journal": "Case reports in medicine", "keywords": null, "medline_ta": "Case Rep Med", "mesh_terms": null, "nlm_unique_id": "101512910", "other_id": null, "pages": "137682", "pmc": null, "pmid": "26457084", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "20660832;23023915;24550425;16150940;22046074;24493389;15553050;3516486;10846261;11529852;15531459;11806505;11862185;1710656;16672295;20308668", "title": "Diffuse Large B Cell Lymphoma with Extensive Cutaneous Relapse.", "title_normalized": "diffuse large b cell lymphoma with extensive cutaneous relapse" }

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{ "abstract": "The objective of the study is to report a case of acute pancreatitis secondary to hypercalcemia induced by primary hyperparathyroidism in a pregnant woman at the end of the first trimester. The case included a 32-year-old woman who was diagnosed with acute pancreatitis and severe hypercalcemia refractory to many regimens of medical therapy in the first trimester of pregnancy. She was successfully treated with parathyroidectomy in the early second trimester with complete resolution of hypercalcemia and pancreatitis. Neonatal course was unremarkable. To our best knowledge, this is a rare case when primary hyperparathyroidism and its complications are diagnosed in the first trimester of pregnancy. In conclusion, primary hyperparathyroidism is a rare life-threatening condition to the fetus and mother especially when associated with complications such as pancreatitis. Early therapeutic intervention is important to reduce the morbidity and mortality. Parathyroidectomy performed in the second trimester can be the only solution.\nLearning how to make diagnosis of primary hyperparathyroidism in a woman during the first trimester of pregnancy.Understanding the complications of hypercalcemia and be aware of the high mortality and sequelae in both fetus and mother.Providing the adequate treatment in such complicated cases with coordinated care between endocrinologists and obstetricians to ensure optimal outcomes.", "affiliations": "Rafic Hariri University Hospital, Beirut, Lebanon.;Rafic Hariri University Hospital, Beirut, Lebanon.;Rafic Hariri University Hospital, Beirut, Lebanon.;Rafic Hariri University Hospital, Beirut, Lebanon.", "authors": "Richa|Carine Ghassan|CG|;Saad|Khadija Jamal|KJ|;Chaaban|Ali Khaled|AK|;El Rawas|Mohamad Souheil|MS|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1530/EDM-17-0175", "fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-17-0175EDM170175Pregnant AdultFemaleWhiteLebanonParathyroidBonePTHCalcitoninHyperparathyroidism (Primary)HypercalcaemiaPancreatitisParathyroid AdenomaPancreatitisHypercalcaemiaAbdominal painNauseaVomitingLeukocytosisPruritusParaesthesiaKidney stonesAmylaseBilirubinAlanine aminotransferaseLipase (serum)Endoscopic ultrasoundCalcium (serum)MagnesiumPhosphate (serum)Urine 24-hour volumeCreatinineCalcium (urine)PTHUltrasound scan25-hydroxyvitamin-D3MRIHistopathologyParathyroidectomyFluid repletionCalcitoninSalineFurosemideZoledronic acidBisphosphonatesCalcium gluconateCalciumCalcitriolObstetricsUnique/Unexpected Symptoms or Presentations of a DiseaseUnique/Unexpected Symptoms or Presentations of a DiseaseA rare case of hypercalcemia-induced pancreatitis in a first trimester pregnant woman C G Richa and othersHyperparathyroidism in pregnancyRicha Carine Ghassan 123Saad Khadija Jamal 124Chaaban Ali Khaled 156El Rawas Mohamad Souheil 1271 Rafic Hariri University Hospital, Beirut, Lebanon2 Department of Medicine, Endocrinology Division, Lebanese University, Hadath, Lebanon3 Endocrinology Department, Rafic Hariri University Hospital, Beirut, Lebanon4 Endocrinology Department, Mount Lebanon Hospital, Beirut, Lebanon5 Department of Radiology, Beirut Governmental University Hospital, Beirut, Lebanon6 Diagnostic Radiology, Radiology Department7 Clinical Endocrinology, Endocrinology Department, Rafic Hariri University Hospital, Beirut, LebanonCorrespondence should be addressed to C G Richa Email: [email protected] 3 2018 2018 2018 17-017525 2 2018 08 3 2018 © 2018 The authors2018The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nThe objective of the study is to report a case of acute pancreatitis secondary to hypercalcemia induced by primary hyperparathyroidism in a pregnant woman at the end of the first trimester. The case included a 32-year-old woman who was diagnosed with acute pancreatitis and severe hypercalcemia refractory to many regimens of medical therapy in the first trimester of pregnancy. She was successfully treated with parathyroidectomy in the early second trimester with complete resolution of hypercalcemia and pancreatitis. Neonatal course was unremarkable. To our best knowledge, this is a rare case when primary hyperparathyroidism and its complications are diagnosed in the first trimester of pregnancy. In conclusion, primary hyperparathyroidism is a rare life-threatening condition to the fetus and mother especially when associated with complications such as pancreatitis. Early therapeutic intervention is important to reduce the morbidity and mortality. Parathyroidectomy performed in the second trimester can be the only solution.\n\nLearning points:\nLearning how to make diagnosis of primary hyperparathyroidism in a woman during the first trimester of pregnancy.\n\nUnderstanding the complications of hypercalcemia and be aware of the high mortality and sequelae in both fetus and mother.\n\nProviding the adequate treatment in such complicated cases with coordinated care between endocrinologists and obstetricians to ensure optimal outcomes.\n\nPatient Demographics\nPregnant adultFemaleWhiteLebanonClinical Overview\nParathyroidBonePTHCalcitoninHyperparathyroidism (primary)HypercalcaemiaPancreatitisParathyroid adenomaDiagnosis and Treatment\nPancreatitisHypercalcaemiaAbdominal painNauseaVomitingLeukocytosisPruritusParaesthesiaKidney stonesAmylaseBilirubinAlanine aminotransferaseLipase (serum)Endoscopic ultrasoundCalcium (serum)MagnesiumPhosphate (serum)Urine 24-hour volumeCreatinineCalcium (urine)PTHUltrasound scan25-hydroxyvitamin-D3MRIHistopathologyParathyroidectomyFluid repletionCalcitoninSalineFurosemideZoledronic acidBisphosphonatesCalcium gluconateCalciumCalcitriolRelated Disciplines\nObstetricsPublication Details\nUnique/unexpected symptoms or presentations of a diseaseMarch2018\n==== Body\nBackground\nMany reports describe the association\n between primary hyperparathyroidism and pancreatitis (3); however, others (7) showed that the rate of acute pancreatitis was not increased in patients with primary hyperparathyroidism. In pregnancy, few cases of primary hyperparathyroidism complicated by pancreatitis and preeclampsia have been reported mainly in the third trimester and in the postpartum period (Table 1). Herein, we present the case of a 32-year-old pregnant woman presenting with an acute pancreatitis secondary to a parathyroid adenoma at the end of the first trimester, with total remission after parathyroidectomy.\nTable 1 Cases of hyperparathyroidism and pancreatitis in pregnancy.\n\nAuthors\tPMH\tGA\tPresenting signs and symptoms\tCa\tMaternal outcomes\tFetal outcomes\tSurgery\t\nHong et al. (1)\tNephrolithiasis 3 consecutives miscarriages in the previous 4 years IVF performed\t30 + 4 weeks\tSevere epigastric pain, vomiting, fever, tachypnea, tachycardia, elevated blood pressure\t17.9a\tARF intubation\tC-section 31 weeks + 3 days MV for 2 days transient hypocalcemia\tDay 6 PP\t\nKryslak et al. (2)\tReccurent miscarriages due to pancreatitis\t8th week\tAbdominal pain, nausea, vomiting, anorexia\t10.4a\tHypercalcemia (12.8a) nephrolithiasis hypotension\tSVD 38 weeks hypercalcemia (11.6a)\tNot done medical therapy: calcitonin\t\nLee et al. (3)\t1 spontaneous abortion\tPP\tAcute abdominal pain\t11.5a\tIA abcess due to pancreatitis hydronephrosis due to nephrolithiasis neurologic complications\tHealthy baby 37 weeks\t11 weeks PP\t\nLiu et al. (4)\tIrrelevant\t31 weeks\tNausea, vomiting, irritability, high blood pressure\t15.16a\tPreeclampsia hypercalcemic crisis (13.12a) pancreatitis PP\tC-section 31 weeks hypercalcemia (12.56a)\tPP\t\nDale et al. (5)\tIrrelevant\t32 weeks\tHigh blood pressure, scotomata epigastric pain\t9.9a\tPreeclampsia hypercalcemia (10.2a)\tC-section 32 weeks\tPP\t\nBurks et al. (6)\tIrrelevant\t11 weeks\tRefractory nausea vomiting\t12.6a\tWorsening symptoms hypercalcemia (14.1a)\tHealthy baby\t12 weeks of gestation\t\nPresent case\t4 years infertility IVF performed\t11 weeks\tEpigastric pain, nausea, vomiting\t12.35a\tRefractory hypercalcemia (12.74a)\tC-section 36 weeks healthy baby\t13 weeks of gestation\t\n\naTotal serum calcium in mg/dL (normal value: 8.5–10.5).\n\nARF, acute respiratory failure; Ca, calcium level; C-section, cesarean section; GA, gestational age; IA, intra-abdominal; MV, mechanical ventilation; PMH, past medical history; PP, postpartum; SVG, spontaneous vaginal delivery.\n\n\n\n\nCase presentation\nA 32-year-old lady, Gravida 1 Para 0, who underwent in vitro fertilization (IVF) because of unexplained infertility, presented at her 11th week of gestation for epigastric pain, nausea and bilious vomiting. She noted recurrent hospitalization for the same complaints even prior to her pregnancy. Past medical history was significant for chronic pruritic rash and nephrolithiasis, which has never been investigated.\n\nInvestigation\nLaboratory tests showed leukocytosis with a left shift (14900/µL with 80% neutrophils), alanine aminotransferase of 116 (normal range: 7–56 IU/L), aspartate aminotransferase of 60 (normal range: 5–40 IU/L), alkaline phosphatase of 140 IU/L (normal range: 44–147 IU/L), gamma-glutamyl transpeptidase of 62 (normal range: 9–48 IU/L), direct bilirubin of 0.48 (normal range <0.3 mg/dL), total bilirubin of 0.74 (normal range: 0.1–1.2 mg/dL) and elevated amylase and lipase: four to five times the upper limits of normal, 340 and 820 IU/L respectively (normal range for amylase: 10–120 IU/L and normal range for lipase: 13–60 IU/L).\n\nPancreatitis was diagnosed based on the clinical presentation and the laboratory findings. The patient was kept null per os (NPO) for few days, with pain control medications (meperidine 50 mg intravenous three times per day), intravenous fluids and total parenteral nutrition (oliclinomel N4 1 L per daily) at a later stage in order to maintain the caloric needs necessary for fetal growth. Lipase levels decreased to 600 IU/L after 48 h, then to 491 IU/L after 72 h.\n\nWhile investigating the etiology of pancreatitis, an ultrasound of her abdomen showed biliary sludge with no signs of cholecystitis and an endoscopic ultrasound confirmed the absence of common bile duct dilatation. However, her calcium level was found to be significantly elevated with a value of 12.35 mg/dL (normal range: 8.5–10.2 mg/dL) with a low serum phosphorus and magnesium levels, 2.03 mg/dL and 1.35 mg/dL respectively (normal phosphorus range: 2.5–4.5 mg/dL and normal magnesium range: 1.7–2.2 mg/dL). A 24-h urine calcium collection showed markedly elevated levels, 380 mg/day (normal range from 100 to 300 mg/day) with a urine volume of 4700 mL/24 h and urine creatinine of 658 mg (normal range: 600–2000 mg/24 h). Parathyroid hormone (PTH) level was elevated, 301.8 pg/mL (normal range: 10–65 pg/mL) with a low 25-hydroxyvitamin D level of 4.2 ng/mL (normal range: 20–50 ng/mL). Based on the above mentioned results, primary hyperparathyroidism was identified and resulting hypercalcemia was thought to be the culprit behind this patient’s pancreatitis.\n\nA neck ultrasound revealed no parathyroid lesions. A subsequent magnetic resonance imaging (MRI) of the neck was preferred over a sestamibi scan view the fetal radiation exposure risk associated with the latter. Neck MRI revealed a 2.8 × 1.7 × 1 cm oval-shaped homogenous high intensity lesion, just inferior to the right thyroid lobe consistent with a parathyroid adenoma (Figs 1, 2 and 3). Thus, a multidisciplinary decision involving the gynecology, endocrinology and surgery teams was undergone and the patient was advised to have a parathyroidectomy in her early second trimester, which is considered the safest period for surgery during pregnancy.Figure 1 Brain magnetic resonance imaging of anterior neck. T2-weighted imaging sagittal view with the arrow showing the parathyroid adenoma.\n\n\nFigure 2 Brain magnetic resonance imaging of anterior neck. T2-weighted imaging axial view with the arrow showing the parathyroid adenoma.\n\n\nFigure 3 Brain magnetic resonance imaging of anterior neck. T2-weighted imaging coronal view demonstrating an oval shape mass inferior to the right lobe of the thyroid consistent with an enlarged right inferior parathyroid adenoma.\n\n\n\n\nTreatment\nAt the same time, the initial target to reduce the patient’s serum calcium level failed despite various attempts using aggressive saline infusion (up to 4 L per day), furosemide (60 mg intravenous daily), calcitonin 4 IU/kg twice daily, later increased to 8 IU/kg three times daily. Moreover, and despite its potential adverse effects in pregnancy, zoledronic acid was administered at a dose of 4 mg intravenously after discussing its risks and benefits with the patient and view the refractory hypercalcemia, but calcium level remained elevated (Figure 4).Figure 4 Variation of calcium level pre and post parathyroidectomy.\n\n\n\n\nSo, an uneventful minimally invasive parathyroidectomy was performed after 14 days of diagnosis, with a subsequent significant intraoperative drop in PTH (from 1332 to 150 pg/mL) indicating adequate adenoma removal. Pathology confirmed the presence of a 2.8 × 1.6 × 1 cm right inferior parathyroid adenoma.\n\nOutcome and follow-up\nThe patient experienced a rapid resolution of her acute pancreatitis with improvement in her abdominal pain and pruritic rash. On postoperative day 3, the calcium level dropped to 8.45 mg/dL, phosphorus level to 1.2 mg/dL and magnesium level to 1.41 mg/dL suggesting hungry bone syndrome. Simultaneously, the patient started complaining of perioral and upper extremity numbness that resolved after 2 g of intravenous calcium gluconate. Thereafter, calcium 600 mg twice daily and calcitriol 1 µg daily were started. The patient was successfully discharged home on day 4 post parathyroidectomy and a one-week follow-up noted the absence of symptoms with a calcium level of 9.2 mg/dL and phosphorus level of 3.8 mg/dL. Calcium and calcitriol replacement were therefore discontinued.\n\nThe patient was closely monitored and after around 6 months (at 36 weeks of gestation), she had an uneventful delivery.\n\nDiscussion\nPrimary hyperparathyroidism causing hypercalcemia, while uncommon during pregnancy, is concerning and requires special care for mother and fetus to prevent problems such as nephrolithiasis, pancreatitis or hypercalcemic crisis and more importantly, major fetal complications such as hypocalcemia and tetany, preterm delivery and fetal demise even when pregnancy and delivery are uneventful (5, 8). Diagnosis is challenging, as symptoms may mimic other features observed frequently in pregnancy. Timely diagnosis and early intervention are crucial in this condition.\n\nPrimary hyperparathyroidism (PHPT) during pregnancy is thought to occur in less than 1% of cases. However, many authors agree that the actual number of cases in pregnancy is underestimated especially that gestational hyperparathyroidism (HPT) remains undiagnosed in a significant number of patients and is often suggested after numerous unexplained miscarriages (9). Despite its rarity, PHPT is the third most common endocrine disease in pregnancy (10) with up to 200 cases reported in the literature (11). Primary adenoma is the most common etiology of PHPT. The majority of patients (23–80%) are asymptomatic (8).\n\nThe diagnosis of primary hyperparathyroidism is very challenging due to the non-specificity of symptoms, the clinical similarities to other obstetrical diseases including hyperemesis gravidarum, the decrease in total calcium levels secondary to gestational hemodilution, increase in glomerular filtration rate leading to hypercalciuria and hypoalbuminemia, transplacental transfer of calcium and elevated estrogen levels in pregnancy (8). Moreover, clinicians have limited radiological options in pregnant women view the risk of fetal radiation which limits the use of sestamibi scan (5). Alternative imaging modalities have been suggested including the99m Tc-MIBI scan (12) and the cervical ultrasound (11).\n\nDecreased fertility in pregnant women with hyperparathyroidism is controversial. Primary hyperparathyroidism can lead to higher rates of fetal complications. The most serious outcomes include neonatal tetany secondary to hypocalcemia and suppression of the fetal parathyroid glands, still birth and respiratory failure in newborns (5, 8).\n\nOn the other hand, obstetrical complications of PHPT are usually uncommon because calcium levels are only mildly elevated in the majority of cases. However, significant calcium elevations can lead to pancreatitis. Hypercalcemic crisis can occur in the postpartum period because of the decreased shunting of calcium to fetus (8).\n\nNorman et al. reported a higher incidence of miscarriages (3.5-fold) in pregnant women with PHPT who did not undergo parathyroidectomy, whereas Abood and Vestergaard, and Hirsh and coworkers found no difference in the outcomes (10).\n\nAbood and Vestergaard also reported no increase in abortion rate and no need for parathyroidectomy but increased risk of delivery by cesarean section in mild PHPT-associated pregnancy. Weight and length birth, and Apgar score are usually not affected in mild PHPT (13). Miscarriages occur most commonly between week 10 and 15, in patients with calcium levels exceeding 11.4 mg/dL and with history of previous miscarriages (9). Women diagnosed with hyperparathyroidism during pregnancy can report one or more miscarriages that can go unnoticed if calcium levels are not alarming.\n\nAcute pancreatitis in pregnancy is also rare with an incidence ranging between 0.02 and 0.1% (5).\n\nGallstone is the most common cause in pregnancy, due to weight and hormonal effects. A second scenario in pregnancy is hypertriglyceride-induced pancreatitis due to high fat levels, increased estrogen and familial tendency (14).\n\nAcute pancreatitis, as well as gallstone disease, occurs more frequently in the third trimester with advanced gestational age (15).\n\nIn addition, primary hyperparathyroidism is rarely a cause of acute or chronic pancreatitis with a prevalence of 3.6% (7).\n\nThe frequency of acute pancreatitis is much higher in pregnant women with hyperparathyroidism (7–13%) than in non-pregnant ones. It is assumed that it is more common in primiparas and mainly in the first and third trimester (2).\n\nIn small subset of patients, primary hyperparathyroidism can be attributed to radiation exposure or to rare genetic abnormalities, mainly MEN-1, MEN-2, familial parathyroid hyperplasia syndromes or jaw-tumor syndrome, especially in young population. Somatic loss of one MEN1 allele results in altered menin protein, which is a tumor suppressor, leading to the formation of adenoma involving one or more parathyroid glands. CDC73 mutations result in decreased parafibromin protein activity, which also acts as a tumor suppressor, leading to the development of adenoma or rarely carcinoma. Cyclin D1 overexpression is seen in adenoma and parathyroid hyperplasia. CaSR and other mutations have also been identified (16). Thus, genetic disease may have consequences on surgical therapy.\n\nManagement of PHPT in pregnancy is individualized according to symptoms, severity of hypercalcemia and gestational age (8). Early recognition and management reduce the complications, especially when diagnosis is established early in pregnancy. Mild hypercalcemia in pregnancy can be safely monitored, as compared to moderate and severe hypercalcemia (12).\n\nManagement is similar in pregnant and non-pregnant patients and consists on initial aggressive saline infusion. If needed, many medications can be used. Calcitonin, a category B drug, lowers calcium by inhibiting osteoclast formation. It is a relatively weak agent that rapidly lowers calcium concentration by a maximum of 1–2 mg/dL with an onset of action of 4–6 h. Its major adverse effect is tachyphylaxis. The efficacy of calcitonin is limited to the first 48 h of diagnosis even with repeated doses. Calcitonin does not cross the placenta and has been safely used in pregnancy. However animal studies showed that high doses of calcitonin may induce low birth weight in offsprings (2).\n\nFurosemide, category C medication, is mainly used to promote calciuresis.\n\nCinacalcet activates calcium-sensing receptors (CaSR) on parathyroid cells, C-cells of the thyroid, and renal distal tubular cells, thus reduces PTH, increases calcitonin release and decreases renal calcium reabsorption. However, its efficacy on the mother and fetus are still lacking. This drug is considered category C. CaSR are present in the placenta; therefore, cinacalcet inhibits active placental calcium transport. Multiple studies suggested adverse effects secondary to its use. Cinacalcet suppresses fetal PTH and can induce neonatal hypocalcemia (12).\n\nBisphosphonates, considered category C drugs, act by decreasing bone resorption. Their optimal benefit is reached 2–4 days after administration; therefore, they should be given in combination with calcitonin. They are the most potent drug category, but their use should be limited to emergent cases when their benefits outweigh their risks, to patients requiring short-term therapy and to those with severe hypercalcemia prior to surgery (17). Bisphosphonates are known to affect fetal bone development.\n\nOral phosphates, labeled as pregnancy category C medication, promote urinary calcium excretion but carry a risk of soft tissue calcifications and diarrhea.\n\nIn addition, management of severe hypercalcemia may require hemodialysis and in refractory cases, parathyroidectomy (8).\n\nIn pregnant patients, special attention is given to the potential complications of treatment and its adverse effects on women and fetuses. Thus, surgical approach remains the safest therapeutic option, preferably performed before pregnancy. During pregnancy, parathyroidectomy is recommended in the second trimester when anesthesia and surgical techniques are relatively safe and fetal organogenesis is complete (9). Anesthesia during parathyroidectomy in the first and third trimesters may lead to spontaneous abortion and premature delivery respectively (11).\n\nOur patient is a good example; she improved dramatically after parathyroidectomy with total amelioration of her abdominal pain, rash, pancreatitis and hypercalcemia.\n\nA major consideration after successful parathyroidectomy is hungry bone syndrome. The incidence of this syndrome during pregnancy is still unknown. Large size of parathyroid adenomas, high preoperative levels of blood urea nitrogen and alkaline phosphatase and old age are important risk factors for the development of hungry bone syndrome.\n\nConclusion\nPrimary hyperparathyroidism is a rare devastating event during pregnancy. Diagnosis can be challenging, and complications may be life threatening. A well-organized multidisciplinary approach is recommended to prevent adverse outcomes in woman and fetus.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nWritten informed consent has been obtained from the patient for publication of the submitted article and accompanying images.\n\nAuthor contribution statement\nDr Carine Ghassan Richa:wrote this article; Dr Mohamad Souheil EL Rawas : patient's physician,, revised critically this manuscript and gave final approval of the version;Dr Khadija Jamal Saad: participated in drafting this manuscript; Dr Ali Khaled Chaaban: contributed to diagnostic imaging.\n==== Refs\nReferences\n1 Hong MK Hsieh CT Chen BH Tu ST Chou PH \nPrimary hyperparathyroidism and acute pancreatitis during the third trimester of pregnancy . Journal of Maternal-fetal Medicine \n2001 \n10 \n214 –218 . (10.1080/jmf.10.3.214.218 )11444793 \n2 Krysiak R Wilk M Okopien B \nRecurrent pancreatitis induced by hyperparathyroidism in pregnancy . Archives of Gynecology and Obstetrics \n2011 \n284 \n531 –534 . (10.1007/s00404-010-1668-x )20848117 \n3 Lee CC Chao AS Chang YL Peng HH Wang TH Chao A \nAcute pancreatitis secondary to primary hyperparathyroidism in a postpartum patient: a case report and literature review. \nTaiwanese Journal of Obstetrics and Gynecology \n2014 \n53 \n252 –255 . (10.1016/j.tjog.2013.01.029 )25017280 \n4 Liu Y Wang J-N Huang Y Zhu Y-H Liu R-L Xu C-F Li X \nAcute pancreatitis and preeclampsia induced by parathyroid sdenoma in pregnancy: a case report and literature review . International Journal of Clinical and Experimental Medicine \n2016 \n9 \n22652 –22655 .\n5 Dale A Holbrook BD Sobel L Rappaport VJ \nHyperparathyroidism in pregnancy leading to pancreatitis and preeclampsia with severe features . Case Reports in Obstetrics and Gynecology \n2017 \n2017 \n1 –3 . (10.1155/2017/6061313 )\n6 Burks M Harary S Solorzano CC Bao S \nPrimary hyperparathyroidism in a first-trimester woman with hyperemesis gravidarum and pancreatitis . AACE Clinical Case Reports \n2017 \n3 \ne31 –e34 . (10.4158/EP151136.CR )\n7 Khoo T Vege SS Abu-Lebdeh HS Ryu E Nadeem S Wermers RA \nAcute pancreatitis in primary hyperparathyroidism: a population-based study . Journal of Clinical Endocrinology and Metabolism \n2009 \n94 \n2115 –2118 . (10.1210/jc.2008-1965 )19318456 \n8 Malekar-Raikar S Sinnott BP \nPrimary hyperparathyroidism in pregnancy – a rare cause of life-threatening hypercalcemia: case report and literature review . Case Reports in Endocrinology \n2011 \n2011 \n1 –6 . (10.1155/2011/520516 )\n9 Norman J Politz D Politz L \nHyperparathyroidism during pregnancy and the effect of rising calcium on pregnancy loss: a call for earlier intervention . Clinical Endocrinology \n2009 \n71 \n104 –109 . (10.1111/j.1365-2265.2008.03495.x )19138316 \n10 Hirsch D Kopel V Nadler V Levy S Toledano Y Tsvetov G \nPregnancy outcomes in women with primary hyperparathyroidism . Journal of Clinical Endocrinology and Metabolism \n2015 \n100 \n2115 –2122 . (10.1210/jc.2015-1110 )25751112 \n11 Rchachi M , et al\nPrimary hyperparathyroidism in pregnancy – a review . Annals of African Medicine \n2017 \n16 \n145 –147 . (10.4103/aam.aam_61_16 )28671157 \n12 Rubin M Silverberg SJ \nUse of cinacalcet and 99mTc-sestamibi imaging during pregnancy . Journal of the Endocrine Society \n2017 \n9 \n1156 –1159 . (10.1210/js.2017-00308 )\n13 Aboud A Vestergaard P \nPregnancy outcomes in women with primary hyperparathyroidism . European Journal of Endocrinology \n2014 \n171 \n69 –76 . (10.1530/EJE-13-0966 )24743398 \n14 Pitchumoni C Yegneswaran B \nAcute pancreatitis in pregnancy . World Journal of Gastroenterology \n2009 \n15 \n5641 –5646 . (10.3748/wjg.15.5641 )19960559 \n15 Abdullah B Kathiresan Pillai T Huay Cheen L Joshua Ryan R \nCase report severe acute pancreatitis in pregnancy . Case Reports in Obstetrics and Gynecology \n2015 \n2015 \n1 –4 . (10.1155/2015/239068 )\n16 Familial isolated hyperparathyroidism . Genetics Home Reference \n2018 \n1 –6 .\n17 Gokkaya N Gungor A Bilen A Bilen H Gviniashvili D Karadeniz Y \nPrimary hyperparathyroidism in pregnancy: a case series and literature review . Gynecological Endocrinology \n2016 \n32 \n783 –786 . (10.1080/09513590.2016.1188916 )27243597\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2052-0573", "issue": "2018()", "journal": "Endocrinology, diabetes & metabolism case reports", "keywords": "2018; 25-hydroxyvitamin-D3; Abdominal pain; Alanine aminotransferase; Amylase; Bilirubin; Bisphosphonates; Bone; Calcitonin; Calcitriol; Calcium; Calcium (serum); Calcium (urine); Calcium gluconate; Creatinine; Endoscopic ultrasound; Female; Fluid repletion; Furosemide; Histopathology; Hypercalcaemia; Hyperparathyroidism (primary); Kidney stones; Lebanon; Leukocytosis; Lipase (serum); MRI; Magnesium; March; Nausea; Obstetrics; PTH; Pancreatitis; Paraesthesia; Parathyroid; Parathyroid adenoma; Parathyroidectomy; Phosphate (serum); Pregnant adult; Pruritus; Saline; Ultrasound scan; Unique/unexpected symptoms or presentations of a disease; Urine 24-hour volume; Vomiting; White; Zoledronic acid", "medline_ta": "Endocrinol Diabetes Metab Case Rep", "mesh_terms": null, "nlm_unique_id": "101618943", "other_id": null, "pages": null, "pmc": null, "pmid": "29623207", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": "11444793;19138316;19318456;19960559;20848117;22937284;24743398;25017280;25628906;25751112;27243597;28487796;28671157;29264570", "title": "A rare case of hypercalcemia-induced pancreatitis in a first trimester pregnant woman.", "title_normalized": "a rare case of hypercalcemia induced pancreatitis in a first trimester pregnant woman" }

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{ "abstract": "Tacrolimus is a commonly used immunosuppressant medication after lung transplantation. In rare cases, tacrolimus causes a medication-induced optic neuropathy (TON) that can lead to significant vision loss.\nIn this series, we describe three cases of TON, 1-10 years after medication use. Two patients were young (22yr and 33yr) females with cystic fibrosis. The last case was a 65yr male with idiopathic pulmonary fibrosis. In 2/3 cases tacrolimus serum levels were normal. Visual acuity ranged from 20/20 to 20/300, and vision loss occurred acutely to sub-acutely, over a span of 2-3 months.\nAs presented here, TON can be highly variable. MRI findings are often non-specific, from normal brain findings to extensive white matter changes. There remains an unclear association with graft-versus-host disease and reduced kidney function. Visual findings are often subtle, including color vision aberration and peripheral visual field deficits, both of which usually require an ophthalmologic evaluation. When diagnosed in a timely fashion, TON is at least partially reversible in up to half of all cases. While rare, the cases described here support post-lung transplant ophthalmologic evaluation in those taking high-risk medications.", "affiliations": "Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY, United States.;Department of Neuro-Ophthalmology, University of California, San Francisco, CA, United States.;Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY, United States.", "authors": "Nanda|Tavish|T|;Rasool|Nailyn|N|;Bearelly|Srilaxmi|S|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.ajoc.2021.101056", "fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936\nElsevier\n\nS2451-9936(21)00047-5\n10.1016/j.ajoc.2021.101056\n101056\nCase Report\nTacrolimus induced optic neuropathy in post-lung transplant patients: A series of 3 patients\nNanda Tavish [email protected]\na∗\nRasool Nailyn b\nBearelly Srilaxmi a\na Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY, United States\nb Department of Neuro-Ophthalmology, University of California, San Francisco, CA, United States\n∗ Corresponding author. 635 W 165th St, New York, NY, 10032, United States. [email protected]\n11 3 2021\n6 2021\n11 3 2021\n22 10105617 7 2020\n21 2 2021\n© 2021 Published by Elsevier Inc.\n2021\n\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPurpose\n\nTacrolimus is a commonly used immunosuppressant medication after lung transplantation. In rare cases, tacrolimus causes a medication-induced optic neuropathy (TON) that can lead to significant vision loss.\n\nObservations\n\nIn this series, we describe three cases of TON, 1–10 years after medication use. Two patients were young (22yr and 33yr) females with cystic fibrosis. The last case was a 65yr male with idiopathic pulmonary fibrosis. In 2/3 cases tacrolimus serum levels were normal. Visual acuity ranged from 20/20 to 20/300, and vision loss occurred acutely to sub-acutely, over a span of 2–3 months.\n\nConclusions and importance\n\nAs presented here, TON can be highly variable. MRI findings are often non-specific, from normal brain findings to extensive white matter changes. There remains an unclear association with graft-versus-host disease and reduced kidney function. Visual findings are often subtle, including color vision aberration and peripheral visual field deficits, both of which usually require an ophthalmologic evaluation. When diagnosed in a timely fashion, TON is at least partially reversible in up to half of all cases. While rare, the cases described here support post-lung transplant ophthalmologic evaluation in those taking high-risk medications.\n\nKeywords\n\nTacrolimus\nOptic neuropathy\nLung transplant\nNeuro-ophthalmology\nToxicity\nOphthalmologic examination\nAbbreviations\n\nACR, acute cellular rejection\nAKI, acute kidney injury\nCNS, central nervous system\nCr, creatinine\nCT, computed tomography\nFLAIR, fluid attenuated inversion recovery\nGVHD, graft versus host disease\nJC, John Cunningham\nMRI, magnetic resonance imaging\nOCT, optical coherence topography\nPET, positron emission tomography\nPRES, posterior reversable encephalopathy syndrome\nTON, tacrolimus optic neuropathy\nVZV, varicella zoster virus\n==== Body\nIntroduction\n\nSince its approval in 1997 tacrolimus is now used in upwards of 93% of all post-lung transplant patients for maintenance immunosuppression.1 Tacrolimus induced optic neuropathy (TON) remains an extremely rare and elusive diagnosis, with only 13 cases published in the literature.2 Due to its infrequency, it remains a diagnosis of exclusion, after infectious, inflammatory, and neoplastic causes are evaluated. In many cases, the diagnosis remains presumptive. The exact mechanism remains unclear. Some authors support the possibility of an ischemic process, with two studies finding a delay or absence in vascular circulation on fluorescein angiography.3, 4, 5, 6, 7, 8 In contrast, biopsy of the optic nerve has demonstrated extensive demyelination without ischemic insult, and cortical cultures have shown direct oligodendritic toxicity and death.9,10 TON is likely distinct from cyclosporine-induced optic neuropathy, as patients who have been switched to cyclosporine due to suspected TON have demonstrated visual improvement.6\n\nClinically, TON usually presents as a slow reduction in visual acuity, progressive visual field deficits, and/or dyschromatopsia, though acute changes have also been described. MRI can show optic nerve and other white matter lesions, even in the context of normal tacrolimus levels.9,11 While tacrolimus can also affect the visual system from posterior involvement of the visual tracts or occipital lobes, due to tacrolimus-induced posterior reversible encephalopathy syndrome (PRES), TON is usually associated with optic nerve edema or pallor.2 Through an institutional review board-approved process (AAAS6456), we reviewed all post-lung transplant inpatient consults performed at our institution between 2014 and 2019. Of 65 consultations, 3 patients were found to have tacrolimus-induced optic neuropathy. This report does not contain any personal information that could lead to the identification of these 3 patients.\n\nFindings\n\nCase 1\n\nA 33-year-old female with a past medical history of diabetes and cystic fibrosis, status post double lung transplant 11 years prior, presented to the neurology service for non-specific headache, vision loss (blurriness, darkness, loss of peripheral vision), weakness, and lethargy. She had several prior admissions for headache, neck pain, and subjective fever. During these admissions, repeat lumbar punctures, along with extensive encephalitis panels, were unremarkable. A previous MRI, however, demonstrated new T2/FLAIR abnormalities along the optic chiasm and proximal optic tracts, hypothalamus, and cerebellum. Based on these findings her tacrolimus dose of 0.5mg/day was discontinued, even though she had remained within therapeutic range (5–20ng/ml). Her creatinine (Cr) function at that time was consistent with acute kidney injury (AKI) of 2.51.\n\n3 months later, on presentation to our institution, she reported continued worsening of her visual symptoms over the course of 2–3 months. On exam, her visual acuity was 20/300 in the right eye and 20/200 in the left eye. She had severe dyschromatopsia on Hardy-Rand-Rittler color plates (0/12 in both eyes). A 24–2 visual field (Fig. 1) demonstrated poor reliability, but suggested bitemporal field loss with significant field constriction. Dilated fundus examination was notable for optic nerve pallor and atrophy. This was confirmed on optical coherence tomography (OCT), which demonstrated diffuse ganglion cell layer loss.Fig. 1 Bitemporal hemianopsia on an automated 24–2 visual field in Case 1.\n\nLegend: Left = Right Eye, Right = Left Eye. Black and grey are regions of reduced sensitivity to visual stimuli when compared to normative data. Note the right worse than left visual field deficits. This visual field demonstrates an incongruent bitemporal hemianopsia with additional infero-nasal deficits in both eyes.\n\nFig. 1\n\nDuring this admission she was diagnosed and treated for a superficial cellulitis of the hand, which improved after intravenous vancomycin. A broader infectious examination - including coccidiomycosis, syphilis, tuberculosis, John Cunningham virus, cytomegalovirus, and bartonella - was negative. Inflammatory and neoplastic evaluation, including a PET scan, were unremarkable. Kidney function improved from her prior admissions (Cr of 1.50) and she underwent a repeat brain, orbit, and spinal MRI. Her MRI abnormalities remained unchanged, with persistent hyperintensity of the optic chiasm (Fig. 2). Her visual symptoms, which persisted after treatment of her cellulitis, along with her neuroradiologic findings, were deemed most consistent with a severe and atypical tacrolimus-induced toxicity.Fig. 2 FLAIR hyperintensity of the optic chiasm in Case 1.\n\nLegend: Left = an axial image with hyperintensity (arrow) over the optic chiasm consistent with TON. Right = a coronal image highlighting the same persistent hyperintensity (arrow).\n\nFig. 2\n\nCase 2\n\nA 65-year-old male with a history of idiopathic pulmonary fibrosis complicated by pulmonary hypertension, underwent a single left lung transplantation 2 years prior to admission. His immediate post-transplant course was complicated by cryptococcal meningitis, which resolved after treatment, with no residual deficits. His immunosuppressive regimen included tacrolimus at an alternating dose of 0.5mg and 0.25mg twice a day, prednisone 10mg daily, and cellcept 500mg three times a day. On admission, he presented with an acute change in mental status and slurring of speech and was found to have maculopapular lesions respecting the midline, consistent with varicella zoster virus (VZV) in the trigeminal V1 distribution.\n\nAt the time the patient also complained of blurry vision in his left eye, which warranted an ophthalmology consultation. On exam, vision was 20/50 in both eyes and was otherwise unremarkable, notable only for tilted optic discs, a benign finding. CT imaging was negative for stroke, but a lumbar puncture was VZV polymerase chain reaction positive, confirming CNS involvement. MRI brain revealed diffuse pachymeningeal enhancement. His titers resolved on intravenous anti-viral treatment with acyclovir, yet he remained lethargic and deconditioned. On treatment, he had a persistently mild AKI (Cr of 1.30–1.60). After several weeks, his condition improved and the patient returned to baseline.\n\nOne month later, however, he was reexamined for a subjective worsening of vision, now in the right eye. At this point, there was a decrease in right eye vision, from 20/50 to 20/70, a new right afferent pupillary defect, and a new temporal visual field deficit. Optic nerve exam demonstrated newfound pallor in both eyes, consistent with a sub-acute to chronic process. Color vision was reduced on Ishihara color plates, 1.5/14 right eye and 11.5/14 left eye. Optic nerve atrophy was confirmed on OCT, which demonstrated diffuse, asymmetric, nerve fiber layer loss (right > left) (Fig. 3). There was no evidence of vasculitis, or any MRI findings suggestive of leptomeningeal spread involving the optic nerves. Systemic infectious work-up remained negative and metabolic causes such as folate or vitamin B12 deficiency were excluded. Kidney function had normalized with fluid management, Cr 1.10–1.20, while being maintained on intravenous acyclovir 500mg twice a day. The interdisciplinary teams agreed that these findings were most consistent with TON, and his tacrolimus dosing was discontinued.Fig. 3 Macular thickness on optical coherence tomography in Case 2.\n\nLegend: Optical coherence tomography provides a detailed view of each layer of the retina. A thin retina is noted by the ‘red’ values in the two quantitative circles, when compared to normative data. While the right eye is off-center (see top box, left side), a qualitative assessment of the retinal layers in the images provided are consistent with retinal nerve fiber layer loss, which occurs in tacrolimus-induced nerve damage. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 3\n\nCase 3\n\nA 23-year-old female with cystic fibrosis, status post bilateral lung transplant one-year prior, was transferred to our medical intensive care unit due to acute on chronic respiratory failure. Prior to admission, her home dose of tacrolimus was 0.5mg daily and prednisone 10mg daily. On admission, she was intubated for acute respiratory distress syndrome. Infectious work up (including bronchoalveolar lavage cultures) remained negative, prompting a diagnosis of acute cellular rejection (ACR). Her tacrolimus level rose from 17 to 53 ng/ml acutely and was held. Of note, she'd had a prior admission one year ago for acute tacrolimus toxicity resulting in AKI, which had resolved. Creatinine on this admission was 2.37, consistent with AKI.\n\nShe was treated with pulse dose steroids, intravenous immunoglobulin and plasma exchange, and Thymoglobulin with eventual clinical improvement. She was extubated 5 days later. At one month, she reported a new right temporal visual field deficit. On exam, vision was 20/20 in both eyes. Visual field was full (Fig. 4A–B). Her dilated exam demonstrated temporal nerve pallor in the right eye and diffuse optic atrophy in the left eye. This was confirmed on optical coherence tomography, which demonstrated asymmetric nerve loss (left > right) and appeared consistent with TON (Fig. 4C–D).Fig. 4 24–2 visual fields and optical coherence tomography in Case 3.\n\nLegend: Panel A–B demonstrates a normal right and left visual field. This would not capture any far temporal peripheral field deficits, since a 24-2 measures only the central 24° of the visual field. In Panel C are quantitative measures of optic nerve health. The left eye (OS) is in red, indicating nerve fiber layer loss. While the left eye was convoluted by artifact (black components of the top right picture), thinning is further confirmed in Panel D which demonstrates a reduced average thickness of the macula. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 4\n\nShe was scheduled for a wider visual field test (Goldmann) to assess for far temporal visual field deficits but developed bifrontal seizures and altered mental status requiring admission to the neuro-intensive care unit. MRI brain demonstrated white matter changes consistent with PRES. Tacrolimus was discontinued with eventual improvement in both her symptoms and brain lesions. She remained hospitalized for another month due to the re-development of ACR requiring further medication management. She was subsequently discharged home on cyclosporine 375mg twice a day and oral prednisone 50mg daily, after a 3-month hospital stay.\n\nDiscussion\n\nThe diagnosis of tacrolimus induced optic neuropathy is clinically challenging. Previous cases report the development of TON anywhere from 2 months to 5 years after initiation.2 Toxicity usually occurs at a plasma level >20 ng/ml but can occur at normal or even sub-therapeutic levels (Table 1).12 Vision loss can be sudden, over a few days, or gradual (>1 year). Like the cases described herein, in which one patient maintained 20/20 vision while another declined to the 20/200–300 range, prior studies have reported 20/20 to light perception vision. Usually, TON is a bilateral process, but can affect one optic nerve prior to the other, as with case 2.2 Similar to case 1, visual deterioration can continue, even after tacrolimus discontinuation.5Table 1 Published Cases of Tacrolimus-Induced Optic Neuropathy (including the present study).\n\nTable 1Source\tAge/Sex\tDuration\tDose\tPlasma Level\tOnset\tVisual Acuity\tColor Vision\tVisual Field\tPupils\tEye\tTransplant\t\nBrazis et al., 2000\t58/M\t2mo\t4mg QD\tNR\t~3mo\tOD: 20/20\nOS: 20/100\tOD: 9.5/10\nOS: 3/10\tOD: Superior arcuate\nOS: Infero-altitudinal\tLeft APD\tOU\tLiver\t\nVenneti et al., 2010\t63/M\t5yr\tNR\t8.8 μg/L\t~2mo\tOD: 20/70\nOS: HM\tReduced\tOD: Inferonasal\nOS: Unable\tSluggish\tOU\tRenal\t\nLake et al., 2003\t38/M\tNR\t4mg QD\tNR\t~12mo\tOD: 3/60\nOD: 2/60\tNR\tOD: Normal\nOS: Normal\tNo APD\tOU\tPancreas\t\nAscaso et al., 2012\t56/F\t6mo\t1.5mg QD\t1.9 ng/ml\tSudden\tOD: 20/20\nOS: LP\tOS: None\tNR\tLeft APD\tOS\tLiver\t\nAkers et al., 2009\t47/F\tNR\tNR\t5.7ng/ml\t~4 days\tOD: 20/25\nOS: 20/40\tOD: 5/10\nOS: 1/10\tOD: Normal\nOS: Inferonasal\tNR\tOS\tRenal\t\nCanovai et al., 2019\t51/M\t3.5yr\t2mg BID\t4.4 μg/L\t~2wks\tOD: CF\nOS: CF\tNR\tOD: Central scotoma\nOS: Central scotoma\tNo APD\tOU\tMulti-visceral\t\nShao et al., 2012\t30/M\t3mo\tNR\t13.9ng/ml\t~5 days\tOD: HM\nOS: HM\tNR\tNR\tSluggish\nNo APD\tOU\tSmall Bowel\t\nYun et al., 2010\t54/M\t6mo\t2.5mg BID\t6.2mg/L\t~3mo\tOD: CF\nOS: CF\tNR\tOD: Cecocentral scotoma\nOS: Cecocentral scotoma\tLeft APD\tOS\tLiver\t\nKessler et al., 2006\t51/F\t5mo\t2mg QD\t12.9ng/ml\t“gradual”\tOD: 20/100\tNR\tNR\tNR\tOD\tPancreas\t\nGupta et al., 2012\t35/F\t2yr\t1mg BID\tNR\t~2wks\tOD: 6/6\nOS: 6/6\tNR\tOD: Normal\nOS: Inferonasal\tLeft APD\tOS\tNephrotic Syndrome\t\nRasool et al., 2018\t55/M\t4yr\t2mg BID\t8ng/ml\t~ few days\tOD: 20/200\nOS: 20/25\tOD: Normal\nOS: Reduced\tOD: Diffuse depression\nOS: Superior/Inferior nasal\tRight APD\tOU\tBMT\t\nRasool et al., 2018\t66/M\t5yr\t0.5mg BID\t10ng/ml\t~3mo\tOD: 20/25\nOS: 20/100\tOD: Reduced\nOS: Reduced\tOD: Temporal-inferior\nOS: Inferior arcuate\tNo APD\tOU\tPBSCT\t\nRasool et al., 2018\t63/M\t4mo\t0.5mg QD\t5ng/ml\t~3 days\tOD: 20/20\nOS: 20/50\tOD: NR\nOS: Reduced\tOD: Diffuse\nOS: Nasal loss\tLeft APD\tOU\tBMT\t\nCurrent Study\t33/F\t10yr\t0.5mg QD\t12.2ng/ml\t~2–3mo\tOD: 20/300\nOS: 20/200\tOD: 0/12\nOS: 0/12\tOD: Temporal field loss\nOS: Temporal field loss\tNo APD\tOU\tLung\t\nCurrent Study\t65/M\t2yr\t0.5mg/0.25mg BID\t8.3ng/ml\t~few days\tOD: 20/50\nOS: 20/50\tOD: 1.5/14\nOS: 11.5/14\tOD: Temporal defect\nOS: Normal\tRight APD\tOU\tLung\t\nCurrent Study\t23/F\t1yr\t0.5mg QD\t53ng/ml\tSudden\tOD: 20/20\nOS: 20/20\tOD: 6/6\nOS: 6/6\tOD: Normal\nOS: Normal\tNo APD\tOU\tLung\t\n\nMRI findings also vary considerably between patients, from extensive white matter changes to normal brain findings.2 Only 35.7% of patients with neurologic symptoms from tacrolimus have white matter abnormalities. Isolated cases of brain stem involvement have also been reported.13,14 In one study, 2/5 patients with tacrolimus toxicity had no reversal of white matter abnormalities upon discontinuation, even in the context of clinical improvement.15 This appears similar to case 1 in which white matter lesions persisted after medication discontinuation.\n\nTacrolimus, even after its metabolism by the liver, can maintain biologic activity. Combined with a wide range in half-life (3.5–40.5 hours), normal plasma levels may not accurately reflect a patient's tacrolimus burden.14,16 Studies have also found different genetic predispositions to drug pharmacokinetics that may increase susceptibility to CNS penetration, and presumably, optic nerve damage.17 One case series suggested that transient breakdown in the blood-brain barrier due to graft-versus-host disease (GVHD) may also allow for increased CNS penetration.2 This concept has been previously considered in other instances of rare medication toxicity, such as eye-drop induced visual hallucinations.18 GVHD is also known to reduce tacrolimus clearance by 20% due to hepatic dysfunction and by 40% from acute kidney injury in patients post hematopoietic transplantation.10 The second case in this series was diagnosed with VZV meningitis, which can also result in blood brain barrier disruption. This mechanism may be fundamentally similar to that of GVHD.19 Case 3 was particularly interestingly due to the subsequent development of PRES after a diagnosis of TON. Shao et al. describes a similar case, in which TON pre-dated the development of PRES.8 TON may be an early sign of vascular dysregulation and blood brain barrier dysfunction, and suggestive of impending posterior involvement.\n\nCase 3 was also convoluted by a history of significant nephrotoxicity and elevated serum tacrolimus level on presentation. The relationship between tacrolimus toxicity and renal function remains unclear, as tacrolimus is not cleared by the kidney. However, several studies have suggested an association between rising creatinine levels and the subsequent development of TON, even with AKI that occurs months prior to symptom development.2 While the other two cases did not present with elevated serum levels or significant nephrotoxicity, both had transient AKI, prior to or during the development of visual symptoms.\n\nConclusions\n\nTo our knowledge, this is the first series to report TON in lung transplant recipients (Table 1). These three cases occurred out of 65 consults, suggesting a higher incidence than expected. Our tertiary care center, however, may be biased towards a higher degree of comorbidity amongst the post-transplant population. Risk stratification is hampered by a wide range of reported doses, duration of use, and normalcy of plasma levels (Table 1). Unlike haemopoietic stem cell transplantation, there are no set guidelines for routine post-lung transplant ophthalmology follow-up.20 In the context of several other medical concerns, continued ophthalmologic follow-up after discharge is likely overlooked by the primary team. This series emphasizes the need for lung transplant services to consider establishing guidelines for outpatient post-transplant ophthalmic follow-up. Due to the presumptive nature of a TON diagnosis, there is likely a subset of patients who remain undiagnosed due to the subtle nature of some early cases, which require a more specialized ophthalmologic approach, including serial color vision and visual field testing. TON may be reversible in ~50% of cases with appropriate care, and immediate discontinuation is necessary to prevent continued visual decline, further highlighting the importance of early detection.2\n\nPatient consent\n\nAs per institutional review board approval, written consent to publish this case series was not required. This report does not contain any personal identifying information.\n\nFunding\n\nThe New York Community Trust--Frederick J and Theresa Dow Wallace Fund, Columbia University (S.B.).\n\nAuthorship\n\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nDeclaration of competing interest\n\nThe following authors have no financial disclosures: TN, NR, SB.\n\nAcknowledgements\n\nNone.\n==== Refs\nReferences\n\n1 Adult lung transplantation statistics Available from: http://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry 2016\n2 Rasool N. Boudreault K. Lessell S. Tacrolimus optic neuropathy J Neuro Ophthalmol 38 2 2018 Jun 1 160 166\n3 Bouvier N. Flinois J.P. Gilleron J. Cyclosporine triggers endoplasmic reticulum stress in endothelial cells: a role for endothelial phenotypic changes and death Am J Physiol-renal 296 1 2009 Jan F160 F169\n4 Stein D.P. Lederman R.J. Vogt D.P. Neurological complications following liver transplantation Ann Neurol 31 6 1992 Jun 644 649 1514776\n5 Brazis P.W. Spivey J.R. Bolling J.P. A case of bilateral optic neuropathy in a patient on tacrolimus (FK506) therapy after liver transplantation Am J Ophthalmol 129 4 2000 Apr 1 536 538 10764869\n6 Wilson S.E. Aksamit A.J. Wiesner R.H. Cyclosporin A-induced reversible cortical blindness J Clin Neuro Ophthalmol 8 4 1988 Dec 215 220\n7 Yun J. Park K.A. Oh S.Y. Bilateral ischemic optic neuropathy in a patient using tacrolimus (FK506) after liver transplantation Transplantation 89 12 2010 Jun 27 1541 1542 20559109\n8 Shao X. He Z. Tang L. Gao L. Tacrolimus-associated ischemic optic neuropathy and posterior reversible encephalopathy syndrome after small bowel transplantation Transplantation 94 9 2012 Nov 15 e58 60 23128973\n9 Venneti S. Moss H.E. Levin M.H. Asymmetric bilateral demyelinating optic neuropathy from tacrolimus toxicity J Neurol Sci 301 1-2 2011 Feb 15 112 115 21112060\n10 McDonald J.W. Goldberg M.P. Gwag B.J. Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures Ann Neurol 40 5 1996 Nov 750 758 8957016\n11 Akagi T. Manabe S. Ishigooka H. A case of cyclosporine-induced optic neuropathy with a normal therapeutic level of cyclosporine Jpn J Ophthalmol 54 1 2010 102 20151288\n12 Jacobson P. Ng J. Ratanatharathorn V. Factors affecting the pharmacokinetics of tacrolimus (FK506) in hematopoietic cell transplant (HCT) patients Bone Marrow Transplant 28 8 2001 Oct 753 758 11781626\n13 Wu Q. Marescaux C. Qin X. Heterogeneity of radiological spectrum in tacrolimus-associated encephalopathy after lung transplantation Behav Neurol 2014 2014\n14 Saadi A. Schmahmann J.D. Pearls & Oy-sters: tacrolimus neurotoxicity presenting as an isolated brainstem lesion Neurology 86 11 2016 Mar 15 e109 e111 26976521\n15 Appignani B.A. Bhadelia R.A. Blacklow S.C. Neuroimaging findings in patients on immunosuppressive therapy: experience with tacrolimus toxicity AJR Am J Roentgenol 166 3 1996 Mar 683 688 8623651\n16 Jain A.B. Abu‐Elmagd K. Abdallah H. Pharmacokinetics of FK506 in liver transplant recipients after continuous intravenous infusion J Clin Pharmacol 33 7 1993 Jul 606 611 7690047\n17 Yamauchi A. Ieiri I. Kataoka Y. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene Transplantation 74 4 2002 Aug 27 571 572 12352921\n18 Nanda T. Rasool N. Callahan A.B. Ophthalmic timolol hallucinations: a case series and review of the literature J Glaucoma 26 9 2017 Sep 1 e214 e216 28671925\n19 Hoyer C. Eisele P. Ebert A.D. Blood-CSF-barrier dysfunction is a marker for encephalitic involvement in patients with aseptic meningitis/meningoencephalitis J Clin Virol 84 2016 Nov 1 82 86 27736668\n20 Majhail N.S. Rizzo J.D. Lee S.J. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation Hemtol Oncol Stem Cell Ther 5 1 2012 Jan 1 1 30\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2451-9936", "issue": "22()", "journal": "American journal of ophthalmology case reports", "keywords": "ACR, acute cellular rejection; AKI, acute kidney injury; CNS, central nervous system; CT, computed tomography; Cr, creatinine; FLAIR, fluid attenuated inversion recovery; GVHD, graft versus host disease; JC, John Cunningham; Lung transplant; MRI, magnetic resonance imaging; Neuro-ophthalmology; OCT, optical coherence topography; Ophthalmologic examination; Optic neuropathy; PET, positron emission tomography; PRES, posterior reversable encephalopathy syndrome; TON, tacrolimus optic neuropathy; Tacrolimus; Toxicity; VZV, varicella zoster virus", "medline_ta": "Am J Ophthalmol Case Rep", "mesh_terms": null, "nlm_unique_id": "101679941", "other_id": null, "pages": "101056", "pmc": null, "pmid": "33778180", "pubdate": "2021-06", "publication_types": "D002363:Case Reports", "references": "23128973;21112060;20559109;1514776;7690047;11781626;8957016;20151288;2977135;22446607;28671925;10764869;27736668;8623651;24970980;26976521;12352921;18987109;29420328", "title": "Tacrolimus induced optic neuropathy in post-lung transplant patients: A series of 3 patients.", "title_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients" }

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TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. 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TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:ARTICLE NUMBER 101056. 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TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:NO INFORMATION", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210326", "receivedate": "20210326", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19062244, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" }, { "companynumb": "US-ACCORD-222001", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyschromatopsia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:ARTICLE NUMBER 101056. 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TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021?22:1?6. DOI:10.1016/J.AJOC.2021.101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210827", "receivedate": "20210412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19120237, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP004229", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, TWICE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.25 MILLIGRAM, TWICE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".25", "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": "500 MILLIGRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Varicella zoster virus infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S.. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM?J?OPHTHALMOL?CASE?REP. 2021?22101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210915", "receivedate": "20210915", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19831548, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-ACCORD-222002", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELLCEPT" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ALTERNATING DOSE OF 0.5 MG AND 0.25 MG TWICE A DAY FROM 2 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pupillary reflex impaired", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Varicella zoster virus infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Visual field defect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:ARTICLE NUMBER 101056. DOI: 10.1016/J.AJOC.2021.101056.", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210413", "receivedate": "20210413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19124128, "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" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK053165", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL 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"reactionoutcome": "6" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS.. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS.. 2021?22", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210412", "receivedate": "20210405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19091018, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-292059", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELLCEPT" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, BID (ALTERNATING DOSE OF 0.5MG AND 0.25MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningitis viral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021?22:101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210420", "receivedate": "20210420", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19157708, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "NVSC2021US076868", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "2", "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": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22(10105):1?6", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210407", "receivedate": "20210407", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19103856, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP004230", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S.. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM?J?OPHTHALMOL?CASE?REP. 2021?22101056.", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210915", "receivedate": "20210915", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19831539, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK053347", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, OD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, OD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Visual field defect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS.. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS.. 2021?22", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210413", "receivedate": "20210413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19125979, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-PBT-000579", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "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": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": "5", "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster meningitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021 MAR 11?22:101056. DOI: 10.1016/J.AJOC.2021.101056. PMID: 33778180? PMCID: PMC7985716.", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210417", "receivedate": "20210417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19149682, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "NVSC2021US076872", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "PREDNISONE." }, { "actiondrug": "1", "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": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22(101056):1?6", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210407", "receivedate": "20210407", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19103860, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-ACCORD-222003", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "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": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:ARTICLE NUMBER 101056. DOI: 10.1016/J.AJOC.2021.101056.", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210413", "receivedate": "20210413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19126095, "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" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0133999", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Visual field defect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:1?6. DOI:10.1016/J.AJOC.2021.101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210827", "receivedate": "20210412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19120235, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0133996", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": 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"24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021?22:1?6. DOI:10.1016/J.AJOC.2021.101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210827", "receivedate": "20210412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19122695, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-ASTELLAS-2021US010660", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "050708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "0.5 MG, ONCE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:NO INFORMATION", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210325", "receivedate": "20210325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19055041, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-292061", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant rejection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021?22:101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210420", "receivedate": "20210420", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19157871, "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" }, { "companynumb": "NVSC2021US076871", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE" }, 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THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, 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"801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22(101056):1?6", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210407", "receivedate": "20210407", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19103861, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK053164", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Dyschromatopsia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS.. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:1?6", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210412", "receivedate": "20210405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19090641, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-PBT-000578", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021 MAR 11?22:101056. DOI: 10.1016/J.AJOC.2021.101056. PMID: 33778180? PMCID: PMC7985716.", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210417", "receivedate": "20210417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19149681, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0133994", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyschromatopsia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021?22:1?6. DOI:10.1016/J.AJOC.2021.101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210827", "receivedate": "20210412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19120101, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-PBT-000580", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "3", "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": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": "5", "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AM J OPHTHALMOL CASE REP. 2021 MAR 11?22:101056. DOI: 10.1016/J.AJOC.2021.101056. PMID: 33778180? PMCID: PMC7985716.", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210417", "receivedate": "20210417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19149683, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-VELOXIS PHARMACEUTICALS-2021VELUS-000237", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "206406", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "AT AN ALTERNATING DOSE OF 0.5 MG AND 0.25 MG TWICE A DAY", 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"drugstructuredosagenumb": ".25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENVARSUS XR" } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Varicella zoster virus infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pupillary reflex impaired", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Visual field defect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S ET.AL. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS.. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210409", "receivedate": "20210409", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19109133, "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" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK053166", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, QD (DAILY)", "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": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD (DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S.. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS.. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS.. 2021?22:101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210409", "receivedate": "20210405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19091053, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-VELOXIS PHARMACEUTICALS-2021VELUS-000235", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "206406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "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": "ENVARSUS XR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "206406", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "0.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENVARSUS XR" } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Visual field defect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic atrophy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. ET.AL. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:ARTICLE NUMBER 101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210408", "receivedate": "20210401", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19081343, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-VELOXIS PHARMACEUTICALS-2021VELUS-000236", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "206406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "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": "ENVARSUS XR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "206406", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "0.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENVARSUS XR" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyschromatopsia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NANDA T, RASOOL N, BEARELLY S. ET.AL.. TACROLIMUS INDUCED OPTIC NEUROPATHY IN POST?LUNG TRANSPLANT PATIENTS: A SERIES OF 3 PATIENTS. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021?22:ARTICLE NUMBER 101056", "literaturereference_normalized": "tacrolimus induced optic neuropathy in post lung transplant patients a series of 3 patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210409", "receivedate": "20210409", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19114463, "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": "OBJECTIVE\nDrug-induced thrombocytopenia (DITP) may be a fatal adverse reaction to many drugs. It is often misdiagnosed as primary immune thrombocytopenia (ITP), and thus diagnosis can be delayed and patients can be treated inappropriately. Amlodipine a calcium-channel blocker, and simvastatin, a statin, have very rarely been implicated in DITP. We report on an investigation of the causal relationship of amlodipine and simvastatin with thrombocytopenia occurring in the same patient, and review the literature.\n\n\nMETHODS\nWe present the case of a 78-year-old female hypertensive diabetic patient with three successive DITPs. The first attack of acute severe thrombocytopenia occurred after a 2-week course of amlodipine, and was initially misdiagnosed as ITP. Her platelet count normalized after the amlodipine was discontinued. The second attack followed her restarting simvastatin 3 weeks later. She had stopped it 2 months earlier having previously taken it for over 5 years. Again, she recovered once the simvastatin was discontinued. The third DITP attack occurred when she accidently took a single dose of amlodipine 9 months later.\n\n\nCONCLUSIONS\nWe provide clear evidence of a causal association of amlodipine with thrombocytopenia, and probable evidence of a causal association of simvastatin with thrombocytopenia. This is the first reported case of DITPs occurring with two of the most widely prescribed drugs in the same patient. Many hypertensive patients need to take multiple drugs in order to achieve their treatment goals and this increases their risk of drug-induced adverse reactions and makes identification of the causal drug (or drugs) extremely difficult.", "affiliations": "Department of Hematology, Clinical Hospital Center Zemun, Belgrade, Serbia. [email protected]", "authors": "Cvetković|Zorica|Z|;Suvajdžić-Vuković|Nada|N|;Todorović|Zoran|Z|;Panić|Miloš|M|;Nešković|Aleksandar|A|", "chemical_list": "D000959:Antihypertensive Agents; D000960:Hypolipidemic Agents; D017311:Amlodipine; D019821:Simvastatin", "country": "England", "delete": false, "doi": "10.1111/jcpt.12051", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-4727", "issue": "38(3)", "journal": "Journal of clinical pharmacy and therapeutics", "keywords": null, "medline_ta": "J Clin Pharm Ther", "mesh_terms": "D000368:Aged; D017311:Amlodipine; D000959:Antihypertensive Agents; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents; D019821:Simvastatin; D013921:Thrombocytopenia", "nlm_unique_id": "8704308", "other_id": null, "pages": "246-8", "pmc": null, "pmid": "23442182", "pubdate": "2013-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Simvastatin and amlodipine induced thrombocytopenia in the same patient: double trouble and a literature review.", "title_normalized": "simvastatin and amlodipine induced thrombocytopenia in the same patient double trouble and a literature review" }

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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078043", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20110307", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20110307", "drugstartdateformat": "102", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078103", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DYSLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "69", "reaction": [ { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CVETKOVIC Z, SUVAJDZIC-VUKOVIC N, TODOROVIC Z, PARUC M, NESKOVIC A. SIMVASTATIN AND AMLODIPINE INDUCED THROMBOCYTOPENIA IN THE SAME PATIENT: DOUBLE TROUBLE AND A LITERATURE REVIEW. JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS. 2013 FEB 26;38:246-248.", "literaturereference_normalized": "simvastatin and amlodipine induced thrombocytopenia in the same patient double trouble and a literature review", "qualification": null, "reportercountry": "RS" }, "primarysourcecountry": "RS", "receiptdate": "20140707", "receivedate": "20140707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10279459, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150326" } ]

{ "abstract": "OBJECTIVE\nMitochondrial disorders (MIDs) may manifest phenotypically with a plethora of clinical features, but polyarthralgia and cutaneous lesions are still infrequently reported and recognized as phenotypic manifestations of a MID.\n\n\nMETHODS\nThe patient is a 27-year-old Caucasian female with a history of preterm birth, symptomatic myopathy, and polyarthralgia since infancy, followed by multiple endocrinopathies including pituitary insufficiency, cardiac conduction defects, nephrolithiasis, aseptic chronic pancreatitis and sialadenitis, anemia, hyperlipidemia, and dysmorphic features. The patient reported to have profited from hydrocortisone and long-term chloroquine, but hardly from long-term immunosuppression with various immunosuppressants. The diagnosis MID was established upon the multiorgan nature of the disease, presence of core clinical features of a MID, and a muscle biopsy indicative of a mitochondrial defect. The family history was positive for mitochondrial features in the mother and grandmother from the mother's side.\n\n\nCONCLUSIONS\nSeronegative and non-destructive polyarthralgia and unexplained cutaneous features mimicking cutaneous lupus should be considered as a phenotypic feature of a multisystem MID (mitochondrial multiorgan disorder syndrome, MIMODS). Mitochondrial metabolic defects may trigger secondary immune reactions. Core clinical features of a non-specific MID with infantile onset include symptomatic myopathy, endocrine abnormalities, cardiac conduction defects, dysmorphism, hyperlipidemia, anemia, and nephrolithiasis.", "affiliations": "Krankenanstalt Rudolfstiftung, Messerli Institute, Veterinary University of Vienna, Vienna, Austria. [email protected].;Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria.;Neurological Institute, Medical University of Vienna, Vienna, Austria.", "authors": "Finsterer|Josef|J|;Melichart-Kotig|Madleine|M|;Woehrer|Adelheid|A|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1007/s00393-018-0551-1", "fulltext": null, "fulltext_license": null, "issn_linking": "0340-1855", "issue": "78(9)", "journal": "Zeitschrift fur Rheumatologie", "keywords": "Arthralgia; Mitochondrion; MtDNA; Myopathy; Neuromuscular; Pituitary insufficiency", "medline_ta": "Z Rheumatol", "mesh_terms": "D000328:Adult; D001172:Arthritis, Rheumatoid; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D028361:Mitochondrial Diseases", "nlm_unique_id": "0414162", "other_id": null, "pages": "875-880", "pmc": null, "pmid": "30291434", "pubdate": "2019-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25264167;26385056;25390621;20562457;25403780;28735506;28334504;29054425;27375219;11579427;22121133", "title": "Mitochondrial disorder mimicking rheumatoid disease.", "title_normalized": "mitochondrial disorder mimicking rheumatoid disease" }

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"2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLECALCIFEROL" } ], "patientagegroup": "4", "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "75", "reaction": [ { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood creatine phosphokinase increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperlipidaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Temporomandibular joint syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nephrolithiasis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Brain natriuretic peptide increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Varicella zoster virus infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anosmia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sialoadenitis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood lactic acid increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ovarian cyst", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diastolic dysfunction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serum ferritin decreased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral haemangioma", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitamin D deficiency", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Secondary hypogonadism", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Migraine", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Menstrual disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bundle branch block right", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cutaneous lupus erythematosus", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pericardial effusion", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrioventricular block complete", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myoglobin blood increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Glomerular filtration rate decreased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Goitre", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Joint dislocation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood triglycerides increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FINSTERER, J.. MITOCHONDRIAL DISORDER MIMICKING RHEUMATOID DISEASE.. Z RHEUMATOL. 2019?78:10.1007/S00393-018-0551-1", "literaturereference_normalized": "mitochondrial disorder mimicking rheumatoid disease", "qualification": "1", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20200604", "receivedate": "20200604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17858919, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "AT-ALKEM LABORATORIES LIMITED-AT-ALKEM-2019-11190", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "JUVENILE IDIOPATHIC ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFASALAZINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "JUVENILE IDIOPATHIC ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFASALAZINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091249", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "27", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "75", "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FINSTERER J, MELICHART-KOTIG M, WOEHRER A. MITOCHONDRIAL DISORDER MIMICKING RHEUMATOID DISEASE. Z RHEUMATOL. 2019?78:875-880", "literaturereference_normalized": "mitochondrial disorder mimicking rheumatoid disease", "qualification": "1", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20201225", "receivedate": "20201225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18664390, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "AT-AMGEN-AUTSP2019215267", "fulfillexpeditecriteria": "2", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FEXOFENADINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, 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MELICHART-KOTIG M.? WOEHRER A.? ET.AL.. MITOCHONDRIAL DISORDER MIMICKING RHEUMATOID DISEASE. Z RHEUMATOL. 2019?78:875-880", "literaturereference_normalized": "mitochondrial disorder mimicking rheumatoid disease", "qualification": "3", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20200123", "receivedate": "20191231", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17220355, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "Primary synovial sarcoma is a very rare tumor of the mediastinum, which is unreported in the entire subcontinent of West Africa, and presents daunting challenges from diagnosis to management with lack of standard management strategies. We present a case of primary monophasic synovial sarcoma of the anterior mediastinum, in a 22-year-old Nigerian lady who presented with cough, chest pain, and pleural effusion. Chest X-ray (CXR) and computed tomography on admission showed a left-sided huge mass in the left anterior mediastinum with no metastasis to the contralateral pleural cavity. Complete resection of the mediastinal tumor was done and histologic and immunohistochemical analyses confirmed a diagnosis of monophasic synovial sarcoma. However, 10 months postoperation she represented with chest pain, productive cough and a repeat CXR showed multiple left pulmonary nodules. She received two cycles of docetaxel and gemcitabine chemotherapy, but declined further treatment until her demise 8 months later.", "affiliations": "Department of Morbid Anatomy, University of Nigeria, Enugu Campus, Enugu, Nigeria.", "authors": "Ukekwe|F I|FI|;Ezemba|N|N|;Olusina|D B|DB|;Igbokwe|U|U|;Ngene|C|C|", "chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C056507:gemcitabine", "country": "India", "delete": false, "doi": "10.4103/1119-3077.175965", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "19(2)", "journal": "Nigerian journal of clinical practice", "keywords": null, "medline_ta": "Niger J Clin Pract", "mesh_terms": "D017024:Chemotherapy, Adjuvant; D002637:Chest Pain; D003371:Cough; D003841:Deoxycytidine; D000077143:Docetaxel; D017809:Fatal Outcome; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms; D008479:Mediastinal Neoplasms; D008482:Mediastinum; D010996:Pleural Effusion; D013902:Radiography, Thoracic; D013584:Sarcoma, Synovial; D043823:Taxoids; D014057:Tomography, X-Ray Computed; D055815:Young Adult", "nlm_unique_id": "101150032", "other_id": null, "pages": "293-7", "pmc": null, "pmid": "26856298", "pubdate": "2016", "publication_types": "D002363:Case Reports; D016422:Letter; D016454:Review", "references": null, "title": "Giant primary synovial sarcoma of the anterior mediastinum: A case report and review of literature.", "title_normalized": "giant primary synovial sarcoma of the anterior mediastinum a case report and review of literature" }

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{ "abstract": "Toxic erythema of chemotherapy (TEC) is an infrequently reported cutaneous condition, with diagnosis predominately based on clinical presentation, histologic findings, and known reported associations. Therefore, it is important to both recognize common presentations of TEC and be mindful of chemotherapeutic agents associated with this cutaneous side effect to prevent misdiagnosis and prolonged time to treatment. Herein, we present a patient with TEC occurring in intertriginous skin (malignant intertrigo) with classic clinical and histologic findings. In our patient this was associated with a combination neoadjuvant gemcitabine and paclitaxel therapy, a relationship that, to our knowledge, has yet to be reported in the literature.", "affiliations": "Department of Dermatology, Lewis Katz School of Medicine, Philadelphia, PA.", "authors": "Jennings|Erin|E|;Huang|Simo|S|;Lee|Jason B|JB|;Cha|Jisun|J|;Hsu|Sylvia|S|", "chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1087-2108", "issue": "26(9)", "journal": "Dermatology online journal", "keywords": null, "medline_ta": "Dermatol Online J", "mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D064146:Chemotherapy-Induced Febrile Neutropenia; D003841:Deoxycytidine; D004890:Erythema; D005260:Female; D006801:Humans; D007402:Intertrigo; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel; D010190:Pancreatic Neoplasms", "nlm_unique_id": "9610776", "other_id": null, "pages": null, "pmc": null, "pmid": "33054938", "pubdate": "2020-09-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel.", "title_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel" }

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TOXIC ERYTHEMA OF CHEMOTHERAPY SECONDARY TO GEMCITABINE AND PACLITAXEL. DERMATOLOGY ONLINE JOURNAL. 2020 SEP?26(9):6:1-3.", "literaturereference_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201130", "receivedate": "20201130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18558698, "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" }, { "companynumb": "US-FRESENIUS KABI-FK202012037", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090242", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "077574", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JENNINGS E, HUANG S, LEE J, CHA J, HSU S. TOXIC ERYTHEMA OF CHEMOTHERAPY SECONDARY TO GEMCITABINE AND PACLITAXEL. DERMATOLOGY ONLINE JOURNAL. 2020 SEP?26 (9):.", "literaturereference_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201112", "receivedate": "20201112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18498731, "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" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0129285", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091365", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Intertrigo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JENNINGS E, HUANG S, LEE J, CHA J, HSU S. TOXIC ERYTHEMA OF CHEMOTHERAPY SECONDARY TO GEMCITABINE AND PACLITAXEL. DERMATOL ONLINE J. 2020?26(9):1?3. DOI:ORG/UC/ITEM/86M5F6HH", "literaturereference_normalized": "toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210715", "receivedate": "20201119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18522371, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Objective Invasive pulmonary aspergillosis (IPA) is a severe and often lethal infection. The possible risk factors, clinical presentation, and treatment of patients with simultaneous liver failure and IPA have received little attention in previous studies. The aim of this study was to investigate the epidemiology of IPA in patients with liver failure in an effort to reduce patient mortality. Methods The patients with liver failure (including acute liver failure , sub-acute liver failure , acute-on-chronic liver failure and chronic liver failure) were recruited from 2011 to 2016. The clinical data of these patients were retrieved for the study. Results In total, 1077 patients with liver failure were included in this study. Of the 1077 patients, 53 (4.9%) had IPA. Forty-four (83%) patients with IPA died. Independent risk factors for IPA were male sex (hazard ratio [HR] = 2.542), hepatorenal syndrome (HR = 2.463), antibiotic use (HR = 4.631), and steroid exposure (HR = 18.615). Conclusions IPA is a fatal complication in patients with liver failure. Male sex, hepatorenal syndrome, antibiotic use, and steroid exposure were independent risk factors for IPA. When patients with liver failure have these risk factors and symptoms of pneumonia such as cough or hemoptysis, clinicians should be cautious about the possibility of IPA.", "affiliations": "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.", "authors": "Zhang|Xuan|X|;Yang|Meifang|M|;Hu|Jianhua|J|;Zhao|Hong|H|;Li|Lanjuan|L|", "chemical_list": "D000900:Anti-Bacterial Agents; D013256:Steroids", "country": "England", "delete": false, "doi": "10.1177/0300060517729907", "fulltext": "\n==== Front\nJ Int Med ResJ. Int. Med. ResIMRspimrThe Journal of International Medical Research0300-06051473-2300SAGE Publications Sage UK: London, England 2923926610.1177/030006051772990710.1177_0300060517729907Clinical ReportsEpidemiology of invasive pulmonary aspergillosis in patients with liver failure: Clinical presentation, risk factors, and outcomes Zhang Xuan Yang Meifang Hu Jianhua Zhao Hong Li Lanjuan State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaLanjuan Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. Email: [email protected] 9 2017 2 2018 46 2 819 827 7 6 2017 15 8 2017 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Objective\nInvasive pulmonary aspergillosis (IPA) is a severe and often lethal infection. The possible risk factors, clinical presentation, and treatment of patients with simultaneous liver failure and IPA have received little attention in previous studies. The aim of this study was to investigate the epidemiology of IPA in patients with liver failure in an effort to reduce patient mortality.\n\nMethods\nThe patients with liver failure (including acute liver failure , sub-acute liver failure , acute-on-chronic liver failure and chronic liver failure) were recruited from 2011 to 2016. The clinical data of these patients were retrieved for the study.\n\nResults\nIn total, 1077 patients with liver failure were included in this study. Of the 1077 patients, 53 (4.9%) had IPA. Forty-four (83%) patients with IPA died. Independent risk factors for IPA were male sex (hazard ratio [HR] = 2.542), hepatorenal syndrome (HR = 2.463), antibiotic use (HR = 4.631), and steroid exposure (HR = 18.615).\n\nConclusions\nIPA is a fatal complication in patients with liver failure. Male sex, hepatorenal syndrome, antibiotic use, and steroid exposure were independent risk factors for IPA. When patients with liver failure have these risk factors and symptoms of pneumonia such as cough or hemoptysis, clinicians should be cautious about the possibility of IPA.\n\nLiver failureinvasive pulmonary aspergillosisepidemiologyrisk factorsclinical presentationoutcomes\n==== Body\nIPA, invasive pulmonary aspergillosis; ACLF, acute-on-chronic liver failure; ALF, acute liver failure; SALF, subacute liver failure; CLF, chronic liver failure; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; INR, international normalized ratio; PTA, prothrombin activity; HIV, human immunodeficiency virus; HR, hazard ratio\n\nIntroduction\nInvasive pulmonary aspergillosis (IPA) is a severe and often lethal infection1 that mainly affects immunocompromised patients, such as those with hematologic malignancies and stem cell or solid organ transplants. Aspergillus spp. can cause invasive infection in patients with liver failure.2–5 Although patients with liver failure have a low incidence of invasive aspergillosis, recent data have indicated that this condition should be reconsidered as a devastating infectious disease in this population.3–5 Wu et al.5 showed that most patients with acute-on-chronic liver failure (ACLF) died within 7 days after the onset of IPA (25/29 patients).\n\nAchieving a clinical diagnosis of IPA is a huge challenge. Invasive diagnostic procedures such as fiberbronchoscopy are necessary to confirm a diagnosis of aspergillus infection, but such procedures are often not feasible in patients with severe respiratory insufficiency and critical illness who are not undergoing mechanical ventilation.6–9 Moreover, the European Organization for Research and Treatment of Cancer (EORTC) restricted the scope of the standard diagnostic definitions to receipt of a solid organ transplant, hereditary immunodeficiencies, connective tissue disorders, and receipt of immunosuppressive agents10; however, these criteria cannot necessarily be extrapolated to patients with liver failure.\n\nFew studies have been performed to evaluate patients with liver failure who develop IPA, and possible risk factors such as the ABO blood group and use of an artificial liver support system have received little attention. Little is known about the clinical presentation and treatment of IPA in patients with liver failure. Therefore, the aim of this study was to collect data about patients with liver failure to investigate the epidemiology and possible risk factors for IPA in an effort to reduce the mortality in this population.\n\nMethods\nStudy design\nThis retrospective study was conducted in the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, China. The study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University, and the need for consent was waived because the study was retrospective and the data were analyzed anonymously.\n\nStudy population\nPatients with liver failure [including acute liver failure (ALF), subacute liver failure (SALF), ACLF, and chronic liver failure (CLF)] were admitted into the infectious disease wards of the First Affiliated Hospital, College of Medicine, Zhejiang University, China from 2011 to 2016. The clinical data of these patients were retrieved for the study. The follow-up period for the patients with IPA was 3 months after discharge.\n\nDiagnostic criteria\nLiver failure was defined according to the following criteria specified by the 13th Asia-Pacific Congress of Clinical Microbiology and Infection Consensus Guidelines for the diagnosis and treatment of liver failure:11\n\nALF: Abrupt onset accompanied by grade II or higher hepatic encephalopathy (HE) (according to the I- to IV-grade classification) and appearance of the following symptoms within 2 weeks: a) fatigue with severe gastrointestinal tract symptoms such as anorexia, abdominal distension, nausea, and vomiting; b) progressive aggravation of jaundice; c) hemorrhagic tendency with an international normalized ratio (INR) of ≥1.5 or prothrombin activity (PTA) of ≤40% and exclusion of other causes; and d) progressive reduction in liver size.\n\nSALF: Slower onset than ALF and appearance of the following symptoms within 2 to 26 weeks: a) fatigue with gastrointestinal tract symptoms, b) rapidly deepening jaundice with a total bilirubin (TBil) level 10 times higher than the upper limit of normality or a daily increase of ≥17.1 µmol/L, c) occurrence of HE, and d) hemorrhagic tendency with an INR of ≥1.5 or PTA of ≤40% and exclusion of other causes.\n\nACLF: Acute or subacute deterioration of liver function in patients with chronic liver disease, usually accompanied by the following symptoms: a) fatigue with gastrointestinal tract symptoms, b) rapidly deepening jaundice with a TBil level 10 times higher than the upper limit of normality or a daily increase of ≥17.1 µmol/L, c) hemorrhagic tendency with an INR of ≥1.5 or PTA of ≤40% and exclusion of other causes, d) progressive reduction in liver size, and e) occurrence of HE.\n\nCLF: Progressive deterioration and decompensation of liver function in patients with liver cirrhosis, usually accompanied by the following symptoms: a) a significant increase in TBil, b) a significant decrease in albumin, c) a hemorrhagic tendency with an INR of ≥1.5 or PTA of ≤40% and exclusion of other causes, d) ascites or other symptoms of portal hypertension, and e) occurrence of HE.\n\nWe used the EORTC consensus definition of invasive Aspergillus infection,10 which was diagnosed if the following two criteria were fulfilled: one microbiologic criterion (positive sputum culture) and one clinical criterion. In the present study, a diagnosis of IPA was made based on the following: a) positive culture of Aspergillus spp. from sputum and b) the presence of one of the following three signs on computed tomography: dense, well-circumscribed lesions(s) with or without a halo sign, air-crescent sign, or cavity.\n\nRisk factors for IPA\nIn this study, the following variables were assessed as risk factors for the occurrence of IPA: sex, age, ABO blood group, type 2 diabetes mellitus, chronic bronchitis, malignancy, human immunodeficiency virus (HIV) infection, antibiotic use, steroid exposure, use of an artificial liver support system, neutropenia, gastrointestinal bleeding, HE, and hepatorenal syndrome (HRS). The definitions of some of these factors are summarized in Table 1.\nTable 1. Risk factors for invasive pulmonary aspergillosis in patients with liver failure.\n\nRisk factors\tRemarks (where applicable)\t\nChronic bronchitis\tDefined as the presence of a productive cough or expectoration for >90 days per year (but on separate days) and for >2 consecutive years, provided that a specific disorder responsible for these symptoms is not present.\t\nMalignancy\tSolid tumor and hematologic malignancy\t\nHIV infection\tDefined as HIV-positive status\t\nAntibiotic use\tAntimicrobial agent use for >5 days\t\nSteroid exposure\tSteroid treatment for >7 days\t\nNeutropenia\tTotal neutrophil count of ≤500/mm3\t\nHIV, human immunodeficiency virus.\n\n\n\nStatistical analysis\nThe statistical analysis was performed using SPSS version 18.0 (SPSS, Chicago, IL, USA). Student’s t-test was performed for descriptive analysis and comparison of continuous variables. Fisher’s exact probability test and the chi-square test were conducted to calculate and compare the percentages for categorical variables. Logistic regression analysis was used to examine the effects of independent variables on IPA. P value of <0.05 was considered statistically significant for all analyses.\n\nResults\nCharacteristics of the study cohort\nIn total, 1077 patients with liver failure were included in this study. Of these 1077 patients, 826 (76.7%) were male and the mean age was 49.22 ± 13.45 years. The characteristics of the patients are shown in Table 2 and Table 3. The most common reason for hospital admission was SCLF (543/50.4%), and the main cause of liver failure was hepatitis B (799/74.2%). A total of 511 (47.4%) patients received artificial liver support therapy, 710 (65.9%) received antibacterial treatment for >5 days, and 84 (7.8%) were exposed to corticosteroids for >7 days. The antibacterial treatments were administered for both prophylaxis and treatment (pneumonia, spontaneous bacterial peritonitis, and septicemia). Steroids were used to decrease persistent hyperbilirubinemia and treat autoimmune diseases. Eight (0.7%) patients developed neutropenia.\nTable 2. Characteristics of 1077 patients with liver failure.\n\nCharacteristic\tNumber of patients (%)\t\nDisease onset\t\t\n ALF\t71 (6.6)\t\n SALF\t51 (4.7)\t\n SCLF\t543 (50.4)\t\n CLF\t412 (38.3)\t\nEtiology of liver failure\t\t\n Hepatitis B\t799 (74.2)\t\n Hepatitis E\t5 (0.5)\t\n Alcohol\t32 (3.0)\t\n Drug\t59 (5.5)\t\n Autoimmunity\t23 (2.1)\t\n Hepatolenticular degeneration\t3 (0.3)\t\n Schistosome\t5 (0.5)\t\n Malignancy\t7 (0.6)\t\n Two or more factors\t69 (6.4)\t\n Unknown\t72 (6.7)\t\nACLF, acute-on-chronic liver failure; ALF, acute liver failure; SALF, subacute liver failure; CLF, chronic liver failure.\n\n\nTable 3. Demographic features of 1077 patients with liver failure and differences between those with and without IPA.\n\n\tAll patients with liver failure\tPatients with IPA\tPatients without IPA\tp value\t\nPatients\t1077\t53\t1024\t–\t\nMale\t826 (76.7)\t46 (86.8)\t780 (76.2)\t0.075\t\nAge (years)\t49.18 ± 13.48\t48.64 ± 12.07\t49.25 ± 13.52\t0.748\t\nABO blood group\t\t\t\t\t\n A\t343 (31.8)\t13 (24.5)\t331 (32.3)\t0.235\t\n B\t271 (25.2)\t9 (17.0)\t262 (25.6)\t0.159\t\n AB\t86 (8.0)\t6 (11.3)\t80 (7.8)\t0.358\t\n O\t377 (35.0)\t25 (47.2)\t351 (34.3)\t0.055\t\nMorbidities\t\t\t\t\t\n Type 2 diabetes mellitus\t102 (9.5)\t3 (5.7)\t99 (9.7)\t0.465\t\n Chronic bronchitis\t50 (4.6)\t2 (3.8)\t49 (4.8)\t0.995\t\n Malignancy\t88 (8.2)\t3 (5.7)\t85 (8.3)\t0.669\t\n HIV infection\t12 (1.1)\t0 (0.0)\t12 (1.2)\t0.903\t\nComplications\t\t\t\t\t\n Gastrointestinal bleeding\t116 (10.8)\t7 (13.2)\t109 (10.6)\t0.557\t\n HE\t484 (44.9)\t26 (49.1)\t458 (44.7)\t0.537\t\n HRS\t141 (13.1)\t14 (26.4)\t127 (12.4)\t0.003\t\nAntibiotic use\t710 (65.9)\t46 (88.5)\t663 (64.7)\t0.001\t\nSteroid exposure\t84 (7.8)\t26 (49.1)\t58 (5.7)\t<0.001\t\nArtificial liver support system\t511 (47.4)\t30 (56.6)\t481 (47.0)\t0.171\t\nNeutropenia\t8 (0.7)\t1 (1.9)\t7 (0.7)\t0.862\t\nData are presented as mean ± standard deviation or n (%). IPA, invasive pulmonary aspergillosis; HIV, human immunodeficiency virus; HE, hepatic encephalopathy; HRS, hepatorenal syndrome\n\n\n\nAmong all 1077 patients, 53 (4.9%) were diagnosed with IPA. The characteristics of the patients with IPA are shown in Table 3. Twenty-five (47.2%) of these patients had blood group O, 30 (56.6%) had received artificial liver support therapy, and 46 (86.8%) and 26 (49.1%) received antibacterial drugs and corticosteroids, respectively.\n\nRisk factors\nLogistic regression analysis showed that male sex [hazard ratio (HR) = 2.542, p = 0.035], HRS (HR = 2.463, p = 0.014), antibiotic use (HR = 4.631, p = 0.001), and steroid exposure (HR = 18.615, p < 0.001) were independent risk factors associated with the occurrence of IPA (Table 4).\nTable 4. Logistic regression analysis of risk factors associated with invasive pulmonary aspergillosis development in patients with liver failure.\n\nRisk factors\tHR\t95% CI for HR\tp value\t\nLower\tUpper\t\nHepatorenal syndrome\t2.463\t1.199\t5.061\t0.014\t\nMale sex\t2.542\t1.065\t6.063\t0.035\t\nAntibiotic use\t4.631\t1.866\t11.496\t0.001\t\nSteroid exposure\t18.615\t9.819\t35.048\t<0.001\t\nHR, hazard ratio; CI, confidence interval.\n\n\n\nClinical characteristics of patients with IPA\nThe symptoms and laboratory data of the 53 patients with IPA are shown in Table 5. Among all patients with IPA 44 (83%) died. After IPA diagnosis, three patients were admitted to the intensive care unit where mechanical ventilation and continuous renal replacement therapy were applied. Moreover, nine (17%) patients did not receive antifungal treatment. Twenty-four (45.3%) patients received voriconazole as antifungal treatment, 16 (30.2%) received caspofungin, and 4 (7.5%) received micafungin. There were no differences in the survival rate among patients treated with different antifungal agents (Table 6).\nTable 5. Characteristics of 53 patients with liver failure who developed invasive pulmonary aspergillosis (IPA).\n\nCharacteristics\tNumber of patients (%)\t\nSymptoms\t\t\n Fever\t53 (100.0)\t\n Cough\t50 (94.3)\t\n Hemoptysis\t23 (43.4)\t\n Dyspnea\t20 (37.7)\t\n Chest pain\t2 (3.8)\t\nLaboratory data\t\t\n Leukocyte count (×109/L)\t11.31 ± 5.71\t\n Neutrophil count (×109/L)\t9.29 ± 5.26\t\n Total bilirubin (µmol/L)\t489.12 ± 135.15\t\n INR\t3.08 ± 1.37\t\nImaging findings (X-ray or CT)\t\t\n Changes in bilateral lung fields\t43 (81.1)\t\n Right unilateral lung\t8 (15.1)\t\n Left unilateral lung\t2 (3.8)\t\n Cavity\t13 (24.5)\t\n Air-crescent sign\t10 (18.9)\t\n Pleural effusion\t19 (35.8)\t\nAntibiotic use (before IPA diagnosis)\t46 (86.8)\t\n One antibiotic\t44 (95.7)\t\n Two antibiotics\t2 (4.3)\t\n Carbapenems\t13 (28.3)\t\n Penicillins\t18 (39.1)\t\n Third-generation cephalosporins\t11 (23.9)\t\n Fourth-generation cephalosporins\t2 (4.3)\t\n Glycopeptides\t2 (4.3)\t\n Quinolones\t2 (4.3)\t\nIPA, invasive pulmonary aspergillosis; INR, international normalized ratio; CT, computed tomography\n\n\nTable 6. Effect of antifungal agents in the treatment of invasive pulmonary aspergillosis.\n\n\tDeath\tRecovery\tp value\t\nPatients\t44 (83%)\t9 (17%)\t–\t\nAntifungal agent\t\t\t\t\n Voriconazole\t19\t5\t0.755\t\n Caspofungin\t13\t3\t0.822\t\n Micafungin\t3\t1\t0.536\t\n Untreated\t9\t0\t0.329\t\n\n\nDiscussion\nInvasive aspergillosis has been traditionally regarded as an infection mainly occurring in immunocompromised or immunodeficient patients, such as those with neutropenia, hematologic malignancies, organ transplantation, or HIV.12 Although invasive aspergillosis has been reported in patients with liver cirrhosis and liver transplantation,13,14,15 IPA has rarely been observed in patients with liver failure.\n\nA previous study16 confirmed invasive aspergillosis as a frequent undiagnosed complication of patients with ALF or end-stage liver disease, with a mortality rate exceeding 70%. In the present study, the mortality rate among patients with liver failure who developed IPA was 83%. The reason for the high mortality was not only the difficulty in diagnosis and treatment of IPA but also a lack of enough recognition of IPA and the heavy economic burden, which led patients to give up treatments.\n\nDiagnosis of IPA in patients with liver failure is challenging. Patients with liver failure often have a high bleeding tendency, which is a contraindication for invasive examinations such as pulmonary puncture biopsy or bronchoscope. Thus, only one patient in our study had tissue evidence of Aspergillus fumigatus infection that was acquired after the recovery of liver failure. Moreover, liver failure is not a host factor of invasive fungal disease in the EORTC consensus; thus, the diagnosis of invasive Aspergillus infection in patients with liver failure is quite difficult according to the EORTC consensus definition. Because of delayed diagnosis and patients’ financial constraints, 17% of patients did not receive antifungal treatment. One study16 showed that a high percentage (52.8%) of patients with acute or advanced liver disease were diagnosed with invasive aspergillosis postmortem. Therefore, further research of the epidemiology, risk factors, and clinical manifestations of IPA in patients with liver failure may improve the diagnosis rate.\n\nIn the present study, the incidence of IPA in patients with liver failure was 4.9%. Bone marrow transplantation, prolonged neutropenia, and solid organ transplantation have been identified as high-risk factors for invasive aspergillosis.17–21 Invasive aspergillosis occurs in 1% to 9% of liver transplant recipients14; this is similar to the morbidity rate of the patients with liver failure in the present study. As a result of a depression of both humoral and cell-mediated immunity, liver disease alone predisposes to bacterial and fungal infections.22 Patients with liver failure patients are immunosuppressed and should be considered an at-risk population for IPA.\n\nAn expert consensus23 recommended that the main risk factors for IPA should include neutropenia, malignancy, and prolonged steroid treatment. In the present study, HRS (p = 0.014), steroid exposure (p < 0.001), and antibiotic use (p = 0.001) were independent risk factors associated with the occurrence of IPA in patients with liver failure. These findings are consistent with those of previous research.3,4,22\n\nIn this study, 26 (49.1%) patients had steroid exposure before IPA diagnosis. Surprisingly, patients with liver failure who took corticosteroids for >7 days had an 18-fold (HR = 18.615) higher risk of developing IPA than those who did not use corticosteroids or used them for <7 days. Corticosteroids predispose patients to opportunistic infections through functional impairment of macrophages and neutrophil function.24 Thus, corticosteroids should be used with caution in patients with liver failure.\n\nHRS may be precipitated by infection.25 Additionally, renal failure has been associated with defective cell-mediated immunity and impaired granulocyte–macrophage function, which are the predominant host defenses against fungal pathogens.26\n\nMoreover, male sex (p = 0.035) was also a risk factor for IPA; this has not been found in previous studies. A possible reason for this result is that immune system damage in male patients with liver failure is more severe than in female patients. However, this needs further research.\n\nIn patients with liver failure, both the clinical diagnosis and treatment of IPA are challenging. The guidelines of the Infectious Diseases Society of America27 recommended voriconazole as the primary therapy for IPA. However, this drug is metabolized in the liver and potentially hepatotoxic.27 Thus, it should be used with caution in patients with liver failure patients. In the present study, 24 (45.3%) patients received voriconazole as an antifungal agent, and the dose of voriconazole was not adjusted. No skin rashes or transient visual disturbances were observed. Moreover, it is difficult to estimate whether liver injury has been induced by voriconazole in patients with liver failure. Because such patients’ liver function is severely damaged, infection could lead to impaired liver function and ultimately higher mortality.28 However, liver function did not worsen after using voriconazole in our recovered patients.\n\nOur study has some limitations. First, the small numbers of patients with some host factors of invasive fungal disease development in the EORTC consensus, such as HIV or neutropenia, may have led to statistical error. Second, liver failure is not a host factor of invasive fungal disease development in the EORTC consensus; therefore, the patients in our study did not fulfill the definition of proven IPA according to the EORTC consensus. Moreover, invasive diagnostic procedures were not feasible in our patients with liver failure, which may have resulted in missing patients with suspected disease based on radiologic imaging. Third, we did not collect data on the daily corticosteroid dose and could not fully explore the impact of dose or duration on mortality. Finally, male sex as a risk factor for IPA was not thoroughly researched.\n\nIn conclusion, IPA is a potentially fatal complication in patients with liver failure, and delayed diagnosis and treatment may contribute to high mortality. Steroid exposure, antibiotic use, male sex, and HRS were independent risk factors associated with the occurrence of IPA. When patients with liver failure have these risk factors and symptoms of pneumonia such as cough or hemoptysis, clinicians should be aware of the possibility of IPA. Early and appropriate antifungal treatment may improve the survival rate in patients with liver failure.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThis study was supported by the Medical and Health Science and Technology Project of Zhejiang province (2015KYA102).\n==== Refs\nReferences\n1 Prodanovic H Cracco C Massard J et al. \nInvasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series . BMC Gastroenterol \n2007 ; 7 : 2 –2 .17266747 \n2 Li D Chen L Ding X et al. \nHospital-acquired invasive pulmonary aspergillosis in patients with hepatic failure . 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Curr Opin Infect Dis \n2014 ; 27 : 174 –183 .24514164 \n8 Koulenti D Vogelaers D Blot S \nWhat’s new in invasive pulmonary aspergillosis in the critically ill? \nIntensive Care Med \n2014 ; 40 : 723 –726 .24647810 \n9 Taccone FS Van AM Bulpa P et al. \nEpidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes . Crit Care \n2015 ; 19 : 7 –7 .25928694 \n10 Pauw BD Walsh TJ Donnelly JP et al. \nRevised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group . Clin Infect Dis \n2008 ; 46 : 1813 –1821 .18462102 \n11 Organization Committee of 13th Asia-Pacific Congress of Clinical Microbiology and Infection . 13th Asia-Pacific congress of clinical microbiology and infection consensus guidelines for diagnosis and treatment of liver failure . Hepatobiliary Pancreat Dis Int \n2013 ; 12 : 346 –354 .23924491 \n12 Segal BH Walsh TJ \nCurrent approaches to diagnosis and treatment of invasive aspergillosis . Am J Respir Crit Care Med \n2006 ; 173 : 707 –717 .16387806 \n13 Barchiesi F Mazzocato S Mazzanti S et al. \nInvasive aspergillosis in liver transplant recipients: epidemiology, clinical characteristics, treatment, and outcomes in 116 cases . Liver Transpl \n2015 ; 21 : 204 –212 .25348192 \n14 Jeurissen S Vogelaers D Sermijn E et al. \nInvasive aspergillosis in patients with cirrhosis, a case report and review of the last 10 years . 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Crit Care \n2005 ; 9 : R191 –R199 .15987390 \n24 Ader F Nseir SBR Leroy S et al. \nInvasive pulmonary aspergillosis in chronic obstructive pulmonary disease:an emerging fungal pathogen . Clin Microbiol Infect \n2005 ; 11 : 427 –429 .15882191 \n25 Mccormick PA \nImproving prognosis in hepatorenal syndrome . Gut \n2000 ; 47 : 166 –167 .10896904 \n26 Consensus Development Conference Panel.Morbidity and mortality of renal dialysis: an NIH consensus conference statement. Ann Intern Med 1994; 121: 62–70 .\n27 Walsh TJ Anaissie EJ Denning DW Herbrecht R et al. \nTreatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America . Clin Infect Dis \n2008 ; 46 : 327 –360 .18177225 \n28 Lin KH Wang FL Wu MS et al. \nSerum procalcitonin and C-reactive protein levels as markers of bacterial infection in patients with liver cirrhosis: a systematic review and meta-analysis . Diagn Microbiol Infect Dis \n2014 ; 80 : 72 –78 .24974271\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0300-0605", "issue": "46(2)", "journal": "The Journal of international medical research", "keywords": "Liver failure; clinical presentation; epidemiology; invasive pulmonary aspergillosis; outcomes; risk factors", "medline_ta": "J Int Med Res", "mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D002908:Chronic Disease; D003371:Cough; D005260:Female; D006469:Hemoptysis; D006530:Hepatorenal Syndrome; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D017093:Liver Failure; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D012737:Sex Factors; D013256:Steroids; D016019:Survival Analysis", "nlm_unique_id": "0346411", "other_id": null, "pages": "819-827", "pmc": null, "pmid": "29239266", "pubdate": "2018-02", "publication_types": "D016428:Journal Article", "references": "24151434;18462102;8198352;18177225;25828927;24647810;15872225;16387806;23817660;20450350;18667083;18195630;17266747;23924491;23206479;25348192;24514164;25928694;11303267;21108575;15882191;24579244;17413611;24726663;10896904;21866367;15987390;24974271", "title": "Epidemiology of invasive pulmonary aspergillosis in patients with liver failure: Clinical presentation, risk factors, and outcomes.", "title_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes" }

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EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. 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JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649927, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108772", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649898, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108123", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649928, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108766", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649926, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108777", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649899, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108774", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649892, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108782", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649802, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108769", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649902, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108779", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649800, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108776", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649900, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108767", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649925, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108768", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649895, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108773", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649901, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108778", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649803, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108770", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649893, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "CN-PFIZER INC-2018108775", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VORICONAZOLE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG, X.. EPIDEMIOLOGY OF INVASIVE PULMONARY ASPERGILLOSIS IN PATIENTS WITH LIVER FAILURE: CLINICAL PRESENTATION, RISK FACTORS, AND OUTCOMES.. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH. 2018?46 (2):819-827", "literaturereference_normalized": "epidemiology of invasive pulmonary aspergillosis in patients with liver failure clinical presentation risk factors and outcomes", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14649903, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" } ]

{ "abstract": "Purpose: A 28-year-old male reported to our hospital with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap syndrome that developed as an adverse drug reaction (ADR) to allopurinol. HLA-B*58:01 allele is associated with an increased risk of developing allopurinol-induced SJS/TEN. Methods: Genomic DNA was extracted from peripheral blood leukocytes. DNA sequencing was done using SANGER sequencing method. Results: Pharmacogenetic testing results revealed positive for HLA-B*58:01 allele. Symptoms of the patient receded after allopurinol withdrawal. Conclusion: The thrust of personalized therapy is from decoding the individual specific genetic variations astutely for better therapeutic outcomes such as reducing the ADRs. Pharmacogenetic testing is emerging as a safe, fast, and economic screening tool for personalized therapy by preventing ADRs. Pharmacogenetic HLA-B*58:01 allele testing before allopurinol administration could significantly reduce the incidence of SJS/TEN and associated mortalities/morbidities and thereby represent a potential cost-effective intervention.", "affiliations": "Manipal Academy of Higher Education, Manipal, Karnataka, India.;Manipal Academy of Higher Education, Manipal, Karnataka, India.;Manipal Academy of Higher Education, Manipal, Karnataka, India.;Manipal Academy of Higher Education, Manipal, Karnataka, India.;Manipal Academy of Higher Education, Manipal, Karnataka, India.;Manipal Academy of Higher Education, Manipal, Karnataka, India.", "authors": "Lavu|Alekhya|A|;Thiriveedi|Sneha|S|;Thomas|Levin|L|;Khera|Kanav|K|;Saravu|Kavitha|K|;Rao|Mahadev|M|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/0018578720934972", "fulltext": null, "fulltext_license": null, "issn_linking": "0018-5787", "issue": "56(6)", "journal": "Hospital pharmacy", "keywords": "Adverse drug reactions; Skin; analgesics; gene therapy; medication safety", "medline_ta": "Hosp Pharm", "mesh_terms": null, "nlm_unique_id": "0043175", "other_id": null, "pages": "660-663", "pmc": null, "pmid": "34732918", "pubdate": "2021-12", "publication_types": "D016428:Journal Article", "references": "26094938;30134124;25647431;21358399;21593754;21906289;21162721;2404462;23981744;15743917;28549177;28329382;17919772;7794310;8420497;28202399;23232549;24988075;28857441", "title": "Clinical Utility of HLA-B*58:01 Genotyping to Prevent Allopurinol-Induced SJS/TEN.", "title_normalized": "clinical utility of hla b 58 01 genotyping to prevent allopurinol induced sjs ten" }

[ { "companynumb": "IN-ACCORD-191033", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "203154", "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": "ALLOPURINOL." } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "SJS-TEN overlap", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "LAVU A, THIRIVEEDI S, THOMAS L, KHERA K, SARAVU K, RAO M. CLINICAL UTILITY OF HLA?B*58:01 GENOTYPING TO PREVENT ALLOPURINOL?INDUCED SJS/TEN. HOSPITAL PHARMACY. 2020. DOI:10.1177/0018578720934972.", "literaturereference_normalized": "clinical utility of hla b 58 01 genotyping to prevent allopurinol induced sjs ten", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20200719", "receivedate": "20200719", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18041206, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "IN-Indoco-000251", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "204467", "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": "ALLOPURINOL" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "SJS-TEN overlap", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "Lavu A, Thiriveedi S, Thomas L, Khera K, Saravu K, Rao M. Clinical Utility of HLA-B*58:01 Genotyping to Prevent Allopurinol-Induced SJS/TEN. Hosp Pharm. 2021 Dec;56(6):660-663.", "literaturereference_normalized": "clinical utility of hla b 58 01 genotyping to prevent allopurinol induced sjs ten", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20211118", "receivedate": "20211118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20084675, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "A pharmacist-managed deep vein thrombosis (DVT) treatment program was put into operation at Jackson Memorial Hospital in Miami, Florida to provide appropriate transition of care to the outpatient setting for patients diagnosed with DVT. A postgraduate year 1 pharmacy practice resident partnered with a clinical pharmacist to establish and implement the DVT pilot program in the emergency department (ED). Once contacted, the pharmacy resident or the clinical pharmacist communicated with the ED physician and made recommendations regarding appropriate anticoagulation. The pharmacist met with the patient to obtain informed consent and provide counseling regarding the anticoagulants. A timely outpatient appointment at the pharmacy-managed warfarin clinic was arranged for the patient and contact information was exchanged between the patient and the pharmacist. On average, patients enrolled in the DVT program from the ED were released 18.29 hours (±7.06) following the time of arrival. Following release from the hospital, 91% of patients attended their outpatient follow-up appointment at the warfarin clinic. Since the initiation of the DVT program, 1 patient experienced a recurrent DVT and major bleed during their treatment course. Due to successful implementation of this pharmacist-managed DVT program in the ED, the services were subsequently extended to inpatients with DVT.", "affiliations": "Pharmacy Department, Jackson Memorial Hospital, Miami, FL, USA. [email protected]", "authors": "Davis|Kyle A|KA|;Miyares|Marta A|MA|;Price-Goodnow|Venessa S|VS|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/0897190012465953", "fulltext": null, "fulltext_license": null, "issn_linking": "0897-1900", "issue": "26(4)", "journal": "Journal of pharmacy practice", "keywords": "anticoagulation; deep vein thrombosis; transition of care; venous thromboembolism", "medline_ta": "J Pharm Pract", "mesh_terms": "D006801:Humans; D010595:Pharmacists; D010607:Pharmacy Service, Hospital; D020246:Venous Thrombosis", "nlm_unique_id": "8900945", "other_id": null, "pages": "438-41", "pmc": null, "pmid": "23172896", "pubdate": "2013-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Optimizing transition of care through the facilitation of a pharmacist-managed deep vein thrombosis treatment program.", "title_normalized": "optimizing transition of care through the facilitation of a pharmacist managed deep vein thrombosis treatment program" }

[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-006494", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "009218", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEEP VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DAVIS KA, MIYARES MA, PRICE-GOODNOW VS. OPTIMIZING TRANSITION OF CARE THROUGH THE FACILITATION OF A PHARMACIST-MANAGED DEEP VEIN THROMBOSIS TREATMENT PROGRAM. V.S. JOURNAL OF PHARMACY PRACTICE. 2013?26(4):438-41", "literaturereference_normalized": "optimizing transition of care through the facilitation of a pharmacist managed deep vein thrombosis treatment program", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200131", "receivedate": "20200131", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17353415, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "OBJECTIVE\nSarcoidosis is a chronic granulomatous disease for which there are limited therapeutic options. This is the first randomized, placebo-controlled study to demonstrate that antimycobacterial therapy reduces lesion diameter and disease severity among patients with chronic cutaneous sarcoidosis.\n\n\nOBJECTIVE\nTo evaluate the safety and efficacy of once-daily antimycobacterial therapy on the resolution of chronic cutaneous sarcoidosis lesions.\n\n\nMETHODS\nA randomized, placebo-controlled, single-masked trial on 30 patients with symptomatic chronic cutaneous sarcoidosis lesions deemed to require therapeutic intervention.\n\n\nMETHODS\nA tertiary referral dermatology center in Nashville, Tennessee.\n\n\nMETHODS\nParticipants were randomized to receive either the oral concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) regimen or a comparative placebo regimen for 8 weeks with a 180-day follow-up.\n\n\nMETHODS\nParticipants were monitored for absolute change in lesion diameter and decrease in granuloma burden, if present, on completion of therapy.\n\n\nMETHODS\nIn the intention-to-treat analysis, the CLEAR-treated group had a mean (SD) decrease in lesion diameter of -8.4 (14.0) mm compared with an increase of 0.07 (3.2) mm in the placebo-treated group (P = .05). The CLEAR group had a significant reduction in granuloma burden and experienced a mean (SD) decline of -2.9 (2.5) mm in lesion severity compared with a decline of -0.6 (2.1) mm in the placebo group (P = .02).\n\n\nCONCLUSIONS\nAntimycobacterial therapy may result in significant reductions in chronic cutaneous sarcoidosis lesion diameter compared with placebo. These observed reductions, associated with a clinically significant improvement in symptoms, were present at the 180-day follow-up period. Transcriptome analysis of sarcoidosis CD4+ T cells revealed reversal of pathways associated with disease severity and enhanced T-cell function following T-cell receptor stimulation.\n\n\nBACKGROUND\nclinicaltrials.gov Identifier: NCT01074554.", "affiliations": "Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee2Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.", "authors": "Drake|Wonder P|WP|;Oswald-Richter|Kyra|K|;Richmond|Bradley W|BW|;Isom|Joan|J|;Burke|Victoria E|VE|;Algood|Holly|H|;Braun|Nicole|N|;Taylor|Thyneice|T|;Pandit|Kusum V|KV|;Aboud|Caroline|C|;Yu|Chang|C|;Kaminski|Naftali|N|;Boyd|Alan S|AS|;King|Lloyd E|LE|", "chemical_list": "D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D017963:Azithromycin; D004977:Ethambutol; D015242:Ofloxacin; D012293:Rifampin", "country": "United States", "delete": false, "doi": "10.1001/jamadermatol.2013.4646", "fulltext": null, "fulltext_license": null, "issn_linking": "2168-6068", "issue": "149(9)", "journal": "JAMA dermatology", "keywords": null, "medline_ta": "JAMA Dermatol", "mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D015496:CD4-Positive T-Lymphocytes; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D004977:Ethambutol; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D015242:Ofloxacin; D012293:Rifampin; D012507:Sarcoidosis; D012720:Severity of Illness Index; D016037:Single-Blind Method; D012871:Skin Diseases; D059467:Transcriptome; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "101589530", "other_id": null, "pages": "1040-9", "pmc": null, "pmid": "23863960", "pubdate": "2013-09", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "18578557;22291603;17190623;22395590;21146388;1656742;12615627;12781508;19218196;10573213;16954298;10472755;18429644;22552860;19622457;23021769;11176663;22596102;19910611;19192299;19131956;18328208;22825614;20397737;17277290;17676945;15332711;18439270;14977983;17357846;19464956;17088357;12453366;20665394;15753209;21553656;17560299", "title": "Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study.", "title_normalized": "oral antimycobacterial therapy in chronic cutaneous sarcoidosis a randomized single masked placebo controlled study" }

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"drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DRAKE WP, OSWALD-RICHTER K, RICHMOND BW, ISOM J, BURKE VE, ALGOOD H, ET AL. ORAL ANTIMYCOBACTERIAL THERAPY IN CHRONIC CUTANEOUS SARCOIDOSIS: A RANDOMIZED, SINGLE-MASKED, PLACEBO-CONTROLLED STUDY. JAMA DERMATOLOGY 01-SEP-2013;149 (9):1040-1049.", "literaturereference_normalized": "oral antimycobacterial therapy in chronic cutaneous sarcoidosis a randomized single masked placebo controlled study", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150525", "receivedate": "20150412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11019571, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]

{ "abstract": "Patients on chronic immunosuppressant therapy after renal transplantation have a high rate of in-hospital mortality and approximately 20% mortality rate per year after conventional valve surgery. While transcatheter aortic valve replacement (TAVR) is an appealing option to consider for such patients, there are not significant outcome data for the procedure in this patient population. We report two cases of aortic root rupture after TAVR in renal transplant patients on chronic immunosuppressant therapy.", "affiliations": "Medical City Hospital, Dallas, Texas; Cardiopulmonary Research Science and Technology Institute, Plano, Texas.", "authors": "Holper|Elizabeth M|EM|;Kim|Rebeca J|RJ|;Brooks|Aaron|A|;Mack|Michael|M|", "chemical_list": "D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": "10.1002/ccd.25513", "fulltext": null, "fulltext_license": null, "issn_linking": "1522-1946", "issue": "85(5)", "journal": "Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions", "keywords": "TAVR; aortic rupture; renal transplant", "medline_ta": "Catheter Cardiovasc Interv", "mesh_terms": "D000368:Aged; D001013:Aorta, Thoracic; D001019:Aortic Rupture; D001024:Aortic Valve Stenosis; D017548:Echocardiography, Transesophageal; D017809:Fatal Outcome; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008875:Middle Aged; D061330:Multidetector Computed Tomography; D065467:Transcatheter Aortic Valve Replacement", "nlm_unique_id": "100884139", "other_id": null, "pages": "909-15", "pmc": null, "pmid": "24740848", "pubdate": "2015-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Aortic root rupture after TAVR in two renal transplant patients on chronic immunosuppressant therapy.", "title_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy" }

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AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. 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AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. 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AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. 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AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. 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AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER-CARDIOVASC-INTERV 2015?85(5):909-915.", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160229", "receivedate": "20160229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12128160, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "US-APOTEX-2016AP006852", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "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." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "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": "CYCLOSPORINE." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M.. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY.. CATHETER-CARDIOVASC-INTERV. 2015?85(5):909-915", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160303", "receivedate": "20160303", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12139565, "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": "US-STRIDES ARCOLAB LIMITED-2016SP001437", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematoma", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER-CARDIOVASC-INTERV. 2015?85(5):909-915", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160304", "receivedate": "20160304", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12144191, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "PHHY2016US022386", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "80336", "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": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "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": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M.. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER-CARDIOVASC-INTERV. 2015?85(5):909-15", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160225", "receivedate": "20160225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12116681, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-112197", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "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": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER CARDIOVASC INTERV. 2015;85(5):909-915", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170906", "receivedate": "20170906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13940161, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-MYLANLABS-2016M1008449", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090596", "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": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLPER EM, KIM RJ, BROOKS A, MACK M. AORTIC ROOT RUPTURE AFTER TAVR IN TWO RENAL TRANSPLANT PATIENTS ON CHRONIC IMMUNOSUPPRESSANT THERAPY. CATHETER-CARDIOVASC-INTERV 2015?85(5):909-915.", "literaturereference_normalized": "aortic root rupture after tavr in two renal transplant patients on chronic immunosuppressant therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160229", "receivedate": "20160229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12128123, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "OBJECTIVE\nTo compare the occurrence of non-infectious uveitis based on the type of tumour necrosis factor (TNF) inhibitor used to manage spondyloarthritis in ankylosing spondylitis (AS) patients.\n\n\nMETHODS\nThe occurrence (new-onset and recurrence) of uveitis was reviewed retrospectively in AS patients receiving different TNF inhibitor therapies (adalimumab [ADA], infliximab [IFX], etanercept [ETN], and golimumab [GOL]) for the management of spondyloarthritis from 2005 to 2018. Kaplan-Meier analysis was performed to calculate the cumulative occurrence rates of uveitis during TNF inhibitor therapy, and a log-rank test was used to analyse differences between the survival curves. Multivariable Cox proportional-hazards models were used to compute hazard ratios (HRs) of different TNF agents for uveitis occurrence after adjusting for concurrent confounding factors.\n\n\nRESULTS\nThe three-year cumulative occurrence rates of uveitis were significantly different according to the type of anti-TNFs used (23.1% in IFX, 18.5% in ETN, and 11.9% in ADA+GOL group) (p=0.020). The risk of new-onset uveitis was similar for different drugs. However, the IFX group showed a 5.4 times higher risk of recurrence than the ADA+GOL group (p=0.022). After adjusting for other confounding factors, IFX use was independently associated with a more frequent occurrence of uveitis in AS patients (HR=2.01; p=0.011).\n\n\nCONCLUSIONS\nA significant number of AS patients who received anti-TNF therapy developed uveitis. Different types of anti-TNF drugs were associated with uveitis recurrence. Particularly, chimeric mouse-human monoclonal antibody (IFX) was found to increase the risk of uveitis occurrence compared to humanised monoclonal antibody (ADA or GOL).", "affiliations": "Department of Ophthalmology, The Institute of Vision Research, Severance Eye Hospital, Yonsei University College of Medicine, Seoul, Korea.;Department of Ophthalmology, The Institute of Vision Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Department of Ophthalmology, The Institute of Vision Research, Severance Eye Hospital, Yonsei University College of Medicine, Seoul, Korea. [email protected].", "authors": "Choi|Eun Young|EY|;Lee|Minwoo|M|;Lee|Christopher Seungkyu|CS|", "chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept", "country": "Italy", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0392-856X", "issue": "38(6)", "journal": "Clinical and experimental rheumatology", "keywords": null, "medline_ta": "Clin Exp Rheumatol", "mesh_terms": "D000068879:Adalimumab; D015331:Cohort Studies; D000068800:Etanercept; D006801:Humans; D000069285:Infliximab; D012189:Retrospective Studies; D013167:Spondylitis, Ankylosing; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014605:Uveitis", "nlm_unique_id": "8308521", "other_id": null, "pages": "1132-1137", "pmc": null, "pmid": "32828140", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": null, "title": "Uveitis occurrence in patients with ankylosing spondylitis according to the type of tumour necrosis factor inhibitor: a cohort study of 175 patients.", "title_normalized": "uveitis occurrence in patients with ankylosing spondylitis according to the type of tumour necrosis factor inhibitor a cohort study of 175 patients" }

[ { "companynumb": "KR-JNJFOC-20200844680", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANKYLOSING SPONDYLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMICADE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Uveitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHOI E, LEE M, LEE C. UVEITIS OCCURRENCE IN PATIENTS WITH ANKYLOSING SPONDYLITIS ACCORDING TO THE TYPE OF TUMOUR NECROSIS FACTOR INHIBITOR:A COHORT STUDY OF 175 PATIENTS. CLINICAL AND EXPERIMENTAL RHEUMATOLOGY. 2020?.", "literaturereference_normalized": "uveitis occurrence in patients with ankylosing spondylitis according to the type of tumour necrosis factor inhibitor a cohort study of 175 patients", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20200908", "receivedate": "20200908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18243208, "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\nTransplantation and immunosuppressive drugs are major limitations to the success of pregnancy. In 1988, the first pregnancy after a heart transplant was reported, which has given female recipients the hope to give birth. During pregnancy, physiologic changes with increased blood volume and hemodilution may influence blood drug level.\n\n\nMETHODS\nWe reported our experience in monitoring on immunosuppressive drugs for 2 cases. Both of them underwent heart transplantation in 2006 and were 34 and 37 years old at time of pregnancy. For both cases, we frequently monitored the blood level and increased the dosage of immunosuppressive drugs accordingly. Both cases had uneventful pregnancy and delivery to healthy babies at the National Taiwan University Hospital in Taiwan. Their postpartum courses were uneventful as well.\n\n\nCONCLUSIONS\nWe advocate adjusting the immunosuppressive dosage according to the blood level before pregnancy.", "affiliations": "Department of Nursing, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Nursing, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.;Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan; Department of Surgery, Fu Jen Catholic University Hospital, and Fu Jen Catholic University College of Medicine, New Taipei City, Taiwan. Electronic address: [email protected].", "authors": "Tsao|C-I|CI|;Chou|N-K|NK|;Chi|N-H|NH|;Huang|S-C|SC|;Tsan|C-Y|CY|;Wang|C-H|CH|;Yu|H-Y|HY|;Wu|I-H|IH|;Chen|Y-S|YS|;Shun|C-T|CT|;Wang|S-S|SS|", "chemical_list": "D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1345", "issue": "48(3)", "journal": "Transplantation proceedings", "keywords": null, "medline_ta": "Transplant Proc", "mesh_terms": "D000328:Adult; D005260:Female; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome", "nlm_unique_id": "0243532", "other_id": null, "pages": "978-81", "pmc": null, "pmid": "27234783", "pubdate": "2016-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Surveillance of Immunosuppression During Pregnancy After Heart Transplantation: Case Report.", "title_normalized": "surveillance of immunosuppression during pregnancy after heart transplantation case report" }

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SURVEILLANCE OF IMMUNOSUPPRESSION DURING PREGNANCY AFTER HEART TRANSPLANTATION: CASE REPORT. 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SURVEILLANCE OF IMMUNOSUPPRESSION DURING PREGNANCY AFTER HEART TRANSPLANTATION: CASE REPORT. TRANSPLANTATION PROCEEDINGS. 2016;48:978-81", "literaturereference_normalized": "surveillance of immunosuppression during pregnancy after heart transplantation case report", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20160608", "receivedate": "20160607", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12442426, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" } ]

{ "abstract": "Here we describe a patient with a rare movement disorder, hemichorea-hemiballismus, which is described as a complication of non-ketotic hyperglycaemia. This complication may be seen in individuals with poorly controlled long-standing diabetes mellitus. Proper diagnosis is established with CT and MRI of the brain, which typically show classic findings in the basal ganglia. Treatment focuses on improvement of glycaemic control and usually results in rapid resolution of the movement disorder. Nevertheless, recurrent episodes of hemichorea-hemiballismus, and even more ominous complications such as ischaemic stroke may occur.", "affiliations": "Universidad de Cuenca, Cuenca, Azuay, Ecuador. [email protected]", "authors": "Carrion|Diego M|DM|;Carrion|Andres F|AF|", "chemical_list": null, "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": "D002819:Chorea; D003937:Diagnosis, Differential; D020820:Dyskinesias; D006801:Humans; D006943:Hyperglycemia; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020521:Stroke; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "23470671", "pubdate": "2013-03-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12127677;13798206;2757526;15205134;20039938;19305947;21995866;20566257;22095170", "title": "Non-ketotic hyperglycaemia hemichorea-hemiballismus and acute ischaemic stroke.", "title_normalized": "non ketotic hyperglycaemia hemichorea hemiballismus and acute ischaemic stroke" }

[ { "companynumb": "EC-APOTEX-2017AP017027", "fulfillexpeditecriteria": "1", "occurcountry": "EC", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN ASPART" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERGLYCAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN ASPART" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INSULIN GLARGINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERGLYCAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN GLARGINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075984", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERGLYCAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APO-METFORMINA" } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemic stroke", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperglycaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ballismus", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chorea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "CARRION DM, CARRION AF.. NON-KETOTIC HYPERGLYCAEMIA HEMICHOREA-HEMIBALLISMUS AND ACUTE ISCHAEMIC STROKE. BMJ CASE REP. 2013;1-3", "literaturereference_normalized": "non ketotic hyperglycaemia hemichorea hemiballismus and acute ischaemic stroke", "qualification": "3", "reportercountry": "EC" }, "primarysourcecountry": "EC", "receiptdate": "20170829", "receivedate": "20170829", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13916152, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.", "affiliations": "Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio.;National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland.;National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland.;Medical Genetics Institute, Cedars Sinai Medical Center, Division of Medical Genetics, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California.;Section of Medical Genetics, Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Section of Medical Genetics, Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.;Greenwood Genetic Center, Columbia, South Carolina.;Greenwood Genetic Center, Columbia, South Carolina.;Laboratory of Pathology, National Cancer Institute, National Institute of Health, Bethesda, Maryland.;Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia.;Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia.;Clinical Genetics Service, Nottingham University Hospitals Trust, Nottingham, United Kingdom.;Medical Genetics Institute, Cedars Sinai Medical Center, Division of Medical Genetics, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California.", "authors": "Russell|Bianca|B|;Johnston|Jennifer J|JJ|;Biesecker|Leslie G|LG|;Kramer|Nancy|N|;Pickart|Angela|A|;Rhead|William|W|;Tan|Wen-Hann|WH|;Brownstein|Catherine A|CA|;Kate Clarkson|L|L|;Dobson|Amy|A|;Rosenberg|Avi Z|AZ|;Vergano|Samantha A Schrier|SA|;Helm|Benjamin M|BM|;Harrison|Rachel E|RE|;Graham|John M|JM|", "chemical_list": "C473949:ASXL1 protein, human; D012097:Repressor Proteins", "country": "United States", "delete": false, "doi": "10.1002/ajmg.a.37131", "fulltext": null, "fulltext_license": null, "issn_linking": "1552-4825", "issue": "167A(9)", "journal": "American journal of medical genetics. Part A", "keywords": "ASXL1; Bohring-Opitz syndrome; Wilms tumor; cyclic vomiting; failure to thrive; hypertrichosis; intellectual disability; myopia; nevus flammeus", "medline_ta": "Am J Med Genet A", "mesh_terms": "D000015:Abnormalities, Multiple; D019046:Bone Marrow Neoplasms; D002648:Child; D002675:Child, Preschool; D003398:Craniosynostoses; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008607:Intellectual Disability; D008297:Male; D009154:Mutation; D012097:Repressor Proteins; D009396:Wilms Tumor", "nlm_unique_id": "101235741", "other_id": null, "pages": "2122-31", "pmc": null, "pmid": "25921057", "pubdate": "2015-09", "publication_types": "D016428:Journal Article; D052060:Research Support, N.I.H., Intramural", "references": "11038445;23505322;9477319;21368916;17498985;12657473;19833123;24255920;10405439;23649928;21706002;7546453;22419483;10861669;20717007;10861670;22186017;7258228;19606480;22897849;23672984;16528754;16925531;23383720;25426837;16691589;12514360;1190170;10861668;17531565", "title": "Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.", "title_normalized": "clinical management of patients with asxl1 mutations and bohring opitz syndrome emphasizing the need for wilms tumor surveillance" }

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CLINICAL MANAGEMENT OF PATIENTS WITH ASXL1 MUTATIONS AND BOHRING?OPITZ SYNDROME, EMPHASIZING THE NEED FOR WILMS TUMOR SURVEILLANCE. AMERICAN JOURNAL OF MEDICAL GENETICS 01-SEP-2015?2015: 167 (9):2122-2131.", "literaturereference_normalized": "clinical management of patients with asxl1 mutations and bohring opitz syndrome emphasizing the need for wilms tumor surveillance", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151013", "receivedate": "20151013", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11622818, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "US-JNJFOC-20150902239", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTINOMYCIN D" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROBLASTOMA", "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": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "050718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LIPOSOME INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HYDROCHLORIDE." } ], "patientagegroup": "3", "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RUSSELL B, JOHNSTON JJ, BIESECKER LG, KRAMER N, PICKART A, RHEAD W, ET AL. CLINICAL MANAGEMENT OF PATIENTS WITH ASXL1 MUTATIONS AND BOHRING-OPITZ SYNDROME, EMPHASIZING THE NEED FOR WILMS TUMOR SURVEILLANCE. AMERICAN JOURNAL OF MEDICAL GENETICS 01-SEP-2015?167 (9):2122-2131.", "literaturereference_normalized": "clinical management of patients with asxl1 mutations and bohring opitz syndrome emphasizing the need for wilms tumor surveillance", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151113", "receivedate": "20151113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11736230, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" } ]

{ "abstract": "For patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are not eligible for intensive chemotherapy because of comorbidities, advanced age, or relapse after heavy salvage regimens, treatment options are very limited and prognosis is poor. We retrospectively analyzed 29 patients with relapsed/refractory DLBCL treated with combination bendamustine plus rituximab (BR) between July 2010 and January 2014 to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and treatment safety. Twenty-eight patients were available for this analysis. ORR was 50% (14 patients), with 39.3% CR (11 patients), and 10.7% PR (3 patients). SD was reported in 2 patients (7.2%) and PD in 12 patients (42.8%). At the median follow up of 8 months (range 1-37.4 months), the median PFS was 8 months for all patients (95% CI 5.5-26.6). The median DOR was 24.7 months (95% CI 3.2-24.7). Grade 3/4 toxicity observed included hematologic events: lymphopenia (42.8%), neutropenia (32.1%), anemia (17.2%), and thrombocytopenia (14.2%). BR can be considered to have a role in the treatment of patients with relapsed/refractory DLBCL with limited therapeutic options, in that it can induce long-term remission in some patients with an acceptable toxicity profile.", "affiliations": "Hematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi, Italy. Electronic address: [email protected].;Hematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi, Italy.;Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari Medical School, Bari, Italy.;Hematology Unit, Department of Medical and Experimental Oncology, IRCCS National Cancer Research Centre \"Giovanni Paolo II\", Bari, Italy.;Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari Medical School, Bari, Italy.;Hematology Unit, Department of Medical and Experimental Oncology, IRCCS National Cancer Research Centre \"Giovanni Paolo II\", Bari, Italy.;Hematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi, Italy.;Hematology Unit, Foundation Hospital Cardinal \"G. Panico\", Tricase, Lecce, Italy.;Hematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi, Italy.", "authors": "Merchionne|Francesca|F|;Quintana|Giovanni|G|;Gaudio|Francesco|F|;Minoia|Carla|C|;Specchia|Giorgina|G|;Guarini|Attilio|A|;Quarta|Giovanni|G|;Pavone|Vincenzo|V|;Melpignano|Angela|A|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D009588:Nitrogen Mustard Compounds; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0145-2126", "issue": "38(12)", "journal": "Leukemia research", "keywords": "Bendamustine; DLBCL; Rituximab; Salvage therapy", "medline_ta": "Leuk Res", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009588:Nitrogen Mustard Compounds; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D015996:Survival Rate", "nlm_unique_id": "7706787", "other_id": null, "pages": "1446-50", "pmc": null, "pmid": "25455656", "pubdate": "2014-12", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a retrospective analysis.", "title_normalized": "bendamustine plus rituximab for relapsed or refractory diffuse large b cell lymphoma a retrospective analysis" }

[ { "companynumb": "IT-ROCHE-1508165", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "375", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENDAMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT A DOSE BETWEEN 70 AND 120 MG/M2 (MEAN 90 MG/M2) ON DAYS 1 AND 2 OF EACH 28-DAY CYCLE FOR UP TO SI", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDAMUSTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": ", QUINTANA G, GAUDIO F, MINOIA C, SPECCHIA G, GUARINI A, QUARTA G, PAVONE V AND MELPIGNANO A. BENDAMUSTINE PLUS RITUXIMAB FOR RELAPSED OR REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA: A RETROSPECTIVE ANALYSIS. LEUKEMIA RESEARCH 2014 DEC 01;38(12):1446-1450.", "literaturereference_normalized": "bendamustine plus rituximab for relapsed or refractory diffuse large b cell lymphoma a retrospective analysis", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20141229", "receivedate": "20141229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10677816, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]

{ "abstract": "Although advancing age can greatly increase the complexities of treating metastatic breast cancer, chronological age alone is insufficient to determine the type or intensity of treatment. Older patients require an individualized approach that takes into account the patient's physical ability, social circumstances and mental capacity to tolerate treatment. This section features three older women treated with eribulin for metastatic breast cancer. In the first case, a 70-year-old woman maintained stable disease into her 34th month of treatment with third-line eribulin. In the remaining cases, two heavily pretreated women (80 and 90 years, respectively) with metastatic disease and liver involvement presented objective radiological benefit to later-line eribulin along with prolonged clinical improvement and good tolerability.", "affiliations": "Medical Oncology Department, Medical-Surgical Hospital of Jaén, Jaén, Spain.;Medical Oncology Department, Medical-Surgical Hospital of Jaén, Jaén, Spain.;Medical Oncology Department, Medical-Surgical Hospital of Jaén, Jaén, Spain.;Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.;Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.;Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.", "authors": "Garrido|Maria Lomas|ML|;Morago|Ana Jaén|AJ|;Rovira|Pedro Sánchez|PS|;Olarte|Paula Espinosa|PE|;Sánchez|Cristina Pernaut|CP|;Sánchez|Luis Manso|LM|", "chemical_list": "D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; C490954:eribulin", "country": "England", "delete": false, "doi": "10.2217/fon-2017-0357", "fulltext": null, "fulltext_license": null, "issn_linking": "1479-6694", "issue": "14(7s)", "journal": "Future oncology (London, England)", "keywords": "elderly; eribulin; metastatic breast cancer", "medline_ta": "Future Oncol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D005260:Female; D005663:Furans; D006801:Humans; D007659:Ketones; D016896:Treatment Outcome", "nlm_unique_id": "101256629", "other_id": null, "pages": "21-27", "pmc": null, "pmid": "29611758", "pubdate": "2018-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Experience with eribulin in the treatment of elderly women with metastatic breast cancer: case studies.", "title_normalized": "experience with eribulin in the treatment of elderly women with metastatic breast cancer case studies" }

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"reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201610" } }, "primarysource": { "literaturereference": "LOMAS GARRIDO M, JAEN MORAGO A, SANCHEZ ROVIRA P, ESPINOSA OLARTE P, PERNAUT SANCHEZ C, MANSO SANCHEZ L. EXPERIENCE WITH ERIBULIN IN THE TREATMENT OF ELDERLY WOMEN WITH METASTATIC BREAST CANCER: CASE STUDIES. 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"drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL/PACLITAXEL LIPOSOME" } ], "patientagegroup": "6", "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Palmar-plantar erythrodysaesthesia syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haematemesis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2013" } }, "primarysource": { "literaturereference": "GARRIDO ML, MORAGO AJ, ROVIRA PS, OLARTE PE, SANCHEZ CP, SANCHEZ LM. EXPERIENCE WITH ERIBULIN IN THE TREATMENT OF ELDERLY WOMEN WITH METASTATIC BREAST CANCER: CASE STUDIES. 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{ "abstract": "Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab. In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14-24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1-90%). Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%. Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.", "affiliations": "Department of Hematology and Oncology, KIM IV, Faculty of Medicine, University Halle-Wittenberg, Halle, Germany.;Division of Endocrinology and Diabetology, Department of Medicine II, University of Freiburg, Freiburg, Germany.;Institute of Pathology, University of Freiburg, Germany.;Department of Nuclear Medicine, University of Freiburg, Germany.;Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.;Institute of Pathology, University of Freiburg, Germany.;Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.;German Cancer Research Center (DKFZ), Heidelberg, Germany.;Outcomes Research Unit, Department of Endocrine Surgery, Endocrine Center Stuttgart, Diakonie Klinikum Stuttgart, Stuttgart, Germany.;Klinikum Villingen-Schwenningen, Hämatologie/Onkologie, Villingen-Schwenningen, Germany.;Department of Nuclear Medicine, University of Freiburg, Germany.;Division of Endocrinology/Diabetology, Department of Internal Medicine, University Hospital Würzburg, Würzburg, Germany.;Zentrum für Strahlentherapie, Freiburg, Germany.;Praxis für Nuklearmedizin, Freiburg, Germany.;Institute of Medical Bioinformatics and Systems Medicine and Institute of Molecular Medicine and Cell Research; Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Eisai GmbH, Frankfurt/Main, Germany.;Outcomes Research Unit, Department of Endocrine Surgery, Endocrine Center Stuttgart, Diakonie Klinikum Stuttgart, Stuttgart, Germany.;Division of Endocrinology and Diabetology, Department of Medicine II, University of Freiburg, Freiburg, Germany.;Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.;Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.;Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.;Department of General and Visceral Surgery, University Hospital Freiburg, Freiburg, Germany.", "authors": "Dierks|Christine|C|;Seufert|Jochen|J|;Aumann|Konrad|K|;Ruf|Juri|J|;Klein|Claudius|C|;Kiefer|Selina|S|;Rassner|Michael|M|;Boerries|Melanie|M|;Zielke|Andreas|A|;la Rosee|Paul|P|;Meyer|Philipp Tobias|PT|;Kroiss|Matthias|M|;Weißenberger|Christian|C|;Schumacher|Tilmann|T|;Metzger|Patrick|P|;Weiss|Harald|H|;Smaxwil|Constantin|C|;Laubner|Katharina|K|;Duyster|Justus|J|;von Bubnoff|Nikolas|N|;Miething|Cornelius|C|;Thomusch|Oliver|O|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1089/thy.2020.0322", "fulltext": "\n==== Front\nThyroid\nThyroid\nthy\nThyroid\n1050-7256\n1557-9077\nMary Ann Liebert, Inc., publishers 140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA\n\n33509020\n10.1089/thy.2020.0322\n10.1089/thy.2020.0322\nThyroid Cancer and Nodules\nCombination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma\nDierks et al.\nLenvatinib/Pembrolizumab in ATC/PDTC\nDierks Christine 12\nSeufert Jochen 3\nAumann Konrad 4\nRuf Juri 5\nKlein Claudius 245\nKiefer Selina 4\nRassner Michael 2\nBoerries Melanie 678\nZielke Andreas 9\nla Rosee Paul 10\nMeyer Philipp Tobias 511\nKroiss Matthias 1213\nWeißenberger Christian 14\nSchumacher Tilmann 15\nMetzger Patrick 816\nWeiss Harald 17\nSmaxwil Constantin 9\nLaubner Katharina 3\nDuyster Justus 2\nvon Bubnoff Nikolas 218*\nMiething Cornelius 2611*\nThomusch Oliver 19*\n1 Department of Hematology and Oncology, KIM IV, Faculty of Medicine, University Halle-Wittenberg, Halle, Germany.\n2 Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.\n3 Division of Endocrinology and Diabetology, Department of Medicine II, University of Freiburg, Freiburg, Germany.\n4 Institute of Pathology, University of Freiburg, Germany.\n5 Department of Nuclear Medicine, University of Freiburg, Germany.\n6 German Cancer Research Center (DKFZ), Heidelberg, Germany.\n7 Comprehensive Cancer Center Freiburg (CCCF), University Medical Center, University of Freiburg, Freiburg, Germany.\n8 Institute of Medical Bioinformatics and Systems Medicine and Institute of Molecular Medicine and Cell Research; Faculty of Medicine, University of Freiburg, Freiburg, Germany.\n9 Outcomes Research Unit, Department of Endocrine Surgery, Endocrine Center Stuttgart, Diakonie Klinikum Stuttgart, Stuttgart, Germany.\n10 Klinikum Villingen-Schwenningen, Hämatologie/Onkologie, Villingen-Schwenningen, Germany.\n11 German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.\n12 Division of Endocrinology/Diabetology, Department of Internal Medicine, University Hospital Würzburg, Würzburg, Germany.\n13 Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.\n14 Zentrum für Strahlentherapie, Freiburg, Germany.\n15 Praxis für Nuklearmedizin, Freiburg, Germany.\n16 Faculty of Biology, University of Freiburg, Freiburg, Germany.\n17 Eisai GmbH, Frankfurt/Main, Germany.\n18 Department of Hematology/Oncology, University of Luebeck, Luebeck, Germany.\n19 Department of General and Visceral Surgery, University Hospital Freiburg, Freiburg, Germany.\n* These authors contributed equally to this work.\n\nAddress correspondence to: Christine Dierks, MD, Department of Hematology and Oncology, KIM IV, Faculty of Medicine, University Halle-Wittenberg, Ernst-Grube-Str. 40, Freiburg D-06120, Germany [email protected]\n01 7 2021 July 2021\n08 7 2021\n08 7 2021\n31 7 10761085\n© Christine Dierks et al., 2021; Published by Mary Ann Liebert, Inc.\n2021\nChristine Dierks et al.\nhttps://creativecommons.org/licenses/by/4.0/ This Open Access article is distributed under the terms of the Creative Commons License [CC-BY] (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBackground: Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab.\n\nPatients and Methods: In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14–24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1–90%).\n\nResults: Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%.\n\nConclusions: Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.\n\nanaplastic thyroid cancer\nATC\nlenvatinib\nPDTC\npembrolizumab\npoorly differentiated thyroid cancer\n==== Body\nIntroduction\n\nAnaplastic thyroid carcinoma (ATC) is a rare disease with an extremely high mortality rate and a 10-year survival below 5% (1). ATCs grow very fast, infiltrate into cervical structures, such as the esophagus, trachea, or blood vessels, and metastasize to the lung, brain, and bone. Even with extensive multimodal therapy (surgery, external beam radiotherapy, and chemotherapy), the median overall survival (OS) is only 3–5 months (1–3). ATC frequently arises from differentiated thyroid carcinoma (DTC) but can also emerge de novo. Typical molecular features of ATC are mutations in TP53 (54–64%), TERT (61%), KRAS/NRAS (28–43%), BRAF (18–28%), NF1, NF2, PI3K, PTEN, and genes in the WNT signaling pathway (4–9). BRAF/MEK inhibitor combinations (dabrafenib/trametinib) are approved for BRAFV600E-mutated ATCs and have significantly enhanced survival and has high treatment response (overall response rate [ORR] 69%) (10,11). All other locally advanced or metastatic ATCs (about 75%) are individually treated with carboplatin, paclitaxel, or doxorubicin containing chemotherapeutic regimens with very modest ORR (10–20%) lasting only for a few months (progression-free survival [PFS] 3–4 months) (12–15). Poorly differentiated thyroid carcinoma (PDTC) has a more favorable prognosis, with some patients being partially responsive to radioiodine therapy (RIT), but 10-year survival is also below 10%.\n\nCompared with DTC, ATC/PDTC are characterized by an elevated tumor mutation burden, higher programmed death ligand 1 (PD-L1) levels, and increased neoangiogenesis (VEGFR/FGFR signaling) (7,16–22), suggesting that they may be sensitivity to immune checkpoint and neoangiogenesis inhibitors.\n\nLenvatinib is an antiangiogenic (VEGFR 1–3/FGFR 1–4) and antiproliferative (RET/PDGFR) tyrosine kinase inhibitor (TKI), which is approved for DTC refractory to radioiodine treatment (23). PFS in DTC is 19.4 months (23–26), but it is reduced to 14.8 months in PDTC, and all patients ultimately develop treatment resistance or treatment intolerance (26). In ATC, the PFS is even shorter (5.6–7.4 months) with variable ORR between 17.4% and 43%, depending on the initial tumor stage (27–29).\n\nPembrolizumab is an immune checkpoint inhibitor targeting PD-1 on immune cells. Response to pembrolizumab treatment is associated with elevated expression of PD-L1 or high tumor mutational burden (TMB) (30–34). DTC have low TMB and low PD-L1 expression (CPS/TPS) and hence have low response rates to immune checkpoint inhibitor treatments (ORR 9%) (35). In ATC with higher PD-L1/TMB, the effect of immune checkpoint inhibitors is still low (ORR <10%) (36,37), as the slow response to treatment (>8 weeks) cannot keep pace with the aggressive tumor growth.\n\nIn vitro studies and mouse experiments indicate synergism between lenvatinib and pembrolizumab (38). Lenvatinib not only blocks tumor neoangiogenesis and proliferation but also enhances immune cell invasion into the tumor and therefore fosters immune responses induced by immune checkpoint inhibitors (38). Furthermore, phase II trials with the lenvatinib/pembrolizumab combination in patients with extensively pretreated metastatic solid tumors (renal, ovarian, and endometrial carcinoma) not only showed acceptable toxicity but also very promising response rates (84% partial response [PR], 16% stable disease [SD]). Phase II/III trials for endometrial, head and neck, and hepatocellular carcinoma validated the high efficacy and safety for this combination (39–42). In ATC, pembrolizumab treatment was used as a salvage strategy after patients had failed lenvatinib or dabrafenib monotherapy or a dabrafenib/trametinib combination therapy. Pembrolizumab was added to the respective TKI and induced PR rates of 43%, but with a very short PFS of only 2.96 months (43).\n\nIn contrast to this study, we directly combined lenvatinib and pembrolizumab as front-line therapy after chemotherapy failure in eight patients with metastatic ATC (n = 6) or PDTC (n = 2) and examined treatment outcome and biomarkers for this approach.\n\nMaterials and Methods\n\nStudy population and patient characteristics\n\nThis is a retrospective, single-center (University Medical Center Freiburg) cohort study of eight patients with metastatic ATC (n = 6) or PDTC (n = 2) treated with a combination of the multikinase inhibitor lenvatinib and the immune checkpoint inhibitor pembrolizumab (L/P). Patient data were collected from March 2016 to December 2019 (Table 1). ATC/PDTC diagnosis was histopathologically confirmed by the Institute for Pathology, Freiburg, in all patients. Patients had no BRAFV600E mutation, but numerous other mutations were present (Supplementary Table S1). All patients were pretreated with irradiation, chemotherapy, or RIT (Table 1 and Supplementary Table S2). Adverse events (AEs) were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 5)–GBG (Table 2). The retrospective study was approved by the Institutional Review Board (IRB) of the University Freiburg.\n\nTable 1. Baseline Characteristics\n\nMedian age at treatment start (range), years\t63.5 (49–88)\t\nSex, n (%)\t\n Men\t4 (50)\t\n Women\t4 (50)\t\nPerformance status, n (%)\t\n ECOG 0\t3 (37.5)\t\n ECOG 1\t3 (37.5)\t\n ECOG 2\t2 (25)\t\nPathological diagnosis, n (%)\t\n ATC\t6 (75)\t\n PDTC\t2 (25)\t\nLocation of metastases, n (%)\t\n Lung\t8 (100)\t\n Bone\t2 (25)\t\n Kidney\t1 (12.5)\t\n Brain\t1 (12.5)\t\n Liver\t1 (12.5)\t\n Skin\t1 (12.5)\t\nCervical relapse, n (%)\t6 (75)\t\nPrevious therapy, n (%)\t\n Surgery\t8 (100)\t\n Radiation ± chemosensitizing\t7 (87.5)\t\n Chemotherapy\t6 (75)\t\n RIT\t2 (25)\t\nATC, anaplastic thyroid carcinoma; ECOG, Eastern Cooperative Oncology Group; PDTC, poorly differentiated thyroid carcinoma; RIT, radioiodine therapy.\n\nTable 2. Adverse Events According to the Common Terminology Criteria for Adverse Events Version 5.0\n\nEvent\tGrade I/II (%)\tGrade III/IV (%)\t\nTotal\t8/8 (100)\t3/8 (36)\t\nHypertension\t5/8 (63)\t \t\nFatigue\t2/8 (25)\t1/8 (13)\t\nAnorexia\t2/8 (25)\t2/8 (25)\t\nOral mucositis\t2/8 (25)\t \t\nJoint/muscle pain\t1/8 (13)\t \t\nHand–foot syndrome\t1/8 (13)\t \t\nDiarrhea\t1/8 (13)\t \t\nProteinuria\t1/8 (13)\t \t\nAbdominal pain\t \t1/8 (13)\t\nCervical bleeding\t \t1/8 (13)\t\nData are given as totals and %. Events reported are listed in descending frequency of columns for grade I/II and grade III/IV. A patients with several multiple occurrences of an adverse event is counted only once with the highest grade. A patient with multiple adverse events is counted only once in the total row.\n\nTreatment strategy\n\nPatients started with lenvatinib 24 mg oral daily if the body weight (BW) was more than 80 kg, or 20 mg for BW less than 80 kg. Pembrolizumab infusions were started in between 1 and 4 weeks after initiation of lenvatinib at a fixed dose of 200 mg total every 3 weeks. Dose for lenvatinib was stepwise reduced upon occurrence of side effects according to clinical judgment. Lenvatinib was given at least for 1 year and was then stopped in patients with confirmed complete response (CR). Pembrolizumab was given for up to 40 months. It will be continued in all patients reaching a CR for two more years.\n\nResponse assessment\n\nRadiology assessment including cervical, chest, and abdominal computed tomography (CT) scans was performed before treatment and then every 3–4 months. Response to therapy was determined centrally using the RECIST 1.1 criteria (Fig. 1A and Supplementary Table S3). Positron emission tomography (PET)–CT using [18F] fluorodeoxyglucose (FDG) (PET/CT) was performed before treatment, and after 12–16 months of treatment to confirm CRs (the European Organisation for Research and Treatment of Cancer [EORTC] response criteria for PET). In case of persistent lesions without tracer uptake on PET/CT (PR according to the RECIST 1.1 [CT scan], but CR according to the EORTC criteria for PET), lesions were surgically removed (1/8) to confirm the absence of viable tumor tissue (pathological CR criteria, Supplementary Table S4).\n\nFIG. 1. (A) ORR after 3–4 months of treatment, 6/8 PR, 1/8 SD, 1/8 PD. (B) BOR within 16 months of treatment. (C) Lenvatinib dosage and changes over time. (D) Treatment duration and ongoing treatment. Patients in CR. BOR, best overall response; CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.\n\nThe efficacy of the combination treatment was assessed by ORR 3–4 months after starting treatment, best overall response (BOR) (Fig. 1B), PFS, and OS. PFS was defined as the time elapsed between starting treatment and progression or death, whichever occurred first. OS was defined as the time between starting treatment and death.\n\nMolecular testing and immunohistochemistry\n\nMolecular testing by whole-exome sequencing (WES) was performed from formalin-fixed and paraffin-embedded tissue specimens at the Deutsches Krebsforschungszentrum Heidelberg (DKFZ) as described previously (44,45). PD-L1 status was determined by immunohistochemistry (antibody clone SP263; Ventana) in tumor tissue specimens obtained at initial diagnosis before treatment. The tumor proportion score (TPS) was determined as proportion of PD-L1-positive tumor cells of 100 tumor cells. The combined proportion score (CPS), as amount of PD-L1-positive tumor and immune cells within 100 tumor cells, was also determined centrally at the Department of Pathology of the University Medical Center Freiburg.\n\nStatistical analysis\n\nKaplan–Meier curves were used for OS and PFS. Descriptive statistics were used to summarize patients' characteristics and AEs. Statistical analysis was performed using IBM SPSS Statistics version 25.\n\nResults\n\nEight patients with metastatic ATC (n = 6) or PDTC (n = 2) were treated with a combination of lenvatinib and pembrolizumab after failing chemotherapy, irradiation, or RIT (Table 1 and Supplementary Table S2). All the 8 patients had been extensively pretreated with surgery (8/8), local cervical external beam radiation therapy (6/8), RIT (2/2), local cerebral irradiation therapy (1/8), or systemic chemotherapy alone (6/8) (carboplatin/paclitaxel [4/8], cisplatin/paclitaxel [1/8], cisplatin/doxorubicin [1/8], and paclitaxel only [1/8]) (Table 1 and Supplementary Table S2). The median patient age was 66.4 years. At the beginning of treatment with lenvatinib/pembrolizumab, all patients had stage IVC. All patients had lung metastasis (8/8), and 2 of 8 skeletal metastasis, 1 of 8 liver metastasis, 1 of 8 kidney metastasis, 1 of 8 skin metastasis, and 1 of 8 brain metastasis. Six of eight patients also had progression of their local tumor. Eastern Cooperative Oncology Group (ECOG) performance status ranged from 0 to 2, with 3 ECOG 0 (38%), 3 ECOG 1 (38%), and 2 ECOG 2 (25%). Molecular diagnostics showed that none of the patients had a BRAFV600E mutation, but numerous other mutations typical for ATC/PDTC were detected and are listed in Supplementary Table S1.\n\nTreatment regimen and AEs\n\nLenvatinib was started at a daily dose of 24 mg in 5 of 8 patients (BW more than 80 kg) and 20 mg in 2 patients with bodyweight less than 80 kg. An 88-year-old woman started on 14 mg/day (Fig. 1C and Table 3). Pembrolizumab treatment was initiated after a median of 2.7 weeks (ranging from 1 to 4 weeks after starting lenvatinib) and was given i.v. at a fixed dose of 200 mg every 3 weeks. In general, the therapy was well tolerated with the predominant grade II to IV AEs (AEs according to the CTCAE) being hypertension (5/8), fatigue (4/8), weight loss/anorexia (3/8), oral mucositis (2/8), diarrhea (2/8), joint/muscle pain (1/8), and hand–foot syndrome (1/8) (Table 2). The lenvatinib dose was reduced stepwise upon occurrence of intolerable side effects from 24 to 20, 14, 12, and 10 mg/day (Fig. 1C). Most side effects resolved after reducing the dose of lenvatinib, but in two patients, lenvatinib-induced AEs required treatment discontinuation (patients 3 and 6, Table 3). One grade IV serious adverse event (SAE) with a lethal cervical bleeding occurred after removal of the tracheostomy in patient 5 despite being in complete remission (Tables 2 and 3).\n\nTable 3. Patient History\n\nPatient\tEntity\tAge, years\tPrior treatment\tORR in 3/4 months\tBOR CT+PET\tPFS, months\tOS, months\tAdverse events (CTCAE in grade °)\tMedian dose lenvatinib, mg/day\tCurrent therapy/ outcome\t\n1\tPDTC\t63\tS Rx C/T\tPR\tPR\t25\t27\tHypertension °II\nFatigue °II\nAnorexia °I\nOral mucositis °I\t24\tPD/death after stopping lenvatinib due to a knee surgery\t\n2\tATC\t76\tS Rx C/T\tPR\tCR\t40\t40\tHypertension °II\nAnorexia °II\t24\tAlive, CR after 12 months lenvatinib/pembrolizumab, now without treatment\t\n3\tPDTC\t49\tS RIT C/T\tPR\tPR\t15\t23\tAnorexia °III\nAbdominal pain °III\t14\tPD/death, lenvatinib on/off due to weight loss/abdominal pain\t\n4\tATC\t68\tS Rx C/T\tPR\tCR\t26\t26\tAnorexia °I\nLoss of appetite °II\nProteinuria °I\nHypertension °II\t20\tAlive, CR after 10 months of treatment, now pembrolizumab mono\t\n5\tATC\t63\tS Rx C/T\tPR\tCR\t11\t11\tDiarrhea °II\nHypertension °II\nCervical bleeding °IV\t20\tCR after 7 months of treatment. Death due to cervical bleeding\t\n6\tATC\t88\tS Rx C/T\tSD\tSD\t4\t7\tDiarrhea °II\nAnorexia °III\nProteinuria °II\nFatigue °III\nOral mucositis °II\t14\tPD/death after stopping medication due to side effects\t\n7\tATC\t64\tS RIT Rx\tPR\tCR\t19\t19\tHypertension °II\nFatigue °II\nJoint pain °II\nHand–foot syndrome °I\t24\tAlive, CR, lenvatinib/pembrolizumab for 12 months, now pembrolizumab mono\t\n8\tATC\t60\tS R C/T\tPD\tPD\t1\t1\tHypertension °II\t24\tPD/death due to cervical tumor progression\t\nPatient characteristics including diagnosis, previous therapy (S, RIT, Rx, C/T), patient age, PFS, ORR, BOR, OS, response after 3 months, maximum response, main side effects, median dose lenvatinib in mg/day, dose pembrolizumab, current treatment/outcome. CTCAE grades in roman numbers. Responses were assessed via the RECIST v1.1 radiology assessment and FDG uptake according to the EORTC criteria for PET.\n\nBOR, best overall response; C/T, chemotherapy; CT, computed tomography; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; FDG, [18F] fluorodeoxyglucose; ORR, overall response rate; OS, overall survival; PD, progressive disease; PET, positron emission tomography; PFS, progression free survival; PR, partial response; Rx, radiation therapy; S, surgery; SD, stable disease.\n\nAfter four months of treatment, lenvatinib/pembrolizumab was discontinued due to severe weight loss/anorexia (grade III) in the 88-year-old patient (patient 6), and she died due to disease progression three months later. One patient was intolerant to lenvatinib treatment due to grade III abdominal pain and weight loss/anorexia (patient 3). Lenvatinib was reduced from 24 to 20 to 14 and 12 mg/day in a stepwise manner, and after 14 months, lenvatinib/pembrolizumab treatment was discontinued. Two patients received the full dose of lenvatinib 24 mg for 24 months (Fig. 1C). Pembrolizumab was given for up to 40 months and will be continued in all patients reaching a CR for two more years (Fig. 1D).\n\nTreatment efficacy\n\nTreatment response was first assessed 3–4 months after lenvatinib/pembrolizumab treatment. Six of eight patients had a PR according to the RECIST v1.1 criteria (Fig. 1A). ORR for ATCs was 66% (4/6 PR). The 88-year-old patient (ATC) at 14 mg lenvatinib had SD (patient 6). One ATC patient (patient 8) did not respond to lenvatinib/pembrolizumab treatment combination and died within the first month of treatment due to cervical tumor progression (1/8 progressive disease) (Fig. 1A and Supplementary Data).\n\nBOR changed in four ATC patients from PR to CR within 16 months of treatment (total CR rate 50%, CR rate for ATC 66%) (Fig. 1B). Individual patient history is summarized in the Supplementary Data. ATC patient 2 had a confirmed CR for all target- and nontarget lesions 16 months after lenvatinib/pembrolizumab treatment, and stopped taking lenvatinib after 2 years (24 mg daily for 24 months), but continued pembrolizumab for 16 more months (40 months total). He stopped treatment for 6 months and is still in CR. ATC patient 4 with lung and brain metastases had a PR 12 months after starting treatment, but all lesions in the lung were without FDG uptake (CR according to the EORTC criteria for PET). All lung lesions were surgically removed and showed a pathological CR (no viable tumor cells). Therefore, the patient was judged as having a CR and has discontinued lenvatinib after 1 year of treatment, and continues with pembrolizumab only (26 months total). Patient 7 with a massive neck tumor and lung metastasis had a PET/CT confirmed CR 12 months after starting treatment. He stopped lenvatinib after 15 months and now continues with pembrolizumab only (19 months total). ATC patient 5 had confirmed CR 10 months after treatment start, but unfortunately died due to bleeding complications after removal of the tracheostomy tube (Table 3 and Supplementary Table S2).\n\nTreatment durations ranged from 1 to 40 months (ATC: 40, 26, 19, 18, 4, and 1 month; PDTC: 25 and 15 months, respectively), with three patients being treated for more than 2 years (Fig. 1D). At the time of data cutoff, 3 of 8 patients (patients 2, 4, and 7, all ATCs) were still alive and on therapy (40, 26, and 19 months). We stopped the treatment of patient 2 after 40 months of treatment, and he is now regularly monitored by CT scans every 3 months. The other patients died due to disease progression (2/6 ATC, 2/2 PDTC) or hemorrhage (grade IV SAE, patient 5, Table 3). ATC patient 8 was resistant to the treatment. ATC patients 1 and 6 died shortly after discontinuation of the lenvatinib treatment caused by lenvatinib intolerance in patient 6 (grade III anorexia), and because lenvatinib had to be discontinued due to an infectious complication after a knee surgery in patient 1 (Table 3). The median PFS for the total cohort was 17.6 months, and the median OS was 19 months (Fig. 2). Data analysis for ATC only showed a median PFS of 16.8 months and a median OS of 17.3 months (Fig. 2).\n\nFIG. 2. Kaplan–Meier curves for ATCs only and total patients. (A) PFS in all patients and ATC only. (B) OS in all patients and ATC only. ATC, anaplastic thyroid carcinoma; OS, overall survival; PFS, progression-free survival.\n\nBiomarkers\n\nTo assess potential predictors of treatment response, we investigated the PD-L1 expression of the tumor cells and macrophages/immune cells. Furthermore, WES was performed in 7 of 8 patients, and sequences were compared to germ line sequences to assess somatic mutations and the TMB. In 1 patient (1/8), targeted sequencing for 11 frequently mutated genes (Supplementary Table S1) was performed due to low material. All tumors were positive for PD-L1 expression with a TPS ranging from 1% to 90%, and 5 of 8 patients with TPS >50% (Table 4). The CPS ranged from 5 to 100 (Table 4). Interestingly, the ATC patient with the lowest TPS (1%) and CPS 5 did not respond to the treatment (patient 8). In contrast, the patients with responses lasting more than two years and those achieving a CR all had PD-L1 TPS >50% (5/8), a CPS >75 (3/8), or a high mutation frequency above 5 mutations per megabase (3/8). The patient (patient 2) with the highest number of mutations (>1400 somatic mutations) has the longest CR duration (30 months).\n\nTable 4. Biomarker Analysis\n\nPatient\tORR after 3/4 months (RECIST 1.1)\tBOR (CT/MRI/PET-CT)\tResponse according to PET-CT\tTPS, %\tCPS\tSomatic mutations\tTMB (mutations/Mb)\t\n1\tPR\tPR\tPR\t50\t40\t106\t13.79\t\n2\tPR\tCR\tCR\t60\t75\t1447\t81.87\t\n3\tPR\tPR\tPR\t10\t10\t79\t4.08\t\n4\tPR\tCR\tCR\t90\t100\t19\t3\t\n5\tPR\tCR\tn.a.\t80\t100\t29\t3.3\t\n6\tSD\tSD\tn.a.\t60\t65\t24\t3.58\t\n7\tPR\tCR\tCR\t5\t7\t138\t5.59\t\n8\tPD\tPD\tn.a.\t1\t5\tn.a.\tn.a.\t\nCPS, combined proportion score; MRI, magnet resonance tomography; n.a., not applicable; TMB, tumor mutation burden; TPS, tumor proportion score.\n\nDiscussion\n\nCurrent treatment options for ATC are limited, and response rates are low and short-lived, with marginal to absent CR (13,14). Only the small proportion of BRAFV600E-mutated ATC (about 20%) can be effectively treated with a BRAF/MEK inhibitor combination of dabrafenib and trametinib (10,11), but for the other 70–80% of ATCs, no treatment options are approved after chemotherapy failure in most countries.\n\nATC and PDTC are characterized by a very high proliferation rate and tumor invasiveness, driven by concurrent mutations in several pro-proliferative pathways (RAS, WNT, loss of TP53), and strongly activated VEGF/FGF signaling. PD-L1 and TMB are upregulated, but the response to single immune checkpoint inhibition often comes too late and is overrun by the aggressiveness of the disease (36).\n\nWhile many kinase inhibitors (sorafenib/pazopanib) failed to show treatment efficacy in ATC (30–32), lenvatinib trials demonstrated some promising effects, with 17.4–43% PRs and up to 50% SD (27–29). CRs were absent and PFS lasted only between 77 days and 7.4 months (27–29). Besides its fast, but short-lived antiproliferative effects, lenvatinib was shown to improve immune responses to immune checkpoint inhibitors in mice. Therefore, by combining both agents, we aimed to use lenvatinib as a fast and effective bridging treatment and immuno-sensitizer for the immune checkpoint inhibitor pembrolizumab in ATC/PDTC patients.\n\nIn contrast to single-agent therapy, the combination of lenvatinib and pembrolizumab was highly effective in our treatment cohort. Eight ATC/PDTC patients who had previously been treated with several lines of therapy including chemotherapy, chemoirradiation, and even single immune checkpoint inhibition (1/8) received a combination of lenvatinib and pembrolizumab for a maximum of 40 months. The combination treatment was well tolerated and could be sustained over one year in half of the patients, and even over two years in 37% (3/8) of the patients. Half of the ATC patients (3/6) were still on therapy at data cutoff with no sustained grade III/IV toxicities despite having initially metastatic disease; three patients had confirmed CR by PET/CT and/or histopathologic examination of former metastatic sites. Seventy-five percent of all patients and 66% of the ATC patients reached a PR/CR within 16 months of treatment. The remission rates observed with lenvatinib/pembrolizumab combination in ATC/PDTC are similar to previously published data for other heavily pretreated solid tumors, such as patients with head and neck tumors, endometrial, renal cell, or hepatocellular carcinoma (39–42). As CRs and long-lasting remissions were rarely observed in ATC patients treated with lenvatinib only (27–29), the addition of pembrolizumab is most likely inducing this effect.\n\nIn patients who are already resistant to TKI treatment, the addition of pembrolizumab is only partially functional with a PFS of only 2.96 months (43), which indicates that the up-front combination of lenvatinib and pembrolizumab might be much more effective than using these drugs sequentially.\n\nTMB and PD-L1 expression levels (TPS/CPS) are independent biomarkers for response to immune checkpoint inhibitors in solid tumors (30,46,47). In our analysis, patients reaching a CR or those who had long-term remission over two years all had a TPS above 50%, a CPS higher than 75, and/or a TMB >5/MB, indicating that those may be biomarkers for response to lenvatinib/pembrolizumab treatment in ATC/PDTC.\n\nIn general, the combination of lenvatinib and pembrolizumab was well tolerated even in the elderly patients with a higher ECOG performance status. Results are encouraging with an ORR of 75%, including a CR rate of 50% (66% in ATCs) and responses over 2 years. Therefore, the treatment results and biomarkers will be further evaluated in a phase II clinical trial with lenvatinib and pembrolizumab in ATC/PDTC patients (ATLEP trial, Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab, EudraCT No. 2017-004570-34).\n\nSupplementary Material\n\nSupplemental data\n\nSupplemental data\n\nSupplemental data\n\nSupplemental data\n\nSupplemental data\n\nAcknowledgments\n\nThanks to our patients and relatives for their support for this study. Thanks to Prof. Roland Mertelsmann for his continuous support and wisdom. Thanks to the molecular tumor board and the CCCF for their support.\n\nAuthors' Contributions\n\nC.D., J.S., C.M., O.T., H.W., and N.B. wrote the article. J.R., C.K., and P.T.M. performed and evaluated PET/CTs. K.A., and S.K. performed PD-L1 staining and evaluation. M.R. designed figures. M.B. and P.M. analyzed WES data. A.Z., P.R., M.K., C.W., T.S., C.S., C.M., C.K., N.B., and K.L. treated patients and revised the article.\n\nAuthor Disclosure Statement\n\nC.D. received honoraria and travel costs for consultancy role at Eisai, AbbVie, and Gilead. M.K. received honoraria and travel costs for consultancy role at Eisai GmbH. A.Z. received honoraria and travel costs for consultancy role at Eisai, J&J, and Merck and participates in the Keynote 158 trial.\n\nFunding Information\n\nResarch funding grant for IIT trials from the University of Freiburg.\n\nSupplementary Material\n\nSupplementary Data\n\nSupplementary Table S1\n\nSupplementary Table S2\n\nSupplementary Table S3\n\nSupplementary Table S4\n==== Refs\nReferences\n\n1. Wendler J, Kroiss M, Gast K, Kreissl MC, Allelein S, Lichtenauer U, Blaser R, Spitzweg C, Fassnacht M, Schott M, Fuhrer D, Tiedje V 2016 Clinical presentation, treatment and outcome of anaplastic thyroid carcinoma: results of a multicenter study in Germany. 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Nature 515 :563–567 25428504\n\n", "fulltext_license": "CC BY", "issn_linking": "1050-7256", "issue": "31(7)", "journal": "Thyroid : official journal of the American Thyroid Association", "keywords": "ATC; PDTC; anaplastic thyroid cancer; lenvatinib; pembrolizumab; poorly differentiated thyroid cancer", "medline_ta": "Thyroid", "mesh_terms": null, "nlm_unique_id": "9104317", "other_id": null, "pages": "1076-1085", "pmc": null, "pmid": "33509020", "pubdate": "2021-07", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "27288464;30913016;27696251;30515783;28383817;29029287;28351340;27718847;25891174;3902203;30638399;27045886;28778959;26629286;23721245;31929884;30762153;27398740;31319771;20200039;26878173;25913680;32913998;30105871;25576899;27926471;10958311;27090296;30895946;28324060;25428504;30832606;31235699;26412456;29372535;25671254;28299283;30922731;29072975;20418080;29996921;23945592", "title": "Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma.", "title_normalized": "combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma" }

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Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma. 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"reactionmeddrapt": "Metastases to kidney", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaplastic thyroid cancer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Dierks C, Seufert J, Aumann K, Ruf J, Klein C, Kiefer S et al.. Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma. 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Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma. THYROID. 2021;31(7):1076-85", "literaturereference_normalized": "combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220302", "receivedate": "20220302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20543320, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "DE-NOVARTISPH-NVSC2022DE048445", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "76959", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (5 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anaplastic thyroid cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "2", "drugtreatmentdurationunit": "802", "medicinalproduct": "CARBOPLATIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (5 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anaplastic thyroid cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "2", "drugtreatmentdurationunit": "802", "medicinalproduct": "PACLITAXEL" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to lung", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to skin", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to bone", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaplastic thyroid cancer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thyroid cancer recurrent", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20180701" } }, "primarysource": { "literaturereference": "Dierks C, Seufert J, Aumann K, Ruf J, Klein C, Kiefer S et al.. Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma. THYROID. 2021;31(7):1076-85", "literaturereference_normalized": "combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220307", "receivedate": "20220307", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20559963, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]

{ "abstract": "Ceftriaxone is a widely used third-generation cephalosporin showing advantageous pharmacokinetic properties and a broad antimicrobial spectrum. We herein report a case of ceftriaxone-induced neurotoxicity in a 56-year-old man on hemodialysis. Seven days after initiating high-dose ceftriaxone, the patient developed impaired consciousness along with facial myoclonus and sporadic phonation. The symptoms clearly disappeared shortly after withdrawal of the drug. Ceftriaxone is considered a safe antibiotic for patients with renal insufficiency, since it is excreted via both haptic and renal pathways. Physicians should note that antibiotic-associated encephalopathy may develop in patients administered ceftriaxone, especially in those complicated with renal dysfunction.", "affiliations": "Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan.;Department of Pharmacy, Osaka University Hospital, Japan.;Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan.;Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan.;Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Japan.;Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Japan.;Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Japan.;Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan.;Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan.", "authors": "Hagiya|Hideharu|H|;Miyawaki|Koji|K|;Yamamoto|Norihisa|N|;Yoshida|Hisao|H|;Kitagawa|Akihiro|A|;Asaoka|Tadafumi|T|;Eguchi|Hidetoshi|H|;Akeda|Yukihiro|Y|;Tomono|Kazunori|K|", "chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.8774-16", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2894356210.2169/internalmedicine.8774-16Case ReportCeftriaxone-induced Neurotoxicity in a Patient after Pancreas-Kidney Transplantation Hagiya Hideharu 1Miyawaki Koji 2Yamamoto Norihisa 1Yoshida Hisao 1Kitagawa Akihiro 3Asaoka Tadafumi 3Eguchi Hidetoshi 3Akeda Yukihiro 1Tomono Kazunori 1\n1 Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, Japan\n2 Department of Pharmacy, Osaka University Hospital, Japan\n3 Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, JapanCorrespondence to Dr.　Hideharu Hagiya, [email protected]\n\n25 9 2017 15 11 2017 56 22 3103 3107 27 12 2016 27 3 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Ceftriaxone is a widely used third-generation cephalosporin showing advantageous pharmacokinetic properties and a broad antimicrobial spectrum. We herein report a case of ceftriaxone-induced neurotoxicity in a 56-year-old man on hemodialysis. Seven days after initiating high-dose ceftriaxone, the patient developed impaired consciousness along with facial myoclonus and sporadic phonation. The symptoms clearly disappeared shortly after withdrawal of the drug. Ceftriaxone is considered a safe antibiotic for patients with renal insufficiency, since it is excreted via both haptic and renal pathways. Physicians should note that antibiotic-associated encephalopathy may develop in patients administered ceftriaxone, especially in those complicated with renal dysfunction. \n\nantibiotic-associated encephalopathyceftriaxonechronic kidney diseasehemodialysisnonconvulsive status epilepticustransplantation\n==== Body\nIntroduction\nCeftriaxone (CTRX) is a common antibiotic frequently used in both in- and outpatients. The pharmacological advantages of CTRX include a broad microbial spectrum, long half-life, and good penetration into systemic tissues, including the central nervous system. In contrast to other beta-lactams, CTRX is metabolized at the liver, and a renal dose adjustment is usually not necessary. In addition, side effects and drug interactions are uncommon. Therefore, it is generally assumed that CTRX can be safely administered to elderly patients, including those with chronic kidney disease (1).\n\nFollowing antimicrobial treatments, some patients may develop antibiotic-associated encephalopathy (AAE). Among beta-lactams, cefepime, a fourth-generation cephalosporin, is known to cause encephalopathy, particularly in elderly patients with renal insufficiency (2,3). According to a previous review, CTRX is listed as a low-to-medium-risk agent based on its structural characteristics (4,5); however, CTRX-associated encephalopathy has rarely been reported. To our knowledge, only 10 such cases have been documented in the literature to date (6-11). In this report, we describe another case of CTRX-induced neurotoxicity complicated by involuntary facial movements.\n\nCase Report\nThe patient was a 56-year-old man (dry body weight: 50.5 kg). He had undergone simultaneous pancreas-kidney transplantation five years earlier, but he was on hemodialysis due to graft failure. One day, he was found to have a low blood pressure and decreased oxygen saturation at a hemodialysis clinic and was immediately transferred to our hospital as an emergency case. On admission, he was alert but in a state of shock. He reported pain in his left chest, which was intensified by deep breaths and dry cough. The patient was prescribed prednisolone (2.5 mg per day), cyclosporine (120 mg per day), mycophenolate mofetil (500 mg per day), and everolimus (1 mg per day). He had no history of neurological disorders or brain surgery. Laboratory results showed elevated serum C-reactive protein levels (CRP, 21.14 mg/dL). A chest radiograph demonstrated permeability decay in his left lower lung, and computed tomography (CT) of his chest revealed diffuse consolidation in the left lower lobe. The patient was diagnosed with septic shock secondary to pneumonia and pleurisy and was hospitalized at an emergency center. Treatment was started empirically with renal doses of meropenem and levofloxacin.\n\nThree days after hospitalization, the patient was moved to a general ward. Although a bacterial culture of his sputum was unremarkable, antibiotic therapy was switched to CTRX (2 g q12h) and minocycline (100 mg q12h) on day 6. Despite antibiotic treatment, the pleural effusion increased, and he underwent paracentesis of the pleural cavity on day 8. The pleural fluid was clear, and a bacterial culture was negative. Nevertheless, the levels of serum inflammatory markers and his body temperature remained high.\n\nOn admission day 13, the patient started to become disoriented and agitated. At that time, he was afebrile, and laboratory data showed the serum CRP level to be 11.1 mg/dL; otherwise, there were no markedly abnormal values. On the same day, continuous air leakage emerged. Chest CT revealed a newly formed pulmonary cavity in the left lower lobe, indicating pulmonary suppuration and a subsequent thoracic empyema. No explanation was found for the patient's altered consciousness, but the patient was subjected to emergency thoracoscopic surgery. Although there was no apparent purulent effusion, pus was found inside the cavity. Postoperatively, the patient was extubated and admitted to an intensive-care unit. The administration of CTRX was continued in combination with levofloxacin (250 mg q48h) and clindamycin (600 mg q6h). Before the operation, he had undergone intermittent hemodialysis three times per week, which was changed to continuous hemodiafiltration postoperatively.\n\nEven after the discontinuation of sedative drugs, his consciousness remained impaired. The patient's conscious state was mostly at E2V2M5 on the Glasgow Coma Scale, but occasionally, he was unresponsive to stimuli or seemed to be confused or agitated. In addition, involuntary facial movements, including rhythmic contractions of the orbicularis oculi muscles and tongue were observed (Supplementary material). Sporadic phonation seemed to be triggered by dispersive contractions of laryngeal muscles. We did not observe convulsion or athetosis. CT and magnetic resonance imaging (MRI) of his head did not reveal any abnormalities; however, an electroencephalogram (EEG) showed bursts of generalized, high-voltage slow-wave activity throughout the measurement period (Fig. 1A). The differential diagnosis included encephalopathy caused by metabolic, renal, and drug-related etiologies, delirium, and a psychogenic reaction. The levels of serum electrolytes, liver function, thyroid function, thiamine, and ammonia were all within normal ranges, while the serum levels of total protein and albumin declined to 5.0 and 2.4 g/dL, respectively. A cerebrospinal fluid examination showed normal findings: initial pressure, 16 cmH2O, cells 1 /μL, protein 36 mg/dL, and glucose 67 mg/dL. Therefore, an adverse drug effect remained a potential cause of the impaired consciousness. Throughout the clinical course, the serum level of cyclosporine was closely monitored and maintained in an appropriate range.\n\nFigure 1. Electroencephalogram (EEG). (A) EEG on day 18. The patient manifested impaired consciousness. Generalized moderate-to-high-amplitude epileptiform bursts continued throughout the test. (B) EEG on day 28. Three days after the patient recovered from unconsciousness. The abnormal spikes completely disappeared, and alpha waves emerged mainly at the occipital lobes.\n\nOn reviewing the patient's course, a high dose of CTRX was continuously administered for 7 days before the patient fell unconscious (usual dose: 1 to 2 g per 24 h). At this point, CTRX-induced neurotoxicity was suspected. The dosage of CTRX was reduced to 2 g per day on day 18, but the patient's condition did not improve. Subsequently, CTRX was discontinued and switched for piperacillin/tazobactam (2.25 g q8h) on day 20. Five days after the cessation of treatment with CTRX, the patient recovered completely. He was still slightly febrile (37.6℃), but his general condition and vital signs were stable, and his serum CRP level decreased to 3.5 mg/dL. A follow-up EEG showed no abnormal patterns (Fig. 1B), and no neurological symptoms recurred until his discharge from the hospital. The patient's clinical course is illustrated in Fig. 2.\n\nFigure 2. Clinical course of the presented patient. Seven days after initiating CTRX, the patient developed impaired consciousness (day 13). He remained unconscious postoperatively but regained consciousness to a full level (GCS, E4V5M6) 5 days after the cessation of CTRX treatment. Aside from antibiotics, the patient did not receive any drugs continuously after hospitalization. CLDM: clindamycin, CTRX: ceftriaxone, GCS: Glasgow Coma Scale, LVFX: levofloxacin, MEPM: meropenem, MINO: minocycline, PIPC/TAZ: piperacillin/tazobactam\n\nDiscussion\nWe encountered a case of CTRX-associated neurotoxicity occurring in a patient after pancreas-kidney transplantation. The onset and resolution of the neurological symptoms appeared to be closely related to the initiation and discontinuation of CTRX administration, and the EEG findings were similar to previous cases (6,9). Although one or more of the other drugs concurrently administered with CTRX (cyclosporine, meropenem, levofloxacin, and minocycline) might have potentially caused the encephalopathy, the influence of any of these drugs seemed unlikely, given the clinical course.\n\nNeurological complications are relatively common after solid organ transplantations, appearing in approximately one-third of such patients (12). Frequent etiologies include immunosuppressive agents (e.g. calcineurin inhibitors), central nervous system infections, and encephalopathy. In particular, the differential diagnosis of neural involvement in the late phase (>6 months) includes viral (Herpes simplex virus, Cytomegalovirus, Epstein-Barr virus, Varicella-zoster virus, and progressive multifocal leukoencephalopathy by JC polyomavirus), fungal (Cryptococcus neoformans, Aspergillus spp., and Mucor), and parasitic (Toxoplasma gondii, Amebiasis, Strongyloides stercoralis) infections (13). In addition, neoplastic etiologies such as post-transplantation lymphoproliferative disorder should also be considered.\n\nTable summarizes the present and previous cases of CTRX-induced neurotoxicity (6-11). Notably, elderly patients with chronic kidney disease are at particularly high risk for drug-associated encephalopathy. Of the 11 cases, 8 (72.7%) were over 60 years of age. In addition, four had chronic kidney disease, and half of the patients were on either hemodialysis or peritoneal dialysis. Renal insufficiency is in general a common factor for AAE; 25% of all cases of AAE and over 70% of cephalosporin-associated cases have been associated with renal insufficiency (14). A possible reason for the association between renal insufficiency and AAE is impaired biliary excretion in patients with renal dysfunction (5). Impaired biliary excretion may be responsible for the delayed elimination of CTRX, and a subsequently higher serum concentration of the drug can trigger the neurotoxicity.\n\nTable. Summary of Reported Cases of Ceftriaxone (CTRX)-induced Neurotoxicity.\n\nCase\tAge\tSex\tRenal function\tDose of CTRX (g/day)\tNeurological manifestation\tDays to onset\tDays to remission\tTreatment\tReference\t\n1\t83\tF\tCKD\t2\tAltered mental status, myoclonus\t4\t5\tDiscontinue, AED\t6\t\n2\t78\tF\tCKD\t2\tAltered mental status, myoclonus\t6\t5\tDiscontinue, AED\t6\t\n3\t60\tF\tCKD\t2\tAltered mental status\t4\t3\tDiscontinue\t7\t\n4\t80\tF\tHemodialysis\t4\tChoreoathetosis\t5\t12\tDiscontinue\t8\t\n5\t72\tF\tHemodialysis\t1\tChoreoathetosis\t2\t1\tDiscontinue\t8\t\n6\t76\tM\tHemodialysis\t2\tChoreoathetosis\t6\tnd\tDiscontinue\t8\t\n7\t76\tM\tHemodialysis\t2\tChoreoathetosis\t5\t2\tDiscontinue\t8\t\n8\t65\tF\tCKD\t2\tGeneralized myoclonic jerks\t5\t2\tDiscontinue\t9\t\n9\t8\tM\tNormal\t1\tAltered mental status\t3\t3\tDiscontinue\t10\t\n10\t37\tF\tPeritoneal dialysis\t2\tAgitation, paranoia, visual hallucination\t3\t1.5\tDiscontinue\t11\t\n11\t56\tM\tHemodialysis\t4\tAltered mental status, Facial myoclonus, sporadic phonation\t7\t5\tDiscontinue\tPresent case\t\nNeurological prognosis of the patients were all favorable.\n\nAED: anti-epileptic drug, CKD: chronic kidney disease, nd: not described\n\nAn excessive dosage can be another predisposing factor for cephalosporin-associated neurotoxicity (15-17). However, the dosages of CTRX administered in the reported cases were mostly normal (≤2 g per day in 8 of 10 adult cases in Table). Thus, the relationship between overdose of the drug and neurotoxicity is uncertain. As few or no reports on the previous CTRX-associated encephalopathy measured the serum concentration of the drug, the association between the serum concentration and neurotoxicity is inconclusive.\n\nAlthough the pathophysiological mechanisms of cephalosporin-associated neurotoxicity have yet to be fully elucidated, beta-lactam associated encephalopathy is believed to be related to the competitive inhibition of γ-aminobutyric acid in brain tissues (15). CTRX penetrates efficiently into the central nervous system and can trigger increased neural excitability even at normal dosages.\n\nOnce recognized, AAE is easily treatable by discontinuing the offending drugs. However, the early diagnosis of CTRX-induced neurotoxicity is challenging for three reasons. First, many clinicians are unaware of this rare adverse effect related to CTRX. Second, the clinical presentations may vary among patients; reported symptoms include altered mental status (6 cases), choreoathetosis (4 cases), and myoclonus (4 cases) (Table). Interestingly, our patient manifested facial myoclonus along with sporadic phonation. Third, radiographic and cerebrospinal fluid examinations do not provide any useful information for the diagnosis. Findings based on EEGs, although not specific, may aid in the diagnosis.\n\nPatients' clinical courses provide the strongest basis for the diagnosis of AAE. The time spans to both the onset and amelioration of AAE have been reported to be 5 days in the median for most offending antibiotics (14). In previous cases of CTRX-induced neurotoxicity, the administration periods before the onset of neurological symptoms were 2 to 6 days, and clinical improvement was seen 1 to 12 days after cessation of the drug (9). In our case, the patient developed neurologic symptoms 7 days after initiation and recovered 5 days after the discontinuation of the drug. Rigorous documentation and observation of the patient's course can therefore lead to a definitive diagnosis of CTRX-induced neurotoxicity.\n\nSpecific treatment for CTRX-induced neurotoxicity may not be available. Hemodialysis is ineffective, as CTRX binds well to serum albumin and therefore cannot be removed from the blood (1). As such, discontinuation of the offending drug following an early diagnosis is crucial (14).\n\nIn conclusion, this report illustrated a case of CTRX-induced transient encephalopathy that involved a patient on hemodialysis. Although CTRX is a widely available and potent antibiotic in various clinical settings, clinicians need to be aware that patients with an impaired renal function may develop neurotoxicity. The clinical manifestations may be subtle or nonspecific, and therefore, the diagnosis of the adverse event is challenging; however, the early recognition followed by the discontinuation of the causal drug can lead to a rapid recovery. Close observation of a patient's clinical course can provide essential cues regarding the diagnosis.\n\n\nInformed consent was obtained from the patient for the publication of this case.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nSupplementary Materials\nVideo file for the involuntary facial movements Rhythmic contractions of orbicularis oculi muscles and tongue were observed.\n\nClick here for additional data file.\n==== Refs\n1. \nPatel I , Sugihara J , Weinfeld R , Wong E , Siemsen A , Berman S \nCeftriaxone pharmacokinetics in patients with various degrees of renal impairment . Antimicrob Agents Chemother \n25 : 438 -442 , 1984 .6329080 \n2. \nLam S , Gomolin IH \nCefepime neurotoxicity: case report, pharmacokinetic considerations, and literature review . Pharmacotherapy \n26 : 1169 -1174 , 2006 .16863493 \n3. \nKim S-Y , Lee I-S , Park SL , Lee J \nCefepime neurotoxicity in patients with renal insufficiency . Ann Rehabil Med \n36 : 159 -162 , 2012 .22506251 \n4. \nChow K , Hui A , Szeto C \nNeurotoxicity induced by beta-lactam antibiotics: from bench to bedside . Eur J Clin Microbiol Infect Dis \n24 : 649 -653 , 2005 .16261307 \n5. \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 \n6. \nMartínez-Rodríguez 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 \n7. \nRoncon-Albuquerque Jr R , 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 \n8. \nSato Y , Morita H , Wakasugi H , et al \nReversible chreoathetosis after the administration of ceftriaxone sodium in patients with end-stage renal disease . Am J Med Sci \n340 : 382 -384 , 2010 .20724905 \n9. \nKim KB , Kim SM , Park W , Kim JS , Kwon SK , Kim H-Y \nCeftiaxone-induced neurotoxicity: case report, pharmacokinetic considerations, and literature review . J Korean Med Sci \n27 : 1120 -1123 , 2012 .22969263 \n10. \nSharma N , Batish S , Gupta A \nCeftriaxone-induced acute reversible encephalopathy in a patient with enteric fever . Indian J Pharmacol \n44 : 124 , 2012 .22345886 \n11. \nSafadi S , Mao M , Dillon JJ \nCeftriaxone-induced acute encephalopathy in a peritoneal dialysis patient . Case Rep Nephrol \n2014 : 108185 , 2014 .25544915 \n12. \nMarco S , Cecilia F , Patrizia B \nNeurologic complications after solid organ transplantation . Transpl Int \n22 : 269 -278 , 2009 .19076332 \n13. \nPruitt AA , Graus F , Rosenfeld MR \nNeurological complications of solid organ transplantation . Neurohospitalist \n3 : 152 -166 , 2013 .24167649 \n14. \nBhattacharyya S , Darby RR , Raibagkar P , Castro LNG , Berkowitz AL \nAntibiotic-associated encephalopathy . Neurology \n86 : 963 -971 , 2016 .26888997 \n15. \nWallace KL \nAntibiotic-induced convulsions . Crit Care Clin \n13 : 741 -762 , 1997 .9330839 \n16. \nSchliamser SE , Cars O , Norrby SR \nNeurotoxicity of Β-lactam antibiotics: predisposing factors and pathogenesis . J Antimicrob Chemother \n27 : 405 -425 , 1991 .1856121 \n17. \nCalandra G , Lydick E , Carrigan J , Weiss L , Guess H \nFactors predisposing to seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/cilastatin . Am J Med \n84 : 911 -918 , 1988 .3284342\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "56(22)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "antibiotic-associated encephalopathy; ceftriaxone; chronic kidney disease; hemodialysis; nonconvulsive status epilepticus; transplantation", "medline_ta": "Intern Med", "mesh_terms": "D000900:Anti-Bacterial Agents; D001927:Brain Diseases; D002443:Ceftriaxone; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D006435:Renal Dialysis", "nlm_unique_id": "9204241", "other_id": null, "pages": "3103-3107", "pmc": null, "pmid": "28943562", "pubdate": "2017-11-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19033476;19299850;22969263;16863493;3284342;11498064;6329080;1856121;22506251;22345886;24167649;9330839;16261307;26888997;19076332;25544915;20724905", "title": "Ceftriaxone-induced Neurotoxicity in a Patient after Pancreas-Kidney Transplantation.", "title_normalized": "ceftriaxone induced neurotoxicity in a patient after pancreas kidney transplantation" }

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"1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HAGIYA, H.. CEFTRIAXONE-INDUCED NEUROTOXICITY IN A PATIENT AFTER PANCREAS-KIDNEY TRANSPLANTATION. INTERNAL MEDICINE. 2017?56 (22):3103-3107", "literaturereference_normalized": "ceftriaxone induced neurotoxicity in a patient after pancreas kidney transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181008", "receivedate": "20171205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14252726, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" }, { "companynumb": "JP-ALVOGEN-2017-ALVOGEN-093741", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", 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CEFTRIAXONE-INDUCED NEUROTOXICITY IN A PATIENT AFTER?PANCREAS-KIDNEY TRANSPLANTATION. INTERN MED. 2017 SEP 25.", "literaturereference_normalized": "ceftriaxone induced neurotoxicity in a patient after pancreas kidney transplantation", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20171013", "receivedate": "20171013", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14084712, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "JP-ACS-000876", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": 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{ "abstract": "Capecitabine, an oral prodrug of 5-fluorouracil (5FU), has been integrated into the management of multiple cancer types because of convenience of administration and efficacy comparable with 5fu. Cardiotoxicity induced by 5FU-in particular angina-has been well described in the literature, but reports of adverse cardiac events with capecitabine are also emerging. The mechanism underlying 5FU cardiotoxicity has long been thought to result from coronary vasospasm, but animal-model studies and patient echocardiographic findings both suggest a cardiomyopathic picture. Although 5FU cardiotoxicity is often reversible and can be managed supportively, presentations that are more severe-including arrhythmias, acute ischemic events, and cardiogenic shock-have been documented. In this report, we describe the case of a patient who ultimately required a pacemaker after developing symptomatic bradycardia and sinus arrest while receiving capecitabine for colon cancer.", "affiliations": "Department of Oncology, McGill University Health Centre, Montreal, QC.", "authors": "Ang|C|C|;Kornbluth|M|M|;Thirlwell|M P|MP|;Rajan|R D|RD|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3747/co.v17i1.437", "fulltext": "\n==== Front\nCurr OncolCOCurrent Oncology1198-00521718-7729Multimed Inc. 66 Martin St. Milton, ON, Canada L9T 2R2 20179805conc17-1-59Case ReportCapecitabine-induced cardiotoxicity: case report and review of the literature Ang C. MD*Kornbluth M. MD†Thirlwell M.P. MD*Rajan R.D. MD** Department of Oncology, McGill University Health Centre, Montreal, QC† Department of Cardiology, McGill University Health Centre, Montreal, QCCorresponding author: Raghu Rajan, Department of Oncology, McGill University, Montreal General Hospital, Room A7-130, Medical Oncology, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4., E-mail: \[email protected] 2010 17 1 59 63 2010 Multimed Inc.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.Capecitabine, an oral prodrug of 5-fluorouracil (5fu), has been integrated into the management of multiple cancer types because of convenience of administration and efficacy comparable with 5fu. Cardiotoxicity induced by 5fu—in particular angina—has been well described in the literature, but reports of adverse cardiac events with capecitabine are also emerging. The mechanism underlying 5fu cardiotoxicity has long been thought to result from coronary vasospasm, but animal-model studies and patient echocardiographic findings both suggest a cardiomyopathic picture. Although 5fu cardiotoxicity is often reversible and can be managed supportively, presentations that are more severe—including arrhythmias, acute ischemic events, and cardiogenic shock—have been documented. In this report, we describe the case of a patient who ultimately required a pacemaker after developing symptomatic bradycardia and sinus arrest while receiving capecitabine for colon cancer.\n\n5-Fluorouracilcapecitabinecardiotoxicitychemotherapy\n==== Body\n1. CASE DESCRIPTION\nA 75-year-old man with known hypertension, diabetes, and dyslipidemia was diagnosed with a stage iiib rectosigmoid adenocarcinoma in July 2007. He underwent a lower anterior resection, and 12 cycles of modified folfox-6 [oxaliplatin 85 mg/m2, 5-fluorouracil (5fu) 400 mg/m2 bolus, and leucovorin (lv) 400 mg/m2, followed by 5fu 2.4 g/m2 by continuous infusion over 46 hours] adjuvant chemotherapy were planned.\n\nFollowing chemotherapy cycle 7 in late January 2008, the patient developed atrial fibrillation, and he was admitted to the coronary care unit (ccu) at the Montreal General Hospital. At that time, echocardiography revealed an ejection fraction of 55%–60%, mild left ventricular diastolic dysfunction, and mild mitral regurgitation, with otherwise normal readings. He was converted to sinus rhythm on oral sotalol (80 mg twice daily), with the plan to initiate anticoagulation upon completion of chemotherapy. One week post discharge, he developed an upper extremity deep venous thrombosis on the side of his implanted catheter, and he was started on dalteparin. Two weeks later, his chemotherapy was changed to capecitabine monotherapy at 1500 mg/m2 twice daily.\n\nAbout 6 days after starting capecitabine, the patient had a syncopal episode lasting approximately 2 minutes. He recovered spontaneously and, after some transient disorientation, returned to his baseline mental status. A few hours later, he experienced two presyncopal episodes accompanied by flushing and dizziness. He went to the emergency department, where he was found to have bradycardia at 54 bpm, although he was hemodynamically stable with a blood pressure of 140/79 mmHg. Initial blood work did not reveal any electrolyte abnormalities or tropinemia. An electrocardiogram demonstrated sinus bradycardia (Figure 1).\n\nWhile on telemetry, the patient had a witnessed episode of presyncope associated with a pulse of 30–40 bpm and systolic pressure between 160– 170 mmHg. With the exception of sotalol, he received the evening doses of all of his other medications (capecitabine, metformin, venlafaxine, and valsartan) and was kept in the emergency department overnight for monitoring. Approximately 6 hours later, he had a sinus arrest of 15 s, from which he spontaneously recovered (Figure 2). Transcutaneous pacemaker pads were placed, and he was transferred to the ccu with atropine at the bedside. All medications were subsequently held.\n\nThe rest of the night was uneventful, but the following morning he had recurrent episodes of symptomatic bradycardia followed by another sinus arrest lasting 10 s. A transvenous pacemaker was inserted followed by a permanent pacemaker a few days later. Sotalol was resumed, and he was discharged without any further complications. He remains in clinical remission from his malignancy, and no further chemotherapy is planned.\n\n2. DISCUSSION\nCoronary vasospasm resulting in angina and even myocardial infarction is a well-known adverse effect of 5fu. Although cardiotoxicity is often reversible with discontinuation of 5fu and application of supportive care 1, the condition has the potential to be fatal. Reported overall mortality rates range from 2.2% to as high as 13.3% 2. The incidence of 5fu-induced cardiotoxicity in the literature ranges from 1.2% to 18%, although its true incidence may actually be higher, given that silent, reversible ST segment deviations on electrocardiography are known to occur 3,4. Other manifestations of 5fu-induced cardiotoxicity include heart failure, hyper- or hypotension, cardiomyopathy, arrhythmias, conduction disturbances, and cardiac arrest 5. However, these latter cardiac adverse events have been reported much less frequently.\n\nCapecitabine is an oral prodrug that is converted to 5fu in a sequential 3-step enzymatic reaction that occurs primarily in the liver and in tumour cells. It has gained popularity because of its efficacy, ease of administration, and milder toxicity profile as compared with 5fu 6. However, as the use of capecitabine becomes more widespread, the rare but significant cardiotoxic potential of the drug is beginning to surface. In a retrospective analysis performed on studies of patients undergoing chemotherapy for metastatic breast and colon cancer, the incidence of cardiotoxicity with capecitabine was found to be comparable to that of 5fu–lv 7. Wijesinghe et al. 8 reported an acute coronary syndrome in a patient with no history of cardiovascular disease who had been on capecitabine for only 2 days. Kosmas et al. 5 documented myocardial infarction, electrocardiographic abnormalities, and ventricular extrasystoles in patients on capecitabine. Furthermore, Goldsmith et al. 9 recently reported exercise-induced global myocardial ischemia with an ejection fraction of 36% in a patient with normal coronary arteries and resting left ventricular function who was on capecitabine for recurrent breast cancer.\n\nWe present the first reported case of a patient who ultimately required a permanent pacemaker after developing symptomatic bradycardia followed by sinus arrest while on capecitabine. Although the patient was taking sotalol, which can itself cause bradycardia and asystole, the sotalol had been started a month before the relevant episode, during which time the patient did not experience any of the noted complications. Given that capecitabine was started less than a week before presentation, it would appear to be the most likely culprit in the absence of other medication changes at the time.\n\nThe clinical manifestations of 5fu cardiotoxicity are frequently attributed to coronary vasospasm. However, anti-vasospastic agents including nitroglycerin and calcium channel blockers have not been consistently effective at relieving symptoms of angina in affected patients 1,5,10. In a study by Freeman et al. 11, ergonovine challenge followed by 5fu infusion did not produce coronary vasospasm in a patient who had developed severe chest pain and ischemic electrocardiographic changes. In vivo studies in animal models have also provided evidence suggesting that mechanisms aside from coronary vasospasm may be responsible. Tsibiribi et al. 12 subjected rabbits to either bolus or infusional 5fu. Rabbits that received the bolus suffered massive hemorrhagic myocardial infarcts with evidence of proximal coronary vasospasm. In contrast, animals in the infusion group demonstrated histologic changes consistent with toxic myocarditis. In addition, echocardiographic studies in patients with 5fu cardiotoxicity have revealed decreased ejection fraction and significant global or regional left ventricular dysfunction consistent with a cardiomyopathic picture 13,14.\n\nThe metabolites of 5fu have been implicated in mediating cardiac damage, in particular fluoroacetate (fac), which is known to be directly myocardiotoxic 15. Fluoroacetate is converted into an inhibitor of citrate metabolism 16 and interestingly, intramyocardial citrate accumulation has been found in guinea pig recipients of 5fu 17. A report by de Forni et al. 18 also noted a trend toward increased urinary excretion of fac during 5fu administration in 14 patients, including 6 who developed cardiotoxicity, although there was no strict temporal relationship with symptom onset. Other hypothesized mechanisms that are undergoing further investigation include the possibility of an autoimmune reaction, endothelial damage, and a procoagulable effect of 5fu 19,20.\n\nThe route of administration, the dose intensity, and the schedule of 5fu also appear to influence the development of cardiotoxicity. In studies by Jensen et al. 2 and Kosmas et al. 5, a higher frequency of symptoms was recorded with continuous 5fu infusions (24 hours) than with shorter (<3 hours) infusions. Given that the pharmacokinetics of capecitabine mimic a continuous 5fu infusion, it is not surprising that the frequency of cardiac symptoms noted with capecitabine is similar to that with the 24-hour infusion 5. Higher doses of 5fu were associated with earlier symptom onset, and a weak trend toward longer symptom duration with capecitabine than with intravenous 5fu was also observed 2.\n\nDrug pharmacokinetics and pharmacodynamics should also be considered to be additional factors that may predispose patients to developing cardiotoxicity with capecitabine. Lethal gastrointestinal toxicities have been reported with capecitabine, which have been attributed to a deficiency of dihydropyridine dehydrogenase (dpd), the first enzymatic step in 5fu catabolism 21. Cytidine deaminase (cda) is a critical enzyme for the activation of capecitabine in hepatocytes and tumour cells. Excessive levels of cda resulting in overmetabolism of capecitabine into 5fu could explain the development of severe toxicities even in patients who are not dpd-deficient 22. Interestingly, geographic differences in tolerance to capecitabine have been documented, with the highest rates of toxicity occurring in American patients and the lowest in East Asian patients 23. Although cultural and dietary differences, in addition to regional variations in the reporting of toxicities, may have contributed to these observations, polymorphisms in the genes responsible for 5fu and capecitabine metabolism may have been a factor as well 23.\n\nThe patient presented here received capecitabine after experiencing a cardiac event (atrial fibrillation) while on 5fu. It is unclear whether his atrial fibrillation was a result of exposure to 5fu. Although the patient had risk factors for coronary artery disease, he never exhibited clinical, electrocardiographic, or laboratory abnormalities to suggest that ischemia contributed to his conduction abnormalities. Nevertheless, this case raises several important issues, the first of which is how one might identify patients who may be at risk of developing cardiotoxicity on 5fu. In some studies, a history of heart disease was a risk factor for experiencing a higher incidence and grade of cardiotoxicity 2,24,25. Conversely, Tsibiribi et al. reported symptoms of cardiotoxicity in 16 patients with no prior cardiac history 26. Other risk factors include advanced age, renal insufficiency 2, and mediastinal irradiation (which induces coronary artery intraluminal hyperplasia and collagen deposition 27). In view of what is being learned about the pharmacokinetics of capecitabine and 5fu, the measurement of key enzymes such as dpd and cda might eventually become important in helping to predict—and hopefully spare patients from—severe toxicities resulting from these drugs.\n\nAnother issue relates to monitoring while on therapy, with the goal of detecting preclinical markers of toxicity. Holubec et al. 28 recently evaluated the utility of measuring brain natriuretic peptide (bnp) and troponin I (tni) in patients receiving 5fu-based chemotherapy for colorectal cancer. In that study, 57% of patients were found to have laboratory evidence of ischemia and heart failure. Upon questioning, patients recalled transient symptoms of angina, dyspnea, and edema, although the timing of biomarker elevation and symptom onset was not precisely defined. Given the high incidence of cardiotoxicity that was observed, the authors proposed that all patients for whom 5fu chemotherapy is planned should undergo baseline electrocardiographic screening or, in those with prior cardiac history, echocardiography. They also suggested that tni and bnp be monitored throughout the course of chemotherapy as surrogate markers of cardiotoxicity.\n\nFinally, there is the question of rechallenging and giving prophylaxis to patients who have experienced cardiotoxicity but who nevertheless stand to benefit from 5fu. Cianci et al. 29 successfully re-administered 5fu to 3 patients who developed symptoms of angina during the initial infusion— albeit using reduced doses administered together with prophylactic trans-epidermal nitroglycerin. In another case series of 6 patients who developed transient asymptomatic bradycardia on infusional 5fu, 4 patients were able to continue treatment, but 2 had to change their regimen because of persistent and recurring bradycardia with subsequent cycles 30. Patients in series reporting more severe cardiotoxicity, such as myocardial infarction, were not rechallenged 7,31. In such patients, for whom a rechallenge of 5fu or capecitabine seems too risky, raltitrexed appears to be a viable substitute 25.\n\n3. CONCLUSIONS\nIn summary, cardiotoxicity induced by 5fu or capecitabine has multiple manifestations and may occur more frequently than previously reported. Although this cardiotoxicity is transient and often reversible, it has the potential to cause serious morbidity and even mortality. There are currently no published guidelines for screening, monitoring, and prophylaxis. Decisions with respect to managing and rechallenging patients who have developed cardiotoxicity on 5fu must be made on an individual basis. Oncologists and cardiologists alike must maintain a heightened awareness of the possibility of this phenomenon and collaborate closely to ensure patient safety.\n\n4. CONFLICT OF INTEREST\nThe authors declare no conflicts of interest.\n\nFIGURE 1 Electrocardiogram taken upon initial presentation of the patient to the emergency department.\n\nFIGURE 2 Electrocardiogram showing development of sinus bradycardia followed by sinus arrest 6 hours after the patient took capecitabine.\n==== Refs\n5. REFERENCES\n1 Robben NC Pippas AW Moore JO The syndrome of 5-fluorouracil cardiotoxicity: an elusive cardiopathy Cancer 1993 71 493 509 8422644 \n2 Jensen SA Sorensen JB Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine Cancer Chemother Pharmacol 2006 58 487 93 16418875 \n3 Akhtar SS Salim KP Bano ZA Symptomatic cardiotoxicity with high-dose 5-fluorouracil infusion: a prospective study Oncology 1993 50 441 4 8233284 \n4 Wacker A Lersch C Scherpinski U Reindl L Seyfarth M High incidence of angina pectoris in patients treated with 5-flurouracil. A planned surveillance study with 102 patients Oncology 2003 65 108 12 12931015 \n5 Kosmas C Kallistratos MS Kopterides P Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study J Cancer Res Clin Oncol 2008 134 75 82 17636329 \n6 Walko CM Lindley C Capecitabine: a review Clin Ther 2005 27 23 44 15763604 \n7 Van Cutsem E Hoff PM Blum JL Abt M Osterwalder B Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil Ann Oncol 2002 13 484 5 11996484 \n8 Wijesinghe N Thompson PI McAlister H Acute coronary syndrome induced by capecitabine therapy Heart Lung Circ 2006 15 337 9 16697705 \n9 Goldsmith YB Roitacher N Baum MS Capecitabine-induced coronary vasospasm J Clin Oncol 2008 17 3802 4 18669470 \n10 Eskilsson J Albertsson M Failure of preventing 5-fluorouracil cardiotoxicity by prophylactic treatment with verapamil Acta Oncol 1990 29 1001 3 2278719 \n11 Freeman NJ Constanza ME 5-Fluorouracil cardiotoxicity Cancer 1998 61 36 45 3275485 \n12 Tsibiribi P Bui–Xuan C Bui–Xuan B Cardiac lesions induced by 5-fluorouracil in the rabbit Hum Exp Toxicol 2006 25 305 9 16866187 \n13 Jakubowski AA Kemeny N Hypotension as a manifestation of cardiotoxicity in three patients receiving cisplatin and 5-fluorouracil Cancer 1988 62 266 9 3383127 \n14 Patel B Kloner RA Ensley J Al-Sarraf M Kish J Wynne J 5-Fluorouracil cardiotoxicity: left ventricular dysfunction and effect of coronary vasodilators Am J Med Sci 1987 294 238 43 3661619 \n15 Lemaire L Malet–Martino MC de Forni M Martino R Lasserre B Cardiotoxicity of 5-fluorouracil vials stems from alkaline hydrolysis of this drug Br J Cancer 1992 66 119 27 1637660 \n16 Mukherjee KL Heidelberger C Studies on fluorinated pyrimidines ix—the degradation of 5-fluorouracil J Biol Chem 1960 235 433 7 14425080 \n17 Matsubara I Kamiya J Imai S Cardiotoxic effects of 5-fluorouracil in the guinea pig Jap J Pharmacol 1980 30 871 9 7241861 \n18 de Forni M Malet–Martino MC Jaillais P Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study J Clin Oncol 1992 10 1795 801 1403060 \n19 Kuzel T Esparaz B Green D Kies M Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin Cancer 1990 65 885 9 2297659 \n20 Alter P Herzum M Soufi M Schaefer JR Maisch B Cardiotoxicity of 5-fluorouracil Cardiovasc Hematol Agents Med Chem 2006 4 1 5 16529545 \n21 Ciccolini J Mercier C Dahan L Toxic death-case after capecitabine–oxaliplatin (xelox) administration: probable implication of dihydropyridine dehydrogenase deficiency Cancer Chemother Pharmacol 2006 58 272 5 16292536 \n22 Mercier C Dupuis C Blesius A Early severe toxicities after capecitabine intake: possible implication of a cytidine deaminase extensive metabolizer profile Cancer Chemother Pharmacol 2009 63 1177 80 19107485 \n23 Haller DG Cassidy J Clark SJ Potential regional differences for the tolerability profiles of fluoropyrimidines J Clin Oncol 2008 26 2118 23 18445840 \n24 Labianca R Beretta G Clerici M Fraschini P Luporini G Cardiac toxicity of 5-fluorouracil: a study of 1083 patients Tumori 1982 68 505 10 7168016 \n25 Ng M Cunninham D Norman AR The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (crc) Eur J Cancer 2005 41 1542 6 15978800 \n26 Tsibiribi P Descotes J Lombard–Bohas C Cardiotoxicity of 5-fluorouracil in 1350 patients with no prior history of heart disease Bull Cancer 2006 93 E27 30 16567310 \n27 Galderisi M Marra F Esposito R Lomoriello VS Pardo M de Divitiis O Cancer therapy and cardiotoxicity: the need of serial Doppler echocardiography Cardiovasc Ultrasound 2007 5 4 17254324 \n28 Holubec L JrTopolcan O Finek J Dynamic monitoring of cardio-specific markers and markers of thyroid gland function in cancer patients—a pilot study Anticancer Res 2007 27 1883 6 17649788 \n29 Cianci G Morelli MF Cannita K Prophylactic options in patients with 5-fluorouracil–associated cardiotoxicity Br J Cancer 2003 88 1507 9 12771913 \n30 Talapatra K Rajesh I Rajesh B Selvamani B Subhashini J Transient asymptomatic bradycardia in patients on infusional 5-fluorouracil J Cancer Res Ther 2007 3 169 71 18079582 \n31 Shoemaker LK Arora U Rocha Lima CM 5fu-induced coronary vasospasm Cancer Control 2004 11 46 9 14749623\n\n", "fulltext_license": "CC BY", "issn_linking": "1198-0052", "issue": "17(1)", "journal": "Current oncology (Toronto, Ont.)", "keywords": "5-Fluorouracil; capecitabine; cardiotoxicity; chemotherapy", "medline_ta": "Curr Oncol", "mesh_terms": null, "nlm_unique_id": "9502503", "other_id": null, "pages": "59-63", "pmc": null, "pmid": "20179805", "pubdate": "2010-02", "publication_types": "D016428:Journal Article", "references": "14749623;12771913;8422644;8233284;15978800;18445840;2297659;17636329;16292536;12931015;7241861;16866187;3275485;17254324;15763604;3383127;19107485;3661619;1403060;16529545;7168016;16418875;2278719;16567310;1637660;18079582;11996484;18669470;14425080;16697705;17649788", "title": "Capecitabine-induced cardiotoxicity: case report and review of the literature.", "title_normalized": "capecitabine induced cardiotoxicity case report and review of the literature" }

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{ "abstract": "Distal intramural spread refers to microscopic tumor implantation in the intestinal wall, distal to the inferior edge of a macroscopic tumor but rarely beyond 2 cm. We report a case of rectal cancer with preoperatively diagnosed distant intramural spread to approximately 6.5 cm. A 75-year-old woman diagnosed with upper rectal cancer was scheduled to undergo low anterior resection 5 weeks after initial presentation. However, preoperative digital rectal examination and anoscopy under general anesthesia revealed a rectal tumor 4 cm proximal to the anal verge; adenocarcinoma was diagnosed based on frozen section analysis of the rectal tumor. Therefore, abdominoperineal resection was performed, and histopathological examination confirmed a moderately differentiated adenocarcinoma with distal intramural spread of 6.5 cm. The patient died 18 months postoperatively owing to lung metastasis. Although distal intramural spread is rare and can be difficult to detect prior to surgery, repeated rectal examination, with prompt histological examination of suspicious lesions, can ensure earlier diagnosis to achieve better local control by radical surgery including sufficient distal margin.", "affiliations": "1Department of Surgery, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192 Aichi Japan.;1Department of Surgery, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192 Aichi Japan.;2Department of Pathology, School of Medicine, Fujita Health University, Toyoake, Japan.;2Department of Pathology, School of Medicine, Fujita Health University, Toyoake, Japan.;Department of Surgery, Rokuwa Hospital, Inazawa, Japan.;1Department of Surgery, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192 Aichi Japan.;1Department of Surgery, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192 Aichi Japan.", "authors": "Sato|Harunobu|H|0000-0003-4637-8853;Shiota|Miho|M|;Okabe|Asako|A|;Tsukamoto|Tetsuya|T|;Honda|Katsuyuki|K|;Morise|Zenichi|Z|;Uyama|Ichiro|I|", "chemical_list": null, "country": "Singapore", "delete": false, "doi": "10.1007/s13691-019-00385-3", "fulltext": null, "fulltext_license": null, "issn_linking": "2192-3183", "issue": "9(1)", "journal": "International cancer conference journal", "keywords": "Distal intramural spread; Rectal cancer; Sphincter-preserving operation", "medline_ta": "Int Cancer Conf J", "mesh_terms": null, "nlm_unique_id": "101734231", "other_id": null, "pages": "9-13", "pmc": null, "pmid": "31950010", "pubdate": "2020-01", "publication_types": "D002363:Case Reports", "references": "7648142;7551328;8625118;12620912;23050553;15637735;22067179;8918426;9102256;30022919;15273550;9711965;6831156;26753380;26671688;14685098", "title": "Rectal cancer with extensive distal intramural spread treated by abdominoperineal resection.", "title_normalized": "rectal cancer with extensive distal intramural spread treated by abdominoperineal resection" }

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{ "abstract": "Cystic hygroma is a congenital malformation of the lymphatic system that mostly presents at birth. Though the classic treatment of this condition is surgical excision, recent alternative treatment modalities such as injection of sclerotherapeutic agents (e.g., bleomycin and OK-432) into the lesion has gained popularity due to its safe and effective response profile with minimal side effects. We report a rare complication of repeated bleomycin sclerotherapy in a follow-up patient of cystic hygroma, where the lesion underwent fibrolipomatous conversion with insinuation into multiple fascial planes, causing mass effect by encasement and compression of major vascular and airway structures. This is the first time such a complication of bleomycin sclerotherapy has been reported in literature. Such an unusual presentation reminds us that, in any patient presenting with recurrent gradually increasing swelling with worsening of symptoms following bleomycin sclerotherapy, a possibility of fibrolipomatous conversion of cystic hygroma should be borne in mind.", "affiliations": "Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.;Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.;Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.", "authors": "Reghunath|Anjuna|A|;Ghasi|Rohini G|RG|;Kushvaha|Suchana|S|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/JCAS.JCAS_152_19", "fulltext": "\n==== Front\nJ Cutan Aesthet Surg\nJ Cutan Aesthet Surg\nJCAS\nJournal of Cutaneous and Aesthetic Surgery\n0974-2077 0974-5157 Wolters Kluwer - Medknow India \n\nJCAS-13-229\n10.4103/JCAS.JCAS_152_19\nCase Report\nThe Curious Case of Fibrofatty Conversion of Cystic Hygroma Treated with Bleomycin Sclerotherapy\nReghunath Anjuna Ghasi Rohini G. Kushvaha Suchana Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India\nAddress for correspondence: Dr. Rohini Gupta Ghasi, Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi 110029, India. E-mail: [email protected]\nJul-Sep 2020 \n13 3 229 232\nCopyright: © 2020 Journal of Cutaneous and Aesthetic Surgery2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Abstract\nCystic hygroma is a congenital malformation of the lymphatic system that mostly presents at birth. Though the classic treatment of this condition is surgical excision, recent alternative treatment modalities such as injection of sclerotherapeutic agents (e.g., bleomycin and OK-432) into the lesion has gained popularity due to its safe and effective response profile with minimal side effects. We report a rare complication of repeated bleomycin sclerotherapy in a follow-up patient of cystic hygroma, where the lesion underwent fibrolipomatous conversion with insinuation into multiple fascial planes, causing mass effect by encasement and compression of major vascular and airway structures. This is the first time such a complication of bleomycin sclerotherapy has been reported in literature. Such an unusual presentation reminds us that, in any patient presenting with recurrent gradually increasing swelling with worsening of symptoms following bleomycin sclerotherapy, a possibility of fibrolipomatous conversion of cystic hygroma should be borne in mind.\n\nKeywords:\nBleomycincystic hygromasclerotherapy\n==== Body\nINTRODUCTION\nLymphangiomas are benign hamartomatous lymphatic tumors, which may occur anywhere in the body, though most frequently seen in neck (75%), axilla (20%), and inguinal areas (2%).[1] Cystic hygroma is the most common form of lymphangioma occurring in head and neck region.[2] Sclerotherapy with bleomycin is a favored treatment regime for cystic hygromas, with minimal side effects and good response rate.[2] Fibrolipomatous conversion of cystic hygroma after recurrent bleomycin sclerotherapy has hitherto been unreported in literature. We report an index case of such a complication, which led to worsening of symptoms in the patient.\n\nCASE REPORT\nA 26-year-old male patient presented with a large swelling on the left side of neck along with the complaints of difficulty in breathing and swallowing. The patient was a previously diagnosed case of congenital cystic hygroma [Figure 1], who had undergone surgical excision twice at the age of 6 months and 8 years, only to gradually develop recurrent swellings at the same site. These swellings were treated with bleomycin sclerotherapy every 3 years. However, patient had an apparent “non-response” to sclerotherapeutic agent such as bleomycin since past 4 years, and hence was referred to us for a contrast-enhanced computed tomography (CECT) to ascertain the cause of increasing size of swelling and worsening of symptoms. The clinical provisional diagnosis was a recurrence of cystic hygroma in the patient.\n\nFigure 1 Frontal radiograph of neck and chest of the patient as an infant shows soft tissue swelling along neck, shoulder, axilla, and chest wall on left side, diagnosed as congenital cystic hygroma\n\nCECT of neck and thorax revealed a large non-encapsulated mass located in the left lateral aspect of neck and chest wall and left axilla [Figure 2]. The mass was a predominantly fat attenuation and contained few areas of coarsely calcified tubular soft tissue structures in the posterior aspect of neck and chest wall [Figure 3]. Few linear enhancing soft tissue components were also seen within the lesion.\n\nFigure 2 Three-dimensional volume-rendered CT image of the patient shows a large swelling on the left side of neck and chest wall\n\nFigure 3 CECT reveals a fatty mass in neck, chest wall, and axilla on left extending into superior mediastinum, with linear enhancing soft tissue components (asterisk) (A) and calcified tubular soft tissue structures (red arrow) (B) within. Lesion is also encasing left subclavian and axillary vessels (yellow arrow) (C) with fatty replacement of left sternocleidomastoid, trapezium, and scalene muscles\n\nThe lesion was diffusely infiltrative, and was seen extending from subcutaneous planes into inter- and intramuscular plane without respecting soft tissue planes, with subsequent fatty replacement of left sternocleidomastoid, trapezius, posterior paravertebral, and scalene muscles [Figure 3]. The lesion extended from scalp in left occipital region to D7 vertebral level along the posterior thoracic wall. No bony erosion was observed. Anteriorly, it reached up to the subcutaneous plane in neck and left anterior chest wall, abutting and narrowing left external jugular vein. Left axillary vessels were narrowed. Superomedially, lesion infiltrated into the floor of mouth, left supraglottis, and glottis, causing deviation of airway toward right side along with significant narrowing of airway and obliteration of left pyriform sinus [Figure 4]. Mass effect was present in the form of right-sided deviation of trachea, esophagus, and thyroid gland [Figure 4]. There was insinuation into superior mediastinum with encasement and narrowing of left internal jugular vein, left common carotid artery, and left subclavian artery. Considering the treatment history and imaging findings, a diagnosis of post-sclerotherapy fibrolipomatous conversion of cystic hygroma was made. The patient was planned for lipectomy in view of symptomatic airway compression.\n\nFigure 4 Axial CECT sections depicting lesion infiltration into the floor of mouth, supraglottis (A, B), and glottis (C) on left, causing narrowing and right-sided deviation of airway (yellow arrow) with complete obliteration of left pyriform sinus. Right pyriform sinus is small but visualized (red arrow). There is right-sided deviation of trachea, esophagus, and thyroid gland by lesion with encasement of left common carotid artery and internal jugular vein (IJV), causing progressive narrowing and elongation of vein (green arrow) in contrast to normal right-sided IJV\n\nDISCUSSION\nLymphangiomas are endothelium-lined spaces containing lymph, which can occur anywhere in the body, with the most common sites being head and neck.[3] Landing and Farber classified them into: (1) lymphangioma simplex, consisting of capillary-sized channels; (2) cavernous lymphangioma, comprising dilated lymphatic channels; and (3) cystic hygroma, consisting of multiple cysts with straw-colored fluid within.[3] Cystic hygroma usually presents as a painless congenital mass, which may be complicated with feeding and respiratory difficulty, fever, or sudden increase in size of lesion due to hemorrhage or infection.[2] Ultrasound is the primary imaging modality, which clearly demonstrates the cystic nature. They are mostly multilocular, containing septations of variable thickness.[2] Infected or hemorrhagic lesions may show fluid-fluid level. Both computed tomography (CT) and magnetic resonance imaging ascertain the extent of lesion and relations of the cyst with neurovascular bundle, especially before surgery.\n\nManagement of choice is surgical excision, however, the feasibility of complete excision of lesion is often questionable due to its infiltrative nature.[3] Chances of vital organ injuries, bleeding, infection, and scar formation are highly associated with surgery.[4] A recurrence rate of 15% is reported whenever residual tissue is left behind.[4] Safe and alternative treatment modalities such as sclerotherapy are now preferred, which can be performed in surgically inaccessible lesions also.[1] OK-432 and bleomycin are currently the most favored sclerotherapy agents for treating cystic hygroma.[5] In addition, cauterization, simple drainage or aspiration, radiofrequency ablation, and laser excision are being tried as an alternative to surgery or to reduce the pressure effect on respiratory and feeding passages.[2] Bleomycin is a deoxyribonucleic acid (DNA) synthesis inhibitor with sclerosing effect on endothelial cells due to inflammatory reaction.[6] According to a study by Kumar et al.,[1] response to bleomycin injection on clinical and Doppler assessment was found as excellent, good, or poor based on 100%, >50%, or <50% regression of lesion, respectively.\n\nIn a large systematic review of literature comparing sclerotherapy agents used in vascular malformation of head and neck by Horbach et al.,[7] the most common side effect following sclerotherapy injection was cellulitis and skin ulceration. Facial nerve palsy and skin necrosis were associated with ethanol and OK-432 sclerotherapy. Mean complication rate of bleomycin therapy was 6% in their study, with skin infection, pain, and swelling being common adverse reactions. In another retrospective review by Alomari et al.,[8] no serious side effect was encountered in patients on bleomycin sclerotherapy. Chen et al.[9] observed that high doses of bleomycin injection could lead to pulmonary fibrosis, especially when total cumulative dose exceeds 400 mg. However, to the best of our knowledge, fibrofatty conversion of cystic hygroma, after bleomycin injection, has never been reported in literature before.\n\nAnother condition that simulates the CECT picture as seen in our case is Madelung’s disease, an idiopathic disease where non-encapsulated fat masses are deposited in the face and cervical region.[10] Surgical treatment of Madelung’s disease includes lipectomy and liposuction, especially to remove the mass effect on vital organs.[10] Use of steroids and antiretroviral drugs, which may cause fat deposition, was excluded in our patient.[8] Hence, in any case of suspected non-response to bleomycin sclerotherapy in cystic hygroma or paradoxical increase in size of lesion or symptoms, the possibility of bleomycin-induced fibrofatty conversion of cystic hygroma should be kept in mind and the patient should undergo imaging for evaluation of the same.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Kumar V Kumar P Pandey A Gupta DK Shukla RC Sharma SP Intralesional bleomycin in lymphangioma: an effective and safe non-operative modality of treatment J Cutan Aesthet Surg 2012 5 133 6 23060708 \n2 Mirza B Ijaz L Saleem M Sharif M Sheikh A Cystic hygroma: an overview J Cutan Aesthet Surg 2010 3 139 44 21430825 \n3 Niramis R Watanatittan S Rattanasuwan T Treatment of cystic hygroma by intralesional bleomycin injection: experience in 70 patients Eur J Pediatr Surg 2010 20 178 82 20178075 \n4 Bill AH Jr Sumner DS A unified concept of lymphangioma and cystic hygroma Surg Gynecol Obstet 1965 120 79 86 14259790 \n5 Muir T Kirsten M Fourie P Dippenaar N Ionescu GO Intralesional bleomycin injection (IBI) treatment for haemangiomas and congenital vascular malformations Pediatr Surg Int 2004 19 766 73 14740248 \n6 Okada A Kubota A Fukuzawa M Imura K Kamata S Injection of bleomycin as a primary therapy of cystic lymphangioma J Pediatr Surg 1992 27 440 3 1381746 \n7 Horbach SE Lokhorst MM Saeed P de Goüyon Matignon de Pontouraude CM Rothová A van der Horst CM Sclerotherapy for low-flow vascular malformations of the head and neck: a systematic review of sclerosing agents J Plast Reconstr Aesthet Surg 2016 69 295 304 26723834 \n8 Alomari AI Karian VE Lord DJ Padua HM Burrows PE Percutaneous sclerotherapy for lymphatic malformations: a retrospective analysis of patient-evaluated improvement J Vasc Interv Radiol 2006 17 1639 48 17057006 \n9 Chen WL Huang ZQ Chai Q Zhang DM Wang YY Wang HJ Percutaneous sclerotherapy of massive macrocystic lymphatic malformations of the face and neck using fibrin glue with Ok-432 and bleomycin Int J Oral Maxillofac Surg 2011 40 572 6 21367582 \n10 Mohanty P Vivekanandh K Dash G Mohapatra L Madelung’s disease: a benign symmetric lipomatosis Indian J Dermatol Venereol Leprol 2018 84 190 1 29405131\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0974-2077", "issue": "13(3)", "journal": "Journal of cutaneous and aesthetic surgery", "keywords": "Bleomycin; cystic hygroma; sclerotherapy", "medline_ta": "J Cutan Aesthet Surg", "mesh_terms": null, "nlm_unique_id": "101525405", "other_id": null, "pages": "229-232", "pmc": null, "pmid": "33209001", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "21430825;20178075;14259790;1381746;14740248;17057006;26723834;23060708;29405131;21367582", "title": "The Curious Case of Fibrofatty Conversion of Cystic Hygroma Treated with Bleomycin Sclerotherapy.", "title_normalized": "the curious case of fibrofatty conversion of cystic hygroma treated with bleomycin sclerotherapy" }

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{ "abstract": "BACKGROUND Calcineurin inhibitor-induced posterior reversible encephalopathy syndrome (PRES) is well described in liver and kidney transplant patients, but there is a paucity of data in heart transplant patients. PRES syndrome in the setting of heart transplantation can occur as early as 5 days following transplantation. CASE REPORT A 32-year-old woman who had recently undergone orthotopic heart transplantation developed headaches, visual disturbances, and generalized tonic clonic seizures 5 days after initiating anti-rejection therapy (tacrolimus, mycophenolate, and prednisone). No focal neurological deficits were noted on physical exam. Multifocal subcortical fluid attenuation inversion recovery (FLAIR) hyperintensity signals and areas of diffusion restriction with postcontrast enhancement, diagnostic of PRES, were found on MRI brain. Her symptoms resolved 2 days after tacrolimus was switched to cyclosporine. A follow-up MRI after 6 weeks demonstrated complete resolution of areas of flair hyperintensity signal. She was sent home on a short course of seizure prophylaxis, which was discontinued after the resolution of radiological findings. She had no further episodes of seizures for 6 months following discontinuation of her anti-epileptic regimen. CONCLUSIONS Tacrolimus-induced PRES can occur as early as 5 days after orthotopic heart transplantation. Early recognition of symptoms and management can prevent permanent neurological sequelae.", "affiliations": "Department of Cardiology, Saint Luke's Mid-America Heart Institute, Kansas City, MO, USA.;Department of Cardiovascular Imaging, Saint Luke's Mid-America Heart Institute, Kansas City, MO, USA.;Department of Cardiology, University of Missouri - Kansas City School of Medicine, Saint Luke's Mid America Heart Institute, Kansas City, MO, USA.", "authors": "Ramirez|Rigoberto|R|;Muskula|Preetham Reddy|PR|;Everley|Mark P|MP|", "chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus", "country": "United States", "delete": false, "doi": "10.12659/ajcr.903403", "fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2846549910.12659/AJCR.903403903403ArticlesPosterior Reversible Encephalopathy Syndrome After Orthotopic Heart Transplantation: A Case Report Ramirez Rigoberto E1Muskula Preetham Reddy EF2Everley Mark P. BE31 Department of Cardiology, Saint Luke’s Mid-America Heart Institute, Kansas City,MO, U.S.A.2 Department of Cardiovascular Imaging, Saint Luke’s Mid-America Heart Institute, Kansas City, MO, U.S.A.3 Department of Cardiology, University of Missouri – Kansas City School of Medicine, Saint Luke’s Mid America Heart Institute, Kansas City, MO, U.S.A.Authors’ 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\nCorresponding Author: Preetham R. Muskula, e-mail: [email protected] 03 5 2017 18 487 490 17 1 2017 14 2 2017 © Am J Case Rep, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 32\n\nFinal Diagnosis: Posterior reversible encephalopathy syndrome\n\nSymptoms: Seizures\n\nMedication: Tacrolimus\n\nClinical Procedure: —\n\nSpecialty: Cardiology\n\nObjective:\nRare disease\n\nBackground:\nCalcineurin inhibitor-induced posterior reversible encephalopathy syndrome (PRES) is well described in liver and kidney transplant patients, but there is a paucity of data in heart transplant patients. PRES syndrome in the setting of heart transplantation can occur as early as 5 days following transplantation.\n\nCase Report:\nA 32-year-old woman who had recently undergone orthotopic heart transplantation developed headaches, visual disturbances, and generalized tonic clonic seizures 5 days after initiating anti-rejection therapy (tacrolimus, mycophenolate, and prednisone). No focal neurological deficits were noted on physical exam. Multifocal subcortical fluid attenuation inversion recovery (FLAIR) hyperintensity signals and areas of diffusion restriction with postcontrast enhancement, diagnostic of PRES, were found on MRI brain. Her symptoms resolved 2 days after tacrolimus was switched to cyclosporine. A follow-up MRI after 6 weeks demonstrated complete resolution of areas of flair hyperintensity signal. She was sent home on a short course of seizure prophylaxis, which was discontinued after the resolution of radiological findings. She had no further episodes of seizures for 6 months following discontinuation of her anti-epileptic regimen.\n\nConclusions:\nTacrolimus-induced PRES can occur as early as 5 days after orthotopic heart transplantation. Early recognition of symptoms and management can prevent permanent neurological sequelae.\n\nMeSH Keywords:\nHeart TransplantationImmunosuppressionSeizuresTacrolimus\n==== Body\nBackground\nCalcineurin inhibitors revolutionized management of patients who underwent solid organ transplantation by effectively reducing acute rejection episodes and improving survival [1]. Neurotoxicity with these medications ranges from a mild tremor, acute confusional state, to status epilepticus or even major speech and motor abnormalities. Posterior reversible encephalopathy is one such neuroradiological phenomenon diagnosed by an MRI. Without prompt recognition and management, it can lead to progression of vasogenic edema to cytotoxic edema, resulting in permanent neurological deficits. This phenomenon is well studied in liver, kidney, and hematopoietic stem cell transplant patients, but very little data exist in the current literature about its incidence in post-heart transplant patients [1–3]. Here, we discuss the clinical course of one such case that was successfully identified and managed appropriately.\n\nCase Report\nA 32-year-old woman with a history of end-stage non-ischemic cardiomyopathy on chronic home milrinone therapy and chronic migraines was admitted to the hospital for cardiogenic shock. An intra-aortic balloon pump was placed as a bridge to orthotopic heart transplantation owing to persistent hypotension despite dual-ionotropic support. She experienced intermittent bouts of her typical migraine headaches consisting of a prodrome of kaleidoscope-like visual disturbances. Her symptoms were generally well controlled with sumatriptan when administered at the advent of her prodrome. However, given the patient’s underlying cardiac complications, intravenous Divalproex sodium was instituted as abortive therapy (continued oral Divalproex sodium for migraine prophylaxis) with successful resolution. After a suitable donor heart was obtained, she underwent orthotopic heart transplantation. Her anti-rejection (immunosuppressive) therapy consisted of mycophenolate mofetil, Prednisone, and tacrolimus. Five days following initiation of tacrolimus, she reported a severe headache that was without prodromal symptoms and was resistant to abortive migraine therapy. A few hours later, she had an episode of generalized tonic clonic seizures, which resolved spontaneously after 1 minute. While an emergent CT head was being performed, she suffered another episode of generalized tonic clonic seizure. This time, seizures subsided following administration of intravenous Ativan. No evidence of bleeding or infarct was noted on the CT head. Vital signs were unremarkable except for a significantly elevated systolic blood pressure of 180/90 mmHg. A comprehensive neurological exam was performed and was noted to be unremarkable without any focal neurologic deficits. Complete blood count and complete metabolic panel were within normal limits. Serum tacrolimus level and magnesium levels were 2·8 ng/ml and 1·5 mg/dl, respectively. She received a loading dose of Divalproex sodium intravenously for seizure prophylaxis and an anti-epileptic regimen was instituted. An electroencephalogram (EEG) demonstrated mild-to-moderate generalized slowing without clear epileptiform discharges. An MRI showed areas of subcortical FLAIR hyperintensity in the bilateral frontal, parietal, and occipital lobes, as well as the cerebellum, consistent with PRES (Figure 1). After the patient regained baseline mentation, she described transient visual disturbances (with patches of green in her visual fields). Considering MRI findings and the recent use of tacrolimus, PRES was our leading hypothesis. Therefore, tacrolimus was switched to cyclosporine. Hypertension was addressed with intravenous hydralazine with a systolic blood pressure goal of less than 140 mmHg, and magnesium was supplemented. Over the course of 3 days, her headache and visual disturbances gradually resolved. A follow-up MRI after 6 weeks demonstrated resolution of previous FLAIR signal abnormalities, with no abnormal post-contrast enhancement, corroborating the diagnosis of PRES. No further episodes of seizures were reported after the discontinuation of her anti-epileptic regimen following radiological resolution.\n\nDiscussion\nHinchey and colleagues were the first to describe posterior reversible encephalopathy syndrome (PRES) in 1996 in 15 patients, most of whom were on immunosuppressive therapy [4]. PRES is a clinico-neuroradiological syndrome that commonly manifests as seizures (77.5%), encephalopathy (62%), headache (29.6%), visual disturbances (22.5%), or focal neurological symptoms (22.5%). A wide range of neurological symptoms are reported with PRES, from mild transient reversible neurological symptoms to severe and debilitating, occasionally resulting in permanent neurologic sequelae. A literature review by Song and colleagues discovered that 89.3% of patients with CNI-associated PRES had a full recovery and an additional 10.7% recovered with neurological sequelae [3]. Patients with notable hemorrhagic lesion on imaging recovered with neurological sequelae. The patho-physiological mechanism underlying PRES is not fully understood. Postulated hypotheses include medication-induced endothelial damage and hypo- or hyperperfusion due to disruption of cerebral autoregulation precipitated by uncontrolled hypertension. Regardless of the underlying mechanism, transient vasogenic edema occurs, which can be detected on MRI. Delayed diagnosis can offset cytotoxic edema and result in permanent neurological sequelae. Frequently implicated triggers are eclampsia, hypertensive emergency, or exposure to immunosuppressive therapy (as reported in our case), as well as numerous other uncommon causes. Commonly implicated immunosuppressant medications are calcineurin inhibitors (e.g., cyclosporine and tacrolimus). Growing numbers of organ transplantations and use of calcineurin inhibitors inadvertently resulted in an escalating incidence of their neurotoxic adverse effects. According to a recent case report, sirolimus has joined this group of implicated medications, although at a much lower frequency [5].\n\nPRES is extensively described in the literature in patients who underwent solid organ and hematopoietic stem cell transplantation. Bartynski et al., studying 4222 patients who underwent solid organ transplantation (SOT) and on immunosuppressive therapy (especially with calcineurin inhibitors), reported that in kidney and liver transplant patients the incidence of PRES was around 0.49% and 0.84%, respectively [2]. The mean time of onset of the toxicity (following transplantation or initiation of immunosuppressant therapy) also varied between different SOT subtypes. When immunosuppressive therapy is the causative factor, dose reduction, switching medication, or discontinuation of the medication were all reasonably successful strategies. Tacrolimus-related PRES was noted to be unrelated to the drug levels. Therapeutic drug monitoring is recommended to prevent tacrolimus toxicity but PRES is known to occur even at normal therapeutic drug levels. Clinical recovery was noted to occur within a few days, while radiological recovery took days to weeks. Hypertension, elevated serum creatinine or CKD/Dialysis, solid organ or hematopoietic stem cell transplantation, hypomagnesemia, pregnancy, and sepsis are among the comorbid conditions associated with PRES. Management of hypertension and hypomagnesemia are noted to be important in the recovery of these patients.\n\nPRES is a neuro-radiological phenomenon characterized by bilateral and symmetric vasogenic edema involving subcortical white matter. It is diagnosed by a FLAIR hyperintensity signal, which has the ability detect even subtle PRES lesions, noted on T-2 weighted images, typically involving the parieto-occipital areas (posterior circulation) on MRI. Supplemental diffusion-weighted imaging (D-WI) and apparent diffusion coefficient (ADC) mapping helps differentiate reversible vasogenic edema (represented by iso-/hyperintense D-WI and hyper-intense ADC correlating with areas of FLAIR hyperintensity) from irreversible cytotoxic edema (hypointense ADC) [6]. Complete reversibility of all these changes on subsequent imaging is a unique characteristic of PRES and is often diagnostic (Figure 1). Rarely, hemorrhages and micro-ischemic infarcts are the residual findings noted on MRI. These changes are associated with residual neurological deficits.\n\nAtypical PRES denotes involvement of areas of the brain other than posterior circulation. Involvement of frontal and fronto-parietal lobes, thalami, internal capsule, isolated brainstem, cerebellum, cortical grey matter, unilateral lesions, foci of permanent injury, and hemorrhage into lesions demonstrable on MRI constitute atypical neuro-imaging findings. Since atypical PRES is more common, the term PRES is essentially considered a misnomer.\n\nConclusions\nDrug-induced PRES can occur in solid-organ transplant patients as early as the first week of initiation of immunosuppressant therapy. Early diagnosis followed by discontinuation of the causative agent, dose reduction, or switching immunosuppressant regimen can result in complete resolution of symptoms. This can also be demonstrated by the resolution of radiological findings on follow-up MRI.\n\nConflicts of interest\n\nNo conflicts of interest to declare.\n\nFigure 1. (A, B) Represent initial MRI brain findings (immediate post-seizure imaging): Areas of subcortical FLAIR hyperintensity in the bilateral parietal and occipital lobes (arrows) consistent with posterior reversible encephalopathy syndrome. (C, D) Represent follow-up MRI brain findings (6 weeks after switching tacrolimus to cyclosporine): Resolution of the previous FLAIR hyperintensity signal abnormality.\n==== Refs\nReferences:\n1. Song T Rao Z Tan Q Calcineurin inhibitors associated posterior reversible encephalopathy syndrome in solid organ transplantation: Report of 2 cases and literature review Medicine (Baltimore) 2016 95 e3173 27057842 \n2. Bartynski WS Tan HP Boardman JF Posterior reversible encephalopathy syndrome after solid organ transplantation Am J Neuroradiol 2008 29 924 30 18272559 \n3. Wu Q Marescaux C Wolff V Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation Eur Neurol 2010 64 169 77 20699617 \n4. Barbas AS Rege AS Castleberry AW Posterior reversible encephalopathy syndrome independently associated with tacrolimus and sirolimus after multivisceral transplantation Am J Transplant 2013 13 808 10 23331705 \n5. Hinchey J Chaves C Appignani B A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996 334 494 500 8559202 \n6. Lee VH Wijdicks EF Manno EM Rabinstein AA Clinical spectrum of reversible posterior leukoencephalopathy syndrome Arch Neurol 2008 65 20 10\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "18()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000328:Adult; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D054038:Posterior Leukoencephalopathy Syndrome; D016559:Tacrolimus", "nlm_unique_id": "101489566", "other_id": null, "pages": "487-490", "pmc": null, "pmid": "28465499", "pubdate": "2017-05-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "23331705;20699617;18268188;8559202;18272559;27057842", "title": "Posterior Reversible Encephalopathy Syndrome After Orthotopic Heart Transplantation: A Case Report.", "title_normalized": "posterior reversible encephalopathy syndrome after orthotopic heart transplantation a case report" }

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{ "abstract": "Omphalocele, exstrophy of the bladder, imperforate anus and spinal defect (OEIS) complex is a rare congenital multisystemic malformation representing unique anomalies. It was first reported in 1978 through a series of cases with an abnormality of body wall development. We are reporting a case of an infant of 36 weeks gestation, with a family history of consanguinity and oral contraceptive pill intake that was discontinued when the mother was 1-month pregnant. The neonatal examination revealed findings that were consistent with OEIS complex along with the presence of genital anomalies. The infant required multi-staged surgical intervention. We conclude that this case report might illustrate some of the possible risk factors and variability of OEIS complex.", "affiliations": "Department of Pediatrics, University of Dammam-King Fahd Hospital of the University, Al Khobar, Saudi Arabia.;Department of Pediatrics, University of Dammam-King Fahd Hospital of the University, Al Khobar, Saudi Arabia.;Department of Surgery, University of Dammam-King Fahd Hospital of the University, Al Khobar, Saudi Arabia.", "authors": "Al-Qurashi|Faisal Othman|FO|;Al-Hareky|Thammer Saad|TS|;Al-Buainain|Hussah Mohammed|HM|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/1658-631X.194258", "fulltext": "\n==== Front\nSaudi J Med Med SciSaudi J Med Med SciSJMMSSaudi Journal of Medicine & Medical Sciences1658-631X2321-4856Medknow Publications & Media Pvt Ltd India SJMMS-5-6710.4103/1658-631X.194258Case ReportOmphalocele, Exstrophy of Bladder, Imperforate Anus and Spinal Defect Complex with Genital Anomalies in a Late Preterm Infant Al-Qurashi Faisal Othman Al-Hareky Thammer Saad Al-Buainain Hussah Mohammed 1Department of Pediatrics, University of Dammam-King Fahd Hospital of the University, Al Khobar, Saudi Arabia1 Department of Surgery, University of Dammam-King Fahd Hospital of the University, Al Khobar, Saudi ArabiaCorrespondence: Dr. Faisal Othman Al-Qurashi, P.O. Box 11286, Dammam 31453, Saudi Arabia. E-mail: [email protected] 2017 16 11 2016 5 1 67 70 Copyright: © 2017 Saudi Journal of Medicine & Medical Sciences2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Omphalocele, exstrophy of the bladder, imperforate anus and spinal defect (OEIS) complex is a rare congenital multisystemic malformation representing unique anomalies. It was first reported in 1978 through a series of cases with an abnormality of body wall development. We are reporting a case of an infant of 36 weeks gestation, with a family history of consanguinity and oral contraceptive pill intake that was discontinued when the mother was 1-month pregnant. The neonatal examination revealed findings that were consistent with OEIS complex along with the presence of genital anomalies. The infant required multi-staged surgical intervention. We conclude that this case report might illustrate some of the possible risk factors and variability of OEIS complex.\n\nملخص البحث:\nتعتبر عقدة الاكشاف المذرقي واحدة من التشوهات الخلقية المتعددة الأجهزة النادرة، وتمثل مجموعة من التشوهات الخلقية المميزة وهي : القيلة السرية، الاكشاف المثاني، والرتق الشرجي وخلل في العمود الفقري. تاريخيا، تم تشخيص أول حالات هذه العقدة في عام 1978 ميلادية من خلال عدد من الحالات التي أظهرت خللا خلقيا في بنية الجدار البطني. يعرض الباحثون حالة خديج في السادس وثلاثين أسبوعا من الحمل ، بتاريخ عائلي من زواج الأقارب، وتناول الأم لحبوب منع الحمل لشهر واحد عند بداية حملها. اثبت فحص الرضيع السريري وجود علامات متماشية مع تشخيص العقدة بالإضافة إلى وجود أعضاء تناسلية ملتبسة . تطلب علاج هذه الحالة إلى تدخل جراحي متعدد المستويات. واستنادا على هذا التقرير، فإننا نخلص إلى أن هذه الحالة النادرة قد توضح بعض عوامل الأخطار المحتملة وتباين عرض عقدة الاكشاف المذرقي. \n\nKey words:\nCloacal exstrophyexstrophy of the bladderomphalocele\n==== Body\nINTRODUCTION\nOmphalocele, exstrophy of the bladder, imperforate anus and spinal defect (OEIS) complex is one of the rarest multisystemic congenital malformations representing unique and characteristic anomalies. It counts for approximately 1:200,000 live births. In 1978, Carey et al. reported a series of cases with an abnormality of body wall development known then by many names, most commonly “exstrophy of the cloaca.” They proposed the term OEIS complex because the term is simple and recalls all of the defects present.[1] Due to the rarity and lack of comprehensive background of such a diagnosis, our aim is to illustrate some of the possible risk factors and the variable presentations of OEIS complex.\n\nCASE REPORT\nA late preterm infant of 36 weeks gestation, product of spontaneous vaginal delivery with Apgar Score of 5 and 7 at 1 and 5 minutes respectively and admitted initially, was admitted initially as a case of multiple congenital anomalies with genital anomalies.\n\nThe infant was born to a 23-year-old Saudi female, G3 P1 + 1, who was not known to have any chronic medical illnesses, but with a history of a previous infant that had died of complicated surgically-corrected diaphragmatic hernia. She was on regular antenatal care follow-up in a private hospital. She had no history of pregnancy-related illnesses or exposure to radiation. There was a history of desogestrel/ethinyl estradiol oral contraceptive pills intake of 3 months duration that was discontinued by the mother who was 1 month pregnant. Regarding the family, there is the first-degree consanguinity between the parents (i.e., cousins), with no similar conditions being reported in the family.\n\nAt 28 weeks gestation, an ultrasound study revealed the presence of fetal omphalocele and accordingly she was referred to our hospital for feto-maternal services. The repeated ultrasound scan was of a limited anomaly. Amniocentesis was tried but failed due to advanced gestation.\n\nThe delivery went smoothly with the cephalic presentation of the infant and complete placental appearance with three umbilical cord vessels (two arteries/one vein). On examination, the infant looked pale but not cyanosed or jaundiced, with no apparent dysmorphic features. Central nervous system examination revealed an active infant moving upper and lower limbs freely, with myelomeningocele at the lumbosacral area (2 cm × 2 cm) that was covered by intact skin. The cardiovascular and respiratory examination was normal. Gastrointestinal and urinary systems examination revealed omphalocele minor below the umbilicus with an intact sac containing only the bowel. The central area of defect was identified as the caecal plate with a dilated prolapsed terminal ileum with the length of 4–5 cm presenting as characteristic “elephant trunk deformity.” There was a small pinhole-sized opening in the proximal ventral aspect of the prolapsed terminal ileum, which noted to be passing the meconium. On lateral aspects, there were exstrophy bladder plates with two hemispheric bladders, each of which contained a visible ureteric orifice. An imperforate anus with an anal dimple was noticed. The genital system examination revealed multiple genital anomalies in the form of asymmetrical widely bifid sacrolabial folds that were hyperpigmented. The gonad was palpable in the left side only with absent phallus and absent urethral opening [Figure 1].\n\nFigure 1 The central area of defect was identified as caecal plate “C” with a dilated prolapsed terminal ileum “I” with the length of 4–5 cm presenting as characteristic “elephant trunk deformity.” A small sized opening on the prolapsed terminal ileum which noted to be passing meconium (arrow). On lateral aspects, there were exstrophy bladder plates with two hemispheric bladders “H” each of which contains a visible ureteric orifice “*”. Genital anomalies with asymmetrical widely bifid sacro labial folds that were hyperpigmented. The gonad was palpable in the left side with absent phallus.\n\nInvestigations were performed, including radiographic studies and chromosomal analysis. Echocardiography showed a normal study. The chromosomal study revealed a normal male karyotype of 46, XY with no numerical or structural abnormalities discernible. A computed tomography (CT) scan revealed mildly balanced congenital scoliosis, widening of symphysis pubis indicating an open book pelvic deformity and evidence of congenital bilateral hip dislocation. A multilevel vertebral failure of formation and segmentation with hemivertebra were noted at the mid-thoracic and lower lumbosacral regions. A posterior spinal dysraphism at the lower lumbosacral region was noted that was associated with a low-lying spinal cord that herniates dorsally with skin coverage representing a tethered cord with myelomeningocele [Figure 2].\n\nFigure 2 Computed tomography image showing widening of symphysis pubis indicating an open book pelvic deformity with bilateral congenital hip dislocation, mildly balanced congenital scoliosis, multilevel vertebral failure of formation and segmentation with hemivertebra seen at the midthoracic and lumbosacral regions, and posterior spinal dysraphism at the lower lumbosacral region, associated with low-lying spinal cord that herniates dorsally representing myelomeningocele.\n\nA multidisciplinary approach had been discussed with a multispecialty surgical team at our center. Due to the absence of a pediatric urology specialty in our hospital, the infant was transferred to a specialized center where the patient underwent a multi-staged surgical intervention to correct the complicated defect.\n\nDISCUSSION\nIn 1978, Carey et al. reported a series of cases with an abnormality of the body wall development. The term OEIS complex was proposed to describe their findings.[1] The description by Carey et al. was based on a retrospective search of medical records and identifying 175 infants with one or more of the above-mentioned malformations. Twenty-nine of these infants had two or more of the four cardinal defects and ten infants exhibited the full complex. Among those, genital anomalies were found in six, e.g., absence of external genitalia, ambiguous genitalia, abnormal phallus, epispadias or bifid scrotum. They assumed that these abnormal genital findings were regarded to be secondary features of the complex. The constellation of the complex findings has since then repeatedly been described in the literature and is regarded as an entity.[2] In our case, the cardinal defects of OEIS complex had been identified clinically with the presence of genital anomalies and variable degrees of spinal defects in the form of myelomeningocele, congenital scoliosis and double thoracic hemivertebrae. Based on histopathologic studies in human embryos, OEIS is most likely the result of a very early defect involving the caudal eminence as opposed to an abnormality related to premature rupture of the cloacal membrane. Anatomically, the cardinal findings of cloacal exstrophy include exstrophy of the hemibladders with hindgut extrusion and imperforate anus. The hemibladders flank the openings of the small intestine, blind-ending large intestine and containing the orifices of ureters and vasa deferentia in males and the uterovaginal canal in females [Figure 3].[3]\n\nFigure 3 Clinical presentation of cloacal exstrophy in a newborn.\n\nAlthough most cases occur sporadically, there have been several reports of recurrence in siblings suggesting that some cases may have a genetic basis.[4] In our review of the literature, we noted that due to its rarity, most of this complex-related knowledge is still under investigation and reporting, one of the complex's biggest challenges is identifying its related risk factors. We believe that parental consanguinity and use of desogestrel/ethinylestradiol oral contraceptive pills during pregnancy may play a role in the etiology of OEIS complex. In one study, Stoll et al. estimated the risk of congenital malformations in consanguineous marriages and found that birth defects in consanguineous couples are 10.3 times more frequent than in offspring of non-consanguineous couples.[5] In another study, Li et al. conducted a case–control study of the relationship between oral contraceptive use after conception to the occurrence of congenital urinary tract anomalies (CUTAs) and found that their results were compatible with the hypothesis that oral contraceptive use after conception predisposes the offspring to the development of CUTAs.[6]\n\nThe prevalence of OEIS has been estimated at 1:200,000 live births; however, the real incidence is unknown since many cases are incorrectly diagnosed prenatally, or the majority of these pregnancies is terminated or ends with in utero fetal demise.[7]\n\nCONCLUSION\nOEIS complex is a congenital multisystemic syndromic entity that should be considered as a medical challenge. Although it was thought to be associated with high mortality risk, this is no longer the case. A crucial modifying step in the management of this complex is its early antenatal diagnosis and detection, where it should be considered as a medical urgency once the diagnosis is reached. A highly specialized multispecialty medical facility is the point of referral where the management must be started initially with stabilizing the patient, then considering either a single-staged or multi-staged surgical intervention. However, given that those patients will have a poor quality of life, such intervention will support the patient's well-being rather than being viewed as active management. As part of our objectives for this case report, identifying unrecognized risk factors will add to the present knowledge of this complex and enhance the treatment that these patients can be offered. We also conclude that parental consanguinity and use of desogestrel/ethinyl estradiol oral contraceptive pills during pregnancy may play a role in the etiology of OEIS complex.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Carey JC Greenbaum B Hall BD The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects) Birth Defects Orig Artic Ser 1978 14 253 63 728566 \n2 Haldar A Sharma AK Phadke SR Jain A Agarwal SS OEIS complex with craniofacial anomalies – Defect of blastogenesis? Am J Med Genet 1994 53 21 3 7802030 \n3 van der Putte SC Spliet WG Nikkels PG Common (“classical”) and covered cloacal exstrophy: A histopathological study and a reconstruction of the pathogenesis Pediatr Dev Pathol 2008 11 430 42 18078363 \n4 Smith NM Chambers HM Furness ME Haan EA The OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): Recurrence in sibs J Med Genet 1992 29 730 2 1433234 \n5 Stoll C Alembik Y Roth MP Dott B Parental consanguinity as a cause for increased incidence of births defects in a study of 238,942 consecutive births Ann Genet 1999 42 133 9 10526655 \n6 Li DK Daling JR Mueller BA Hickok DE Fantel AG Weiss NS Oral contraceptive use after conception in relation to the risk of congenital urinary tract anomalies Teratology 1995 51 30 6 7597655 \n7 Soper RT Kilger K Vesico-intestinal fissure J Urol 1964 92 490 501 14226477\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "2321-4856", "issue": "5(1)", "journal": "Saudi journal of medicine & medical sciences", "keywords": "Cloacal exstrophy; exstrophy of the bladder; omphalocele", "medline_ta": "Saudi J Med Med Sci", "mesh_terms": null, "nlm_unique_id": "101675905", "other_id": null, "pages": "67-70", "pmc": null, "pmid": "30787756", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "10526655;14226477;1433234;18078363;728566;7597655;7802030", "title": "Omphalocele, Exstrophy of Bladder, Imperforate Anus and Spinal Defect Complex with Genital Anomalies in a Late Preterm Infant.", "title_normalized": "omphalocele exstrophy of bladder imperforate anus and spinal defect complex with genital anomalies in a late preterm infant" }

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OMPHALOCELE, EXSTROPHY OF BLADDER, IMPERFORATE ANUS AND SPINAL DEFECT COMPLEX WITH GENITAL ANOMALIES IN A LATE PRETERM INFANT. SAUDI-J-MED-MED-SCI 2017;5(1):67-70.", "literaturereference_normalized": "omphalocele exstrophy of bladder imperforate anus and spinal defect complex with genital anomalies in a late preterm infant", "qualification": "1", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20170711", "receivedate": "20170711", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13741691, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "Topiramate is used to treat a variety of neurologic and psychiatric diseases due to its benign safety profile. Data regarding the toxicity and toxicokinetics of topiramate in acute overdose are limited. A case of massive, acute ingestion resulting in the highest reported topiramate level is presented, including toxicokinetic evaluation. A 37-year-old woman presented with coma unresponsive to naloxone following topiramate ingestion. She had normal vital signs without respiratory depression. She was intubated for airway protection, given 3.5 mg lorazepam IV for facial and neck muscle twitching, and transferred to our facility. No additional sedation was required for 18 h on the ventilator. Following mental status improvement, the patient was extubated. Confusion, dysarthria, and imbalance resolved over the next 2 days. Nonanion gap metabolic acidosis persisted for 3 days. Peak serum topiramate level was 356.6 microg/ml (reference range, 5-20 microg/ml). Massive topiramate ingestion led to prolonged coma with normal vital signs and nonanion gap metabolic acidosis. Coma of this severity has not been previously reported. Serum half-life, which has not been studied after overdose, was 16 h. Despite the large ingestion and significant presenting symptoms, the patient recovered fully with supportive intensive care alone. Massive acute topiramate ingestion may lead to nonanion gap metabolic acidosis and prolonged coma which resolves with intensive supportive care. Toxicokinetic data following large, suicidal ingestion of topiramate were similar to previously published pharmacokinetic information.", "affiliations": "Division of Medical Toxicology, Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. [email protected]", "authors": "Lynch|Michael J|MJ|;Pizon|Anthony F|AF|;Siam|Mohamed G|MG|;Krasowski|Matthew D|MD|", "chemical_list": "D000927:Anticonvulsants; D006993:Hypnotics and Sedatives; D000077236:Topiramate; D005632:Fructose; D008140:Lorazepam", "country": "United States", "delete": false, "doi": "10.1007/s13181-010-0065-y", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-9039", "issue": "6(2)", "journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology", "keywords": null, "medline_ta": "J Med Toxicol", "mesh_terms": "D000138:Acidosis; D000328:Adult; D000927:Anticonvulsants; D001714:Bipolar Disorder; D001784:Blood Gas Analysis; D003128:Coma; D003422:Critical Care; D062787:Drug Overdose; D005260:Female; D005632:Fructose; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006993:Hypnotics and Sedatives; D008140:Lorazepam; D012121:Respiration, Artificial; D000077236:Topiramate", "nlm_unique_id": "101284598", "other_id": null, "pages": "135-8", "pmc": null, "pmid": "20376593", "pubdate": "2010-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": null, "title": "Clinical effects and toxicokinetic evaluation following massive topiramate ingestion.", "title_normalized": "clinical effects and toxicokinetic evaluation following massive topiramate ingestion" }

[ { "companynumb": "US-GLENMARK PHARMACEUTICALS-2017GMK027690", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "077627", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 UNK, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscle twitching", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Clonus", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Unresponsive to stimuli", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LYNCH M J, PIZON A F, SIAM M G, KRASOWSKI M D.. CLINICAL EFFECTS AND TOXICOKINETIC EVALUATION FOLLOWING MASSIVE TOPIRAMATE INGESTION. AMERICAN COLLEGE OF MEDICAL TOXICOLOGY. 2010;6:135-138", "literaturereference_normalized": "clinical effects and toxicokinetic evaluation following massive topiramate ingestion", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170602", "receivedate": "20170602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13604764, "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": "Type 1 reactions, characterized by increasing lesion erythema, pain, and nerve damage, commonly complicate leprosy. Dapsone hypersensitivity syndrome (DHS) is a potentially fatal reaction occurring 6-8 weeks into dapsone therapy. We present a case of intercurrent Type 1 reaction and DHS in a multibacillary leprosy patient recently started on multidrug treatment.", "affiliations": "Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada.;Department of Pediatrics, University of Toronto, Toronto, Canada.;Faculty of Medicine, University of Toronto, Toronto, Canada.;Public Health Ontario Laboratory, Public Health Ontario, Toronto, Canada.", "authors": "Craig|Jeffrey|J|;MacRae|Cara|C|;Melvin|Rochelle G|RG|;Boggild|Andrea K|AK|", "chemical_list": "D007917:Leprostatic Agents; D003622:Dapsone", "country": "United States", "delete": false, "doi": "10.4269/ajtmh.18-0953", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9637", "issue": "100(5)", "journal": "The American journal of tropical medicine and hygiene", "keywords": null, "medline_ta": "Am J Trop Med Hyg", "mesh_terms": "D003622:Dapsone; D004342:Drug Hypersensitivity; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007917:Leprostatic Agents; D056006:Leprosy, Multibacillary; D008297:Male; D008875:Middle Aged; D009166:Mycobacterium leprae; D012871:Skin Diseases; D062606:Tertiary Care Centers; D016896:Treatment Outcome", "nlm_unique_id": "0370507", "other_id": null, "pages": "1145-1148", "pmc": null, "pmid": "30915953", "pubdate": "2019-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "8698924;23614255;14707226;12592301;16889287;10575418;2913915;23761718;24587958;12721394;23060374;15401496;24152261;22307940;28167593;2491425;29507748;30326738", "title": "Case Report: A Case of Type 1 Leprosy Reaction and Dapsone Hypersensitivity Syndrome Complicating the Clinical Course of Multibacillary Leprosy.", "title_normalized": "case report a case of type 1 leprosy reaction and dapsone hypersensitivity syndrome complicating the clinical course of multibacillary leprosy" }

[ { "companynumb": "CA-VIRTUS PHARMACEUTICALS, LLC-2019VTS00021", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DAPSONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "204074", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEPROSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DAPSONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEPROSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VITAMIN D NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN D NOS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEPROSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEPROSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "065", "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": "UNSPECIFIED PROTON PUMP INHIBITOR" } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CRAIG J., MACRAE C., MELVIN R.G., BOGGILD A.K. CASE REPORT: A CASE OF TYPE 1 LEPROSY REACTION AND DAPSONE HYPERSENSITIVITY SYNDROME COMPLICATING THE CLINICAL COURSE OF MULTIBACILLARY LEPROSY. [ARTICLE IN PRESS] AM. J. TROP. MED. HYG.. 2019", "literaturereference_normalized": "case report a case of type 1 leprosy reaction and dapsone hypersensitivity syndrome complicating the clinical course of multibacillary leprosy", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190429", "receivedate": "20190429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16251142, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" } ]

{ "abstract": "We performed a prospective study to evaluate the efficacy and safety of secondary antifungal prophylaxis (SAP) for patients with a history of invasive pulmonary aspergillosis (IPA) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, the prophylactic agents used were chosen based on treatment response to initial antifungal therapy. One hundred and thirty-six patients undergoing allo-HSCT with prior IPA were enrolled in this multicenter study. The agents of SAP included itraconazole in 24, voriconazole in 74, caspofungin in 32, and liposomal amphotericin B in 6. Eighty-eight patients had stable IPA and 48 had active IPA at the time of transplantation. The success rate of SAP was 91.2%. Twelve patients developed breakthrough invasive fungal disease (IFD), and none discontinued antifungal agents because drug-related adverse events. The incidence of breakthrough IFD was neither different among the different antifungal agents (P = .675) nor between patients with active and stable IPA (P = .080). The 1-year cumulative incidence of IFD and IPA relapse was 27.3% ± 4.5% and 24.7% ± 4.4%, respectively. Our data indicate that SAP with antifungal agents based on initial antifungal therapy has favorable efficacy and safety in allo-HSCT recipients with prior IPA. Active IPA might not increase the risk of breakthrough IFD after transplantation.", "affiliations": "Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: [email protected].;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Guangzhou General Hospital of Guangzhou Command, Guangzhou, China.;Department of Hematology, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Department of Hematology, Guangzhou General Hospital of Guangzhou Command, Guangzhou, China.;Department of Hematology, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.", "authors": "Liu|Qifa|Q|;Lin|Ren|R|;Sun|Jing|J|;Xiao|Yang|Y|;Nie|Danian|D|;Zhang|Yu|Y|;Huang|Fen|F|;Fan|Zhiping|Z|;Zhou|Hongsheng|H|;Jiang|Qianli|Q|;Zhang|Fuhua|F|;Zhai|Xiao|X|;Xu|Dan|D|;Wei|Yongqiang|Y|;Song|Jiayin|J|;Li|Yiqing|Y|;Feng|Ru|R|", "chemical_list": "D000935:Antifungal Agents", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "20(8)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": "Allogeneic hematopoietic stem cell transplantation; Antifungal prophylaxis; Invasive pulmonary aspergillosis", "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D055732:Pulmonary Aspergillosis; D012307:Risk Factors; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "9600628", "other_id": null, "pages": "1198-203", "pmc": null, "pmid": "24769013", "pubdate": "2014-08", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Antifungal agents for secondary prophylaxis based on response to initial antifungal therapy in allogeneic hematopoietic stem cell transplant recipients with prior pulmonary aspergillosis.", "title_normalized": "antifungal agents for secondary prophylaxis based on response to initial antifungal therapy in allogeneic hematopoietic stem cell transplant recipients with prior pulmonary aspergillosis" }

[ { "companynumb": "CN-JNJFOC-20140716324", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "020657", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unspecified", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHOPULMONARY ASPERGILLOSIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Systemic mycosis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood bilirubin increased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LIU Q, LIN R, SUN J, XIAO Y, NIE D, ZHANG Y, ET AL. ANTIFUNGAL AGENTS FOR SECONDARY PROPHYLAXIS BASED ON RESPONSE TO INITIAL ANTIFUNGAL THERAPY IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS WITH PRIOR PULMONARY ASPERGILLOSIS. BIOL BLOOD MARROW TRANSPLANT 2014;20:1198-1203.", "literaturereference_normalized": "antifungal agents for secondary prophylaxis based on response to initial antifungal therapy in allogeneic hematopoietic stem cell transplant recipients with prior pulmonary aspergillosis", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20140801", "receivedate": "20140801", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10357893, "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\nThe cetuximab plus platinum-based chemotherapy regimen is a standard of care in the treatment of recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The feasibility in the elderly population is currently unknown.\n\n\nMETHODS\nWe performed a retrospective study in order to assess the efficacy and safety of the cetuximab plus platinum-based chemotherapy regimen in patients >65 years with recurrent or metastatic HNSCC. We performed a retrospective review of all medical records from recurrent or metastatic HNSCC patients >65 years treated with the cetuximab plus platinum-based chemotherapy regimen between September 2008 and December 2013 in our institution (Centre Paul Strauss, Strasbourg, France).\n\n\nRESULTS\nA total of 59 patients were identified. Carboplatin in combination with 5-fluorouracil (FU) was the only cetuximab-associated chemotherapy regimen used for treating elderly patients. The median progression-free survival was 4 months (95% confidence interval [CI]: 2.9-4.7), and the median overall survival was 9.1 months (95% CI: 6.5-13.1). Grade 3 or 4 toxicity adverse events occurred in 52% (n = 31) of the patients (mostly hematologic toxicities and infections).\n\n\nCONCLUSIONS\nThis retrospective study suggests that the cetuximab plus carboplatin-5FU chemotherapy is an effective treatment option for elderly patients with recurrent or metastatic HNSCC.", "affiliations": "Medical Oncology Department, Centre Paul Strauss, Strasbourg, France.", "authors": "Burgy|Mickaël|M|;Barthélémy|Philippe|P|;Lefevre|François|F|;Dupret-Bories|Agnès|A|;Truntzer|Pierre|P|;Korenbaum|Clement|C|;Flesch|Henri|H|;Bronner|Guy|G|;Borel|Christian|C|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D016190:Carboplatin; D002945:Cisplatin; D005472:Fluorouracil", "country": "Switzerland", "delete": false, "doi": "10.1159/000454732", "fulltext": null, "fulltext_license": null, "issn_linking": "0030-2414", "issue": "93(1)", "journal": "Oncology", "keywords": "Cetuximab; Chemotherapy; Elderly patients; Recurrent or metastatic head and neck squamous-cell carcinoma", "medline_ta": "Oncology", "mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil; D005602:France; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D016896:Treatment Outcome", "nlm_unique_id": "0135054", "other_id": null, "pages": "11-17", "pmc": null, "pmid": "28423384", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": null, "title": "Cetuximab-Carboplatin-5-Fluorouracil Regimen in Elderly Patients with Recurrent or Metastatic Head and Neck Squamous-Cell Carcinoma: A French Retrospective Survey.", "title_normalized": "cetuximab carboplatin 5 fluorouracil regimen in elderly patients with recurrent or metastatic head and neck squamous cell carcinoma a french retrospective survey" }

[ { "companynumb": "FR-CIPLA LTD.-2017FR08302", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/M2/DAY FROM DAY 1 TO DAY 4", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077383", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AUC 5 ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "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": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "250 MG/M2, WEEKLY DOSES FOR MAXIMUM OF 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "400 MG/M2, UNK, INITIAL DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BURGY M, BARTHELEMY P, LEFEVRE F, DUPRET-BORIES A, TRUNTZER P, KORENBAUM C, ET AL;. CETUXIMAB-CARBOPLATIN-5-FLUOROURACIL REGIMEN IN ELDERLY PATIENTS WITH RECURRENT OR METASTATIC HEAD AND NECK SQUAMOUS-CELL CARCINOMA: A FRENCH RETROSPECTIVE SURVEY. 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CETUXIMAB-CARBOPLATIN-5-FLUOROURACIL REGIMEN IN ELDERLY PATIENTS WITH RECURRENT OR METASTATIC HEAD AND NECK SQUAMOUS-CELL CARCINOMA: A FRENCH RETROSPECTIVE SURVEY. 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ONCOLOGY. 2017;1 TO 7", "literaturereference_normalized": "cetuximab carboplatin 5 fluorouracil regimen in elderly patients with recurrent or metastatic head and neck squamous cell carcinoma a french retrospective survey", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170509", "receivedate": "20170509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13527135, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "FR-CIPLA LTD.-2017FR08322", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077383", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AUC 5 ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "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": "1", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "400 MG/M2, INITIAL DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/M2/DAY FROM DAY 1 TO DAY 4", "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA OF HEAD AND NECK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "250 MG/M2, WEEKLY DOSES FOR MAXIMUM OF 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BURGY M, BARTHELEMY P, LEFEVRE F, DUPRET-BORIES A, TRUNTZER P, KORENBAUM C, ET AL;. CETUXIMAB-CARBOPLATIN-5-FLUOROURACIL REGIMEN IN ELDERLY PATIENTS WITH RECURRENT OR METASTATIC HEAD AND NECK SQUAMOUS-CELL CARCINOMA: A FRENCH RETROSPECTIVE SURVEY. ONCOLOGY. 2017;1 TO 7", "literaturereference_normalized": "cetuximab carboplatin 5 fluorouracil regimen in elderly patients with recurrent or metastatic head and neck squamous cell carcinoma a french retrospective survey", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170509", "receivedate": "20170509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13527123, "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": "This study was designed to characterize failure-free survival (FFS) as a novel end point for clinical trials of chronic graft-versus-host disease (GVHD). The study cohort included 400 consecutive patients who received initial systemic treatment of chronic GVHD at our center. FFS was defined by the absence of second-line treatment, nonrelapse mortality, and recurrent malignancy during initial treatment. The FFS rate was 68% at 6 months and 54% at 12 months after initial treatment. Multivariate analysis identified 4 risk factors associated with treatment failure: time interval <12 months from transplantation to initial treatment, patient age ≥60 years, severe involvement of the gastrointestinal tract, liver, or lungs, and Karnofsky score <80% at initial treatment. Initial steroid doses and the type of initial treatment were not associated with risk of treatment failure. Lower steroid doses after 12 months of initial treatment were associated with long-term success in withdrawing all systemic treatment. FFS offers a potentially useful basis for interpreting results of initial treatment of chronic GVHD. Incorporation of steroid doses at 12 months would increase clinical benefit associated with the end point. Studies using FFS as the primary end point should measure changes in GVHD-related symptoms, activity, damage, and disability as secondary end points.", "affiliations": "Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Departments of Medicine.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Departments of Medicine.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Pediatrics, and.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Departments of Medicine.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Biostatistics, University of Washington School of Medicine, Seattle, WA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Departments of Medicine.", "authors": "Inamoto|Yoshihiro|Y|http://orcid.org/0000-0003-4881-0427;Flowers|Mary E D|ME|http://orcid.org/0000-0003-1631-0911;Sandmaier|Brenda M|BM|http://orcid.org/0000-0002-9767-9739;Aki|Sahika Z|SZ|;Carpenter|Paul A|PA|http://orcid.org/0000-0001-9810-1798;Lee|Stephanie J|SJ|http://orcid.org/0000-0003-2600-6390;Storer|Barry E|BE|http://orcid.org/0000-0003-1565-435X;Martin|Paul J|PJ|http://orcid.org/0000-0001-9051-1215", "chemical_list": "D013256:Steroids", "country": "United States", "delete": false, "doi": "10.1182/blood-2014-03-563544", "fulltext": null, "fulltext_license": null, "issn_linking": "0006-4971", "issue": "124(8)", "journal": "Blood", "keywords": null, "medline_ta": "Blood", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D064591:Allografts; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D033581:Stem Cell Transplantation; D013256:Steroids; D015996:Survival Rate; D013997:Time Factors", "nlm_unique_id": "7603509", "other_id": null, "pages": "1363-71", "pmc": null, "pmid": "24876566", "pubdate": "2014-08-21", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "21464398;16338616;10204198;3042041;24152907;21493797;12720215;22683612;21467544;11400948;20601033;16503494;23321253;22576252;19470693;22058206;19896545;15292060;19270260;12070007;11090092;21633087;21689773;21621629;18621929", "title": "Failure-free survival after initial systemic treatment of chronic graft-versus-host disease.", "title_normalized": "failure free survival after initial systemic treatment of chronic graft versus host disease" }

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{ "abstract": "Patients with upper-tract carcinoma in situ (UT-CIS) that have failed treatment with BCG are recommended for radical nephroureterectomy (RNU). We describe a cohort of patients with BCG-refractory UT-CIS that were treated with docetaxel, a novel agent in the approach to topical therapy.\n\n\n\nPatients with pathologically proven UT-CIS from 2012 to 2020 with an imperative indication for organ preservation and history of BCG-refractory disease were included. Each patient underwent ureteroscopy with biopsy and selective cytology pre- and postinduction, and after each maintenance course. Complete response (CR) was defined as the absence of visualized lesions on ureteroscopy, negative selective cytology, and absence of clinical progression. No response (NR) was defined as persistence of lesions after induction or absence of visualized lesions with persistently positive cytology.\n\n\n\nSeven patients and 10 renal units were treated. Six of the 10 renal units had initial CR (60%). Three patients with NR went on to have RNU, one of which subsequently died due to cancer-specific mortality. One patient with bilateral disease had NR in 10 renal unit and cure in the other. This patient subsequently developed recurrence in his remaining renal unit. A second patient had CR in both kidneys for 6 years, but 1 year after finishing maintenance regimen developed HG disease in 1 ureter. Average follow-up was 33 months.\n\n\n\nThis study demonstrates efficacy of docetaxel as a treatment option for patients with UT-CIS with a contraindication to RNU after failing BCG. Response rates of 60% appear to be similar to those of BCG-refractory bladder CIS.", "affiliations": "Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY. Electronic address: [email protected].;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.;Icahn School of Medicine at Mount Sinai, Department of Urology, New York, NY.", "authors": "Katims|Andrew B|AB|;Tam|Andrew W|AW|;Rosen|Daniel C|DC|;Zampini|Anna M|AM|;Atallah|William|W|;Mehrazin|Reza|R|;Gupta|Mantu|M|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.urolonc.2020.08.002", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1439", "issue": "39(4)", "journal": "Urologic oncology", "keywords": "Chemotherapy; Topical therapy; Upper tract; Urothelial carcinoma", "medline_ta": "Urol Oncol", "mesh_terms": null, "nlm_unique_id": "9805460", "other_id": null, "pages": "234.e9-234.e13", "pmc": null, "pmid": "32958446", "pubdate": "2021-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Novel treatment of upper tract urothelial carcinoma in situ with docetaxel in BCG refractory patients.", "title_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients" }

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NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY: SEMINARS AND ORIGINAL INVESTIGATIONS. 2021?39(4):234E9?13", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20210604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19373084, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2021-00861", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "205934", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX WEEKLY INSTILLATIONS OF 80 MG OF DOCETAXEL", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT CARCINOMA IN SITU", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL, UNKNOWN" } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS A, TAM A, ROSEN D, ZAMPINI A, ATALLAH W, MEHRAZIN R. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY. 2020 AUG 02?39(4):234. E9?234 E 13. DOI:10.1016/J.UROLONC.2020.08.002", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210707", "receivedate": "20210707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19499148, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-009507513-2105USA007536", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "102821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INSTILLATION FLUID", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLADDER CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICE BCG" } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB., TAM AW., ROSEN DC., ZAMPINI AM., ATALLAH W, MEHRAZIN R.. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY: SEMINARS AND ORIGINAL INVESTIGATIONS. 2021?39(4):234E9?13", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20210604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19373268, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-009507513-2105USA007531", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "102821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INSTILLATION FLUID", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLADDER CANCER STAGE 0, WITH CANCER IN SITU", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICE BCG" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB., TAM AW., ROSEN DC., ZAMPINI A M., ATALLAH W, MEHRAZIN R,. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY: SEMINARS AND ORIGINAL INVESTIGATIONS. 2021?39(4):234E9?13", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20210604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19373106, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2021-00859", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207575", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT CARCINOMA IN SITU", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE, UNKNOWN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT CARCINOMA IN SITU", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS A, TAM A, ROSEN D, ZAMPINI A, ATALLAH W, MEHRAZIN R. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS.. UROLOGIC ONCOLOGY. 2020 AUG 02?39 (4):234.E9?234.E13. DOI:10.1016/J.UROLONC.2020.08.002", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210707", "receivedate": "20210707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19499146, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-MYLANLABS-2021M1037820", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL 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": "GEMCITABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM, QW MAINTENANCE THERAPY; 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PERCUTANEOUS NEPHROSTOMY TUBE; INDUCTION THERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091062", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL 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": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB, TAM AW, ROSEN DC, ZAMPINI AM, ATALLAH W, MEHRAZIN R, ET AL. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROL?ONCOL 2021?39(4):234.E9?234.E13.", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210628", "receivedate": "20210628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19470659, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-009507513-2105USA007532", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "102821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INSTILLATION FLUID", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLADDER CANCER STAGE 0, WITH CANCER IN SITU", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICE BCG" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB., TAM AW., ROSEN DC., ZAMPINI AM., ATALLAH W, MEHRAZIN R.. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY: SEMINARS AND ORIGINAL INVESTIGATIONS. 2021?39(4):234E9?13", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20210604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19373182, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-009507513-2105USA007534", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "102821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INSTILLATION FLUID", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT CARCINOMA IN SITU", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICE BCG" } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB, TAM AW, ROSEN C, ZAMPINI AM, ATALLAH W, MEHRAZIN R. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY: SEMINARS AND ORIGINAL INVESTIGATIONS. 2021?39(4):234E9?13", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20210604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19373232, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-MYLANLABS-2021M1037819", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "208859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM 6 WEEKS INDUCTION THERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "208859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM, QW, MAINTENANCE THERAPY; FOR THREE WEEKS AT 3, 6, 12, 18, 24, AND 36 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BCG VACCINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL 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": "BCG" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB, TAM AW, ROSEN DC, ZAMPINI AM, ATALLAH W, MEHRAZIN R, ET AL. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROL?ONCOL 2021?39(4):234.E9?234.E13.", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210630", "receivedate": "20210630", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19477220, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2021-00860", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "205934", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT CARCINOMA IN SITU", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL, UNKNOWN" } ], "patientagegroup": "6", "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastatic neoplasm", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS A, TAM A, ROSEN D, ZAMPINI A, ATALLAH W, MEHRAZIN R. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY. 2020 AUG 02?39(4):234. E9?234 E 13. 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NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. 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NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY: SEMINARS AND ORIGINAL INVESTIGATIONS. 2021?39(4):234E9?13", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20210604", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19373183, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-MYLANLABS-2021M1037821", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": "208859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM, QW MAINTENANCE THERAPY; FOR THREE WEEKS AT 3, 6, 12, 18, 24, AND 36 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": "208859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM INDUCTION THERAPY 6 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BCG VACCINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSITIONAL 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": "BCG" } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS AB, TAM AW, ROSEN DC, ZAMPINI AM, ATALLAH W, MEHRAZIN R, ET AL. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROL?ONCOL 2021?39(4):234.E9?234.E13.", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210630", "receivedate": "20210630", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19477253, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2021-00858", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "205934", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION TREATMENT, SIX WEEKLY INSTILLATIONS", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT CARCINOMA IN SITU", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL, UNKNOWN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "205934", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE THERAPY: WEEKLY FOR THREE WEEKS AT 3, 6, 12, 18, 24, AND 36 MONTHS FOLLOWING INDUCTION.", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL, UNKNOWN" } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATIMS A, TAM A, ROSEN D, ZAMPINI A, ATALLAH W, MEHRAZIN R. NOVEL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA IN SITU WITH DOCETAXEL IN BCG REFRACTORY PATIENTS. UROLOGIC ONCOLOGY. 2020 AUG 02?39 (4):234. E9?234 E 13. DOI:10.1016/J.UROLONC.2020.08.002", "literaturereference_normalized": "novel treatment of upper tract urothelial carcinoma in situ with docetaxel in bcg refractory patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210710", "receivedate": "20210710", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19513683, "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": "A 54-year-old man with a long history of severe haemophilia A treated prophylactically with efmoroctocog alpha (3,000 IU twice weekly) was diagnosed with COVID-19 infection. He had multiple risk factors for COVID-19 severity including obesity, diabetes mellitus and hypertension. He required prolonged intensive care unit (ICU) stay due to the severity of respiratory failure until his death on day 24. During his ICU stay, he received a continuous infusion of efmoroctocog alpha in order to maintain factor VIII activity between 80 and 100%, together with therapeutic doses of low-molecular-weight heparin targeting anti-Xa activity above 0.5 IU/mol. He tolerated numerous invasive procedures without bleeding. At post-mortem examination, there was no evidence for thrombosis or haemorrhage in the different organs.", "affiliations": "Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium, [email protected].;Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Haematology, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Haematology, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium.", "authors": "Pinto Pereira|João|J|;Hantson|Philippe|P|;Gerard|Ludovic|L|;Wittebole|Xavier|X|;Laterre|Pierre-François|PF|;Lambert|Catherine|C|;Hermans|Cédric|C|", "chemical_list": "D006495:Heparin, Low-Molecular-Weight; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C587014:factor VIII-Fc fusion protein; D005169:Factor VIII", "country": "Switzerland", "delete": false, "doi": "10.1159/000510591", "fulltext": null, "fulltext_license": null, "issn_linking": "0001-5792", "issue": "144(3)", "journal": "Acta haematologica", "keywords": "COVID-19; Coagulopathy; Haemophilia", "medline_ta": "Acta Haematol", "mesh_terms": "D001780:Blood Coagulation Tests; D000086382:COVID-19; D005169:Factor VIII; D006467:Hemophilia A; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D007141:Immunoglobulin Fc Fragments; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins; D000086402:SARS-CoV-2; D012720:Severity of Illness Index", "nlm_unique_id": "0141053", "other_id": null, "pages": "319-321", "pmc": null, "pmid": "32980842", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": null, "title": "Management of COVID-19 Coagulopathy in a Patient with Severe Haemophilia A.", "title_normalized": "management of covid 19 coagulopathy in a patient with severe haemophilia a" }

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"24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Pereira JP, Hantson P, Gerard L, Wittebole X, Laterre PF, Lambert C, Hermans C. Management of COVID-19 Coagulopathy in a Patient with Severe Haemophilia A. Acta haematologica. 2021; 144(3):317-9. DOI: 10.1159/000510591", "literaturereference_normalized": "management of covid 19 coagulopathy in a patient with severe haemophilia a", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20211027", "receivedate": "20211027", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 20002752, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "BE-SA-2020SA123498", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USE IN UNAPPROVED INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EFMOROCTOCOG ALFA" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3000 IU; TWICE A WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FACTOR VIII DEFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3000", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELOCTA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PINTO PEREIRA J, HANTSON P, GERARD L, WITTEBOLE X, LATERRE PF, LAMBERT C, EL AT.. MANAGEMENT OF COVID-19 COAGULOPATHY IN A PATIENT WITH SEVERE HAEMOPHILIA A.. ACTA HAEMATOL.. 2020?UNK:UNK", "literaturereference_normalized": "management of covid 19 coagulopathy in a patient with severe haemophilia a", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20201207", "receivedate": "20200513", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17779451, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210113" } ]

{ "abstract": "Favipiravir is a novel antiviral drug approved for influenza treatment in Japan. Little is known about favipiravir pharmacokinetics in critically ill patients. Here, we report a patient with influenza treated with favipiravir and undergoing continuous venovenous haemofiltration (CVVH) on the Intensive Care Unit of a tertiary hospital in the Netherlands. Pharmacokinetic analyses showed increased clearance and decreased plasma levels compared to healthy volunteers. CVVH has no clinically relevant contribution to total clearance. Despite susceptibility to favipiravir, the influenza virus was not cleared. A multi-disciplinary approach is needed to ensure optimal favipiravir treatment in critically ill patients.", "affiliations": "Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, the Netherlands.;Laboratory of Medical Microbiology and Immunology, St Elisabeth Hospital Tilburg, Tilburg, the Netherlands.;Centre for Infectious Diseases Research, Diagnostics and Screening, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.;Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, the Netherlands.;Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, the Netherlands.;Intensive Care, University Medical Center Utrecht, Utrecht, the Netherlands.", "authors": "Favié|Laurent Ma|LM|;Murk|Jean-Luc|JL|;Meijer|Adam|A|;Nijstad|A Laura|AL|;van Maarseveen|Erik M|EM|;Sikma|Maaike A|MA|", "chemical_list": "D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D053139:Oseltamivir; C462182:favipiravir", "country": "England", "delete": false, "doi": "10.3851/IMP3210", "fulltext": null, "fulltext_license": null, "issn_linking": "1359-6535", "issue": "23(5)", "journal": "Antiviral therapy", "keywords": null, "medline_ta": "Antivir Ther", "mesh_terms": "D000577:Amides; D000998:Antiviral Agents; D016638:Critical Illness; D017809:Fatal Outcome; D006440:Hemofiltration; D006801:Humans; D007251:Influenza, Human; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D053139:Oseltamivir; D011719:Pyrazines; D062606:Tertiary Care Centers", "nlm_unique_id": "9815705", "other_id": null, "pages": "457-461", "pmc": null, "pmid": "29185991", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza.", "title_normalized": "pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza" }

[ { "companynumb": "NL-ROCHE-2244417", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FAVIPIRAVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3600 MILLIGRAM DAILY; LOADING DOSE ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAVIPIRAVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OSELTAMIVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021087", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM DAILY; LOADING DOSE ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "H1N1 INFLUENZA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OSELTAMIVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OSELTAMIVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021087", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MILLIGRAM DAILY; MAINTENANCE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OSELTAMIVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FAVIPIRAVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MILLIGRAM DAILY; MAINTENANCE DOSE; HALF OF THE MAINTENANCE DOSE WAS GIVEN BECAUSE OF UNKNOWN EFF", "drugenddate": null, "drugenddateformat": null, "drugindication": "H1N1 INFLUENZA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAVIPIRAVIR" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "67", "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FAVIE L, MURK J-L, MEIJER A, LAURA NIJSTAD A, VAN MAARSEVEEN EM, SIKMA MA. PHARMACOKINETICS OF FAVIPIRAVIR DURING CONTINUOUS VENOVENOUS HAEMOFILTRATION IN A CRITICALLY ILL PATIENT WITH INFLUENZA.. ANTIVIRAL-THER 2018?23 (5):457-461.", "literaturereference_normalized": "pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15835894, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-TEVA-2018-NL-991717", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OSELTAMIVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "211125", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM DAILY; LOADING DOSE ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "H1N1 influenza", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OSELTAMIVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OSELTAMIVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "211125", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MILLIGRAM DAILY; MAINTENANCE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OSELTAMIVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FAVIPIRAVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3600 MILLIGRAM DAILY; LOADING DOSE ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "H1N1 influenza", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1800", "drugstructuredosageunit": "003", "drugtreatmentduration": "4", "drugtreatmentdurationunit": "804", "medicinalproduct": "FAVIPIRAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FAVIPIRAVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MILLIGRAM DAILY; MAINTENANCE DOSE; HALF OF THE MAINTENANCE DOSE WAS GIVEN BECAUSE OF UNKNOWN EFF", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": "4", "drugtreatmentdurationunit": "804", "medicinalproduct": "FAVIPIRAVIR" } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "67", "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Favie LMA, Murk J-L, Meijer A, Laura Nijstad A, Van Maarseveen EM, Sikma MA. Pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza. Antiviral-Ther 2018;23(5):457-461.", "literaturereference_normalized": "pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20220304", "receivedate": "20220222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20503586, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220423" } ]

{ "abstract": "BACKGROUND\nEarly detection and monitoring for malignant arrhythmias is fundamental to prenatal care in long QT syndrome (LQTS). Recently, we studied the feasibility of isolating the fetal electrocardiogram (fECG) and measuring electrocardiographic intervals with a noninvasive fECG device using blind source separation with reference signal. Our aim was to evaluate the ability of fECG to diagnose LQTS.\n\n\nMETHODS\nWe identified 3 cases of clinically suspected LQTS based on fetal echocardiogram (2 had sinus bradycardia, 1 had second-degree atrioventricular block with negative maternal anti-SSA/SSB antibody titers). With institutional review board approval, these patients were prospectively enrolled for fECG acquisition. Offline post-processing generated fECG waveforms and calculated QT intervals. Case 1 and 3 had a maternal history of LQTS. Two of the three fetuses with suspected LQTS had confirmed LQTS by postnatal ECG and genetic testing. FECG was able to identify a prolonged corrected QT interval in both cases. One of these also had fetal magnetocardiography (fMCG), which yielded similar findings to the fECG. The third fetus had a normal fECG; fMCG and postnatal ECG were also normal.\n\n\nCONCLUSIONS\nIn 3 cases, fECG findings corroborated the diagnosis of LQTS. Noninvasive fECG may offer a novel method for fECG that is portable and more clinically accessible.", "affiliations": "Division of Cardiology, Children's National Hospital, Washington, District of Columbia, USA, [email protected].;Department of Advanced Interdisciplinary Biomedical Engineering, Tohoku University School of Medicine, Sendai-shi, Miyagi, Japan.;Division of Cardiology, Children's National Hospital, Washington, District of Columbia, USA.;Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, District of Columbia, USA.;Division of Cardiology, Children's National Hospital, Washington, District of Columbia, USA.;Biomagnetism Laboratory, University of Wisconsin-Madison, Madison, Wisconsin, USA.;Division of Cardiology, Herma Heart Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.;Division of Cardiology, Children's National Hospital, Washington, District of Columbia, USA.;Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.;Department of Advanced Interdisciplinary Biomedical Engineering, Tohoku University School of Medicine, Sendai-shi, Miyagi, Japan.;Division of Cardiology, Children's National Hospital, Washington, District of Columbia, USA.", "authors": "Sethi|Neeta|N|;Funamoto|Kiyoe|K|;Ingbar|Catherine|C|;Mass|Paige|P|;Moak|Jeffrey|J|;Wakai|Ronald|R|;Strasburger|Janette|J|;Donofrio|Mary|M|;Khandoker|Ahsan|A|;Kimura|Yoshitaka|Y|;Krishnan|Anita|A|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000508043", "fulltext": null, "fulltext_license": null, "issn_linking": "1015-3837", "issue": "47(9)", "journal": "Fetal diagnosis and therapy", "keywords": "Arrhythmias; Congenital long QT syndrome; Noninvasive fetal electrocardiography; Prenatal diagnosis", "medline_ta": "Fetal Diagn Ther", "mesh_terms": "D000328:Adult; D004562:Electrocardiography; D005260:Female; D005318:Fetal Heart; D006340:Heart Rate, Fetal; D006801:Humans; D008133:Long QT Syndrome; D053798:Magnetocardiography; D011247:Pregnancy; D011295:Prenatal Care; D011296:Prenatal Diagnosis; D055815:Young Adult", "nlm_unique_id": "9107463", "other_id": null, "pages": "711-716", "pmc": null, "pmid": "32615554", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "21908954;22776830;24858320;11920893;19731233;12767447;25640061;29654130;10962758;24218437;24763516;17260855;31172229;18486565;22717013;27539165;12478635;28491768", "title": "Noninvasive Fetal Electrocardiography in the Diagnosis of Long QT Syndrome: A Case Series.", "title_normalized": "noninvasive fetal electrocardiography in the diagnosis of long qt syndrome a case series" }

[ { "companynumb": "US-PFM-2022-03516", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Long QT syndrome", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "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": "PROPRANOLOL" } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Sethi N, Funamoto K, Ingbar C, Mass P, Moak J, Wakai R et al. Noninvasive fetal electrocardiography in the diagnosis of long QT syndrome: A case series. Fetal diagnosis and therapy. 2020;47(9):711-6", "literaturereference_normalized": "noninvasive fetal electrocardiography in the diagnosis of long qt syndrome a case series", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220614", "receivedate": "20220614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20958066, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]

{ "abstract": "Pneumocystis jirovecii is a common cause of pneumonia in patients with advanced HIV. In a lot of cases, there is a concomitant pulmonary infection. Cryptococcosis presents as a common complication for people with advanced HIV. However, it usually presents as meningitis rather than pneumonia. We present a case of a patient with coinfection by P. jirovecii and Cryptococcus spp without neurological involvement and a single nodular pulmonary lesion.", "affiliations": "Internal Medicine Department, Centro Medico ABC, Ciudad de México, Mexico [email protected].;Internal Medicine Department, Centro Medico ABC, Ciudad de México, Mexico.;Escuela de Medicina, Instituto Tecnologico y de Estudios Superiores de Monterrey Campus Ciudad de Mexico, Tlalpan, Mexico.", "authors": "Valente-Acosta|Benjamin|B|http://orcid.org/0000-0001-9885-3594;Padua-Garcia|José|J|;Tame-Elorduy|Andrés|A|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/bcr-2019-233607", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "13(4)", "journal": "BMJ case reports", "keywords": "Cryptococcus; HIV / AIDS; cryptococcosis; pneumonia (infectious disease)", "medline_ta": "BMJ Case Rep", "mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D060085:Coinfection; D003453:Cryptococcosis; D003454:Cryptococcus; D015658:HIV Infections; D006801:Humans; D008168:Lung; D008297:Male; D008800:Mexico; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32295797", "pubdate": "2020-04-14", "publication_types": "D002363:Case Reports", "references": null, "title": "Pulmonary coinfection by Pneumocystis jirovecii and Cryptococcus species in a patient with undiagnosed advanced HIV.", "title_normalized": "pulmonary coinfection by pneumocystis jirovecii and cryptococcus species in a patient with undiagnosed advanced hiv" }

[ { "companynumb": "MX-GILEAD-2020-0467218", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EMTRICITABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "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": "EMTRIVA" }, { "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": "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": "VIREAD" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOLUTEGRAVIR" }, "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": "DOLUTEGRAVIR" } ], "patientagegroup": "5", "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VALENTE-ACOSTA B., PADUA-GARCIA J., TAME-ELORDUY A.. PULMONARY COINFECTION BY PNEUMOCYSTIS JIROVECII AND CRYPTOCOCCUS SPECIES IN A PATIENT WITH UNDIAGNOSED ADVANCED HIV. BMJ CASE REPORTS. 2020?13 (4):NO PAGINATION", "literaturereference_normalized": "pulmonary coinfection by pneumocystis jirovecii and cryptococcus species in a patient with undiagnosed advanced hiv", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20200519", "receivedate": "20200519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17804294, "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" } ]

{ "abstract": "BACKGROUND\nTacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT).\n\n\nMETHODS\nTwenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake.\n\n\nRESULTS\nThirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele.\n\n\nCONCLUSIONS\nCYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.", "affiliations": "Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan. [email protected].;Department of Pharmacy, Akita University Hospital, Akita, Japan.;Department of Pharmacy, Akita University Hospital, Akita, Japan.;Department of Pharmacy, Akita University Hospital, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.", "authors": "Yamashita|Takaya|T|;Fujishima|Naohito|N|;Miura|Masatomo|M|;Niioka|Takenori|T|;Abumiya|Maiko|M|;Shinohara|Yoshinori|Y|;Ubukawa|Kumi|K|;Nara|Miho|M|;Fujishima|Masumi|M|;Kameoka|Yoshihiro|Y|;Tagawa|Hiroyuki|H|;Hirokawa|Makoto|M|;Takahashi|Naoto|N|", "chemical_list": "D000935:Antifungal Agents; D001393:Azoles; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus", "country": "Germany", "delete": false, "doi": "10.1007/s00280-016-3060-4", "fulltext": "\n==== Front\nCancer Chemother PharmacolCancer Chemother. PharmacolCancer Chemotherapy and Pharmacology0344-57041432-0843Springer Berlin Heidelberg Berlin/Heidelberg 306010.1007/s00280-016-3060-4Original ArticleEffects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation Yamashita Takaya Fujishima Naohito [email protected] Miura Masatomo Niioka Takenori Abumiya Maiko Shinohara Yoshinori Ubukawa Kumi Nara Miho Fujishima Masumi Kameoka Yoshihiro Tagawa Hiroyuki Hirokawa Makoto Takahashi Naoto Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan Division of Blood Transfusion, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543 Japan Department of Pharmacy, Akita University Hospital, Akita, Japan Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan 23 5 2016 23 5 2016 2016 78 111 118 15 12 2015 10 5 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.Background\nTacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT).\n\nDesign and methods\nTwenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake.\n\nResults\nThirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele.\n\nConclusions\nCYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1007/s00280-016-3060-4) contains supplementary material, which is available to authorized users.\n\nKeywords\nOnce-daily tacrolimus formulationCYP3A5 polymorphismAzole antifungal agentPharmacokineticsHematopoietic stem cell transplantationissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2016\n==== Body\nIntroduction\nTacrolimus has been widely used to prevent graft rejection following solid organ transplantation and hematopoietic stem cell transplantation (HSCT). Tacrolimus plus methotrexate is regarded as one of the standard methods of graft-versus-host disease (GVHD) prophylaxis after allogeneic HSCT. Given that tacrolimus has a narrow therapeutic window and that there are inter- and intra-individual variations in pharmacokinetics, blood concentrations of tacrolimus are usually monitored to maintain adequate exposure and to prevent drug-related toxicities [1].\n\nTacrolimus is given intravenously in the early phase after HSCT and then switched to oral administration. Oral tacrolimus was first developed as a twice-daily (BID: bis in die) formulation (Tac-BID). Then, a once-daily modified-release (QD: quaque die) formulation of tacrolimus (Tac-QD) was developed to provide more convenient dosing and to improve patient adherence [2]. In solid organ transplantation, initial clinical trials showed that the pharmacokinetic parameters of Tac-BID and Tac-QD were equivalent on a mg for mg basis, and Tac-QD was well tolerated with similar efficacy and safety profiles to Tac-BID [3–6]. However, studies of the pharmacokinetics of Tac-QD administration in the HSCT setting are few in number compared with solid organ transplantation. Thus, the pharmacokinetics of inter-individual variations of blood concentration of tacrolimus in transplant patients with Tac-QD after HSCT are yet to be determined.\n\nMany clinical and genetic factors affect the pharmacokinetics of tacrolimus [7]. Cytochrome P450 (CYP) 3A4, CYP3A5 and ATP-binding cassette subfamily B member 1 (ABCB1) reportedly contribute to inter-individual variability in the absorption, metabolism and tissue distribution of tacrolimus. Moreover, CYP3A5 may play a dominant role over that of CYP3A4 in the metabolism of tacrolimus in individuals who express the CYP3A5 enzyme [8–12]. CYP3A5 is polymorphically expressed, and more than 10 single nucleotide polymorphisms (SNPs) have been identified [9]. The most important SNP related to functional variation is CYP3A5 6986A > G, in which the wild-type allele is CYP3A5*1 and the variant allele is CYP3A5*3 [13]. Homozygous carriers of the CYP3A5*3 gene (CYP3A5*3/*3) should lack functional CYP3A5 protein [14–18]. There are racial differences in the frequencies of CYP3A5 polymorphisms [15, 19–21]. The frequencies of CYP3A5*3/*3 were reported to be 56.7–60.5 % in Japanese, 86 % in Caucasians and 23 % in the African-American population. Although there are many genetic variants of CYP3A4 and ABCB1, the majority of studies have failed to find an association between the CYP3A4 or ABCB1 genotypes and tacrolimus pharmacokinetics [9]. These studies have demonstrated that trough blood concentrations or area under the blood concentration–time curve (AUC) of tacrolimus was higher in patients with the CYP3A5*3/*3 genotype than those with the CYP3A5*1 allele, and the required daily dosage of tacrolimus was significantly reduced.\n\nOur colleagues have previously reported the impact of CYP3A5 polymorphism on the pharmacokinetics of tacrolimus in kidney transplantation patients receiving Tac-QD administration [22–25]. However, the effect of the CYP3A5 genotype on the pharmacokinetics of Tac-QD in HSCT patients has yet to be clarified [13]. Although azole antifungal agents (AZ) are most often used for the prevention as well as the treatment of these infections in HSCT patients, these agents interfere with the metabolism and transport of tacrolimus [26]. In addition, the magnitude of drug interactions between AZs and tacrolimus differs between AZs (itraconazole = voriconazole > fluconazole) [27, 28]. Here, we investigated the safety and efficacy of Tac-QD in HSCT patients. We focused on CYP3A5 polymorphism and the interaction of Tac-QD with AZ.\n\nMethods\nRecipients and protocols of transplantation\nThis study was conducted as a single-institution, prospective cohort study to evaluate the safety and efficacy of Tac-QD in allogeneic HSCT patients. The eligibility criteria for the present study were as follows: (1) HSCT patients were given the same immunosuppressive regimens for the prophylaxis of GVHD; (2) age > 16 years; (3) no hypersensitivity to tacrolimus (Prograf® or Graceptor®); (4) no liver dysfunction [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level < fivefold the upper normal range and total bilirubin level < 2.0 mg/dL]; (5) no renal dysfunction (serum creatinine level < 2.0 mg/dL or creatinine clearance > 30 mL/min); and (6) no consumption of drugs or food affecting CYP3A and ABCB1 function. Twenty-four patients (17 males and 7 females) who underwent allogeneic HSCT at Akita University Hospital between April 2012 and October 2014 were enrolled in this study.\n\nProphylaxis regimens against GVHD included tacrolimus and methotrexate in the majority of patients, or variations including mycophenolate mofetil. Continuous infusion of 0.03 mg/kg/day tacrolimus was administered from the day prior to stem cell infusion. Tacrolimus administration was converted from intravenous administration to once-daily oral intake after adequate oral intake was observed. A quadruple dose of intravenous daily dose as an initial Tac-QD was administrated orally. The target whole blood concentrations of tacrolimus were 10–20 ng/mL with continuous infusion and 5–10 ng/mL after switching to oral administration. The whole blood concentrations of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay (CMIA).\n\nIntravenous infusion of micafungin was given to prevent fungal infection during the neutropenic phase. Seven days after switching from tacrolimus continuous infusion to Tac-QD, antifungal agents were switched from intravenous micafungin to oral AZ.\n\nThis study was approved by the Ethics Committee of the Akita University School of Medicine, and each patient provided written informed consent in accordance with the Declaration of Helsinki.\n\nGenotyping\nDNA was extracted from a peripheral blood sample using the QIAamp Blood kit (Qiagen, Hilden, Germany) and stored at −80 °C until analysis. The CYP3A5*3 allele was detected using a PCR-restriction fragment length polymorphism (RFLP) method [20]. The results obtained from PCR–RFLP analyses were confirmed using a fully automated SNP detection system (prototype i-density™; ARKRAY, Kyoto, Japan). The results of CYP3A5 genotyping were not used to adjust Tac-QD dosage or to score acute GVHD.\n\nBlood concentration of tacrolimus\nWhole blood samples were collected with EDTA just prior to the morning administration of Tac-QD 4–7 days after switching from continuous infusion to Tac-QD. Also, samples were collected 4–7 days after switching from intravenous micafungin to oral AZ. During both periods, whole blood tacrolimus concentrations were measured every day to confirm the stability of tacrolimus trough concentrations. Whole blood tacrolimus concentrations were determined using CMIA on the Architect-i1000® system (Abbott Laboratories, Abbott Park, IL) according to the manufacturer’s instructions. The Architect tacrolimus assay is a semiautomated, robust and highly sensitive immunoassay. It represents an alternative approach for laboratories that are not equipped with an LC-MSMS, and it meets the 1 ng/mL LOQ recommendation of the European Consensus Conference on Tacrolimus Optimization [29]. LOQ values for CMIA are reported to be 0.5–0.8 ng/mL, and CMIA exhibits cross-reactivity of 94 % to the tacrolimus active metabolite, 31-O-demethyl tacrolimus (M-II) [29, 30]. The reliable range of determination of tacrolimus with the Architect-i1000® instrument is between 0.5 and 30 ng/mL [31, 32].\n\nDefinition of acute kidney injury\nAcute kidney injury (AKI) was defined according to CTCAE version 4.0: serum creatinine increased 0.3 mg/dL or more, or more than 1.5 times from the baseline of serum creatinine. Baseline serum creatinine was the value obtained before the start of conditioning therapy.\n\nStatistical analyses\nThe primary endpoint of this study was the analysis of the pharmacokinetic behavior of Tac-QD based on CYP3A5 polymorphisms. The secondary endpoints were the assessments of the development of acute GVHD and the transplantation-related mortality on day 100. The Kolmogorov–Smirnov test was used to assess distribution. The clinical characteristics of the HSCT patients, dose-adjusted blood concentrations and changes in these parameters were expressed as medians (quartiles 1–3). The Chi-square test was used to examine differences in categorical data, except when the expected number of cells was <5, in which case the Fisher’s exact test was used. The Mann–Whitney U test was used to determine the significance of difference between continuous values between the groups. The Wilcoxon paired signed-rank test was used to determine the significance of differences in continuous values within each patient. A receiver operating characteristic (ROC) curve was used to determine the best cutoff values for predictive factors that had a minimum distance from the upper left corner to a point on the ROC curve. The proportion of patients showing no clinical events was estimated using the Kaplan–Meier method. The time to clinical events was compared between the groups using the stratified log-rank test. A P value <0.05 was considered to be statistically significant. For post hoc power analysis, an effect size was calculated in comparison with clinical characteristics between recipients with or without AKI after co-administration of AZs. An effect size >0.5 was considered clinically meaningful. Statistical analyses were performed using SPSS version 20.0 software for Windows (SPSS IBM Japan, Tokyo, Japan). Power was calculated using G*Power version 3.1 software.\n\nResults\nCYP3A5 genetic polymorphism and outcome after HSCT\nThe characteristics of patients are given in Table 1. The CYP3A5 genotype frequency was in Hardy–Weinberg equilibrium [19]. Eleven patients had either the CYP3A5*1/*1 or *1/*3 genotype, and 13 patients had the CYP3A5*3/*3 genotype. There was no significant difference in the ages, body weights, underlying diseases, pre-HSCT disease status, graft sources, extents of HLA allele matching or conditioning regimens between the two groups. Three patients could not switch to oral AZ due to severe infection. Fluconazole was used in 15 of 21 patients who were given oral AZ. Three patients received itraconazole, whereas another 3 patients were treated with voriconazole.Table 1 Characteristics of HSCT recipients\n\nCharacteristics\t\nCYP3A5\n\t\nCYP3A5\n\t\nP value\t\n\n*1/*1 or *1/*3\n\t\n*3/*3\n\t\nNumber of recipients\t11\t13\t\t\nMale/female\t8/3\t9/4\t\t\nAge [years, median (range)]\t39 (21–63)\t55 (36–65)\t0.124\t\nBody weight [kg, median (range)]\t51 (49–66)\t61 (49–69)\t0.825\t\nDiagnosis\t\t\t0.622\t\n AML/MDS\t8\t11\t\t\n ALL\t3\t2\t\t\nState before HSCT\t\t\t0.265\t\n CR1\t2\t4\t\t\n CR2 or CR3\t3\t5\t\t\n Non-remission\t6\t4\t\t\nGraft source\t\t\t0.247\t\n BM from unrelated donors\t10\t8\t\t\n PBSC from sibling donors\t0\t2\t\t\n Umbilical cord blood\t1\t3\t\t\nHLA allele matching\t\t\t0.543\t\n 5/8\t1\t2\t\t\n 6/8\t2\t0\t\t\n 7/8\t2\t7\t\t\n 8/8\t6\t4\t\t\nConditioning\t\t\t0.271\t\n Reduced intensity\t3\t7\t\t\n Myeloablative\t8\t6\t\t\nGVHD prophylaxis\t\t\t0.397\t\n MTX\t11\t11\t\t\n MMF\t0\t1\t\t\n MTX + MMF\t0\t1\t\t\nIn combination with AZ\t\t\t0.855\t\n Fluconazole\t7\t8\t\t\n Itraconazole\t1\t2\t\t\n Voriconazole\t1\t2\t\t\n\nAML acute myeloid leukemia, MDS myelodysplastic syndrome, ALL acute lymphoblastic leukemia, HSCT hematopoietic stem cell transplantation, CR complete remission, BM bone marrow, PBSC peripheral blood stem cell, HLA human leukocyte antigen, GVHD graft-versus-host disease, MTX methotrexate, MMF mycophenolate mofetil, AZ azole antifungal agent\n\n\n\nThere was no transplantation-related mortality on day 100 in the present study cohort (Table 2). Two patients with relapse of the underlying disease and two patients with fungal infection were noted. There was a significant difference in the cumulative incidence of grade III–IV severe acute GVHD between the patients with the CYP3A5*1 allele and the CYP3A5*3/*3 allele (36 vs. 0 %, P = 0.017). The incidence of AKI was higher in the CYP3A5*3/*3 group than in the *1 allele group (46 vs. 9 %, respectively, P = 0.046).Table 2 Acute GVHD, TRM, relapse, fungal infection and AKI during the first 100 days\n\n\nCYP3A5 genotype\t\n*1/*1 or *1/*3 (n = 11)\t\n*3/*3 (n = 13)\t\nP value\t\nAcute GVHD\t\t\t0.173\t\n Grade 0\t5\t8\t\t\n Grade 1\t1\t1\t\t\n Grade 2\t1\t4\t\t\n Grade 3\t3\t0\t\t\n Grade 4\t1\t0\t\t\nAcute GVHD\t\t\t0.017\t\n Grade 0–2\t7\t13\t\t\n Grade 3–4\t4\t0\t\t\nTRM\t0\t0\t\t\nRelapse\t1\t1\t0.902\t\nFungal infection\t1\t1\t0.902\t\nAKI\t1\t6\t0.046\t\n\nGVHD graft-versus-host disease, TRM transplantation-related-mortality, AKI acute kidney injury\n\n\n\nPharmacokinetics of Tac-QD during administration of oral AZ\nWithout co-administration of oral AZ, neither the tacrolimus C0 nor the median daily dose of tacrolimus differed between the CYP3A5*3/*3 and the CYP3A5*1 allele groups (3.5 vs. 3.3 mg/day, respectively, P = 0.965 or 7.9 vs. 4.9 ng/mL, P = 0.053) (Fig. 1a). On the other hand, in the presence of AZ, tacrolimus C0 values were higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele (10.1 vs. 7.4 ng/mL, respectively, P = 0.034) (Fig. 1b). The daily dose of tacrolimus was significantly lower in patients with the CYP3A5*3/*3 allele than with the *1 allele (2.0 vs. 4.0 mg/day, respectively, P = 0.041).Fig. 1 Comparison of doses (box and whiskers plots) and the tacrolimus trough levels (open circles) between the CYP3A5*1*1 + *1/*3 group and the *3/*3 group. a Before co-administration of AZ and b after co-administration of AZ. Graphical analysis was performed using an SPSS box and whiskers plot. The box spans data between two quartiles (IQR), with the median represented as a bold horizontal line. The ends of the whiskers (vertical lines) represent the smallest and largest values that were not outliers. The gray circles represent the outlier of dose. AZ azole antifungal agent\n\n\n\nAKI occurred in the CYP3A5*3/*3 group after co-administration of AZ\nSeven patients developed AKI in the present study. In order to properly study the impact of Tac-QD and co-administration of AZ, we excluded the three patients who did not receive AZ and the one patient who developed AKI prior to the administration of Tac-QD (Table 3). The median tacrolimus C0 with administration of AZ in patients with AKI was about twice that of patients without AKI (16.3 vs. 8.6 ng/mL, P = 0.020, effect size = 0.517). Furthermore, only the patients with the CYP3A5*3/*3 developed AKI (6/6 vs. 6/14 patients, P = 0.024, effect size = 0.535). AKI occurred within 14 days of starting co-administration of AZ (Supplementary Fig. 1).Table 3 Comparison of clinical characteristics between recipients with or without AKI after co-administration of azole antifungal agents\n\n\tWith AKI\tWithout AKI\t\nP value\t\nSex\t\t\t0.613\t\n Male\t4\t10\t\t\n Female\t2\t4\t\t\nCYP3A5 genotypes\t\t\t0.024\t\n *1/*1 or *1/*3\n\t0\t8\t\t\n *3/*3\n\t6\t6\t\t\nAge [years, median (range)]\t60 (39–63)\t53 (37–61)\t0.353\t\nBody weight [kg, median (range)]\t55.1 (46.8–63.3)\t61.5 (48.6–75.0)\t0.097\t\nIn combination with\t\t\t0.239\t\n Fluconazole\t4\t11\t\t\n Itraconazole\t2\t1\t\t\n Voriconazole\t0\t2\t\t\nDose of tacrolimus (mg/day)\t2.0 (1.5–5.0)\t3.5 (3.0–4.0)\t0.659\t\nTacrolimus C0 (ng/mL)\t16.3 (13.4–16.4)\t8.6 (6.8–9.1)\t0.020\t\n\nAKI acute kidney injury\n\n\n\nThe tacrolimus C0 value was higher after co-administration of AZ in most patients than without, and AKI was observed only after co-administration of AZ (Fig. 2). The area under the ROC for the tacrolimus C0 to develop AKI after co-administration of AZ was 0.833, which gave the best sensitivity (83.3 %) and specificity (85.7 %) at a tacrolimus C0 threshold of 10.1 ng/mL (data not shown).Fig. 2 Comparisons of the tacrolimus trough levels according to the presence or absence of a co-administered AZ. Circles fluconazole; triangles voriconazole; boxes itraconazole; closed figures patients with AKI. AZ azole antifungal agent, AKI acute kidney injury\n\n\n\nEighty percent of the CYP3A5*3/*3 group were required to reduce the daily dose of Tac-QD by 50 % or more within 14 days of co-administration of AZ (Fig. 3). The reduction in the Tac-QD dosage in patients with the CYP3A5*3/*3 was significantly faster than those with the CYP3A5*1 allele (P = 0.020).Fig. 3 Cumulative incidence of dose attenuation of tacrolimus from baseline (<50 %) after co-administration of AZ. Solid line, CYP3A5*1*1 + *1/*3; dotted line, CYP3A5*3/*3. Median time to reduction in tacrolimus dosage was 8.0 days in the CYP3A5*3/*3 group and not reached in the CYP3A5*1*1 + *1/*3 group. AZ azole antifungal agent\n\n\n\nDiscussion\nThis is the first study to assess the inter-individual variability of tacrolimus blood concentrations in allogeneic HSCT patients who were given Tac-QD. The results were clearly dependent upon the CYP3A5 polymorphism. There are three clinically important findings in the present study. First, the CYP3A5 polymorphism had a great influence on the blood concentrations of tacrolimus, even when the once-daily modified-release formulation was used. Second, the blood concentrations of tacrolimus in patients with CYP3A5*3/*3 was elevated markedly after co-administration of AZ, even when the patients had been given fluconazole, which is recognized as having the lowest CYP3A4 inhibitory activity among AZs. Finally, the CYP3A5*3/*3 group with AZ developed AKI when the blood concentrations of tacrolimus were over 10.1 ng/mL.\n\nOur colleagues previously reported that the CYP3A5 polymorphism had no impact on the dose-adjusted AUC0–24 of tacrolimus during continuous intravenous infusion in kidney transplantation patients. However, the bioavailability of oral tacrolimus was higher for the CYP3A5*3/*3 group than for the CYP3A5*1 allele group [33]. Also in the present study, we investigated the pharmacokinetics of tacrolimus when switching from intravenous infusion to oral administration and antifungal agents. AZ has a stronger inhibitory effect on CYP3A4 activity than on CYP3A5 in the small intestine [27, 28], and tacrolimus is metabolized by CYP3A4 in patients expressing CYP3A5*3/*3. As a result of CYP3A4 inhibition with AZ in the small intestine, we found that the C0 of tacrolimus was elevated markedly in CYP3A5*3/*3 patients after co-administration of AZ (Fig. 1). It has been reported that the blood concentration of tacrolimus was higher in patients with the CYP3A5*3/*3 than those with the CYP3A5*1 allele in the absence of co-administration of AZ in HSCT and kidney transplantation [17, 34]. We previously confirmed that the influence of CYP3A5 polymorphism on the tacrolimus dosage became evident 14 days after kidney transplantation [35]. Between the two genotypes, we did not observe a significant difference in the C0 value of tacrolimus or daily doses of Tac-QD before co-administration of oral AZ. However, it may be too short a time to observe differences in the blood concentration and doses of tacrolimus after switching to oral tacrolimus.\n\nCYP3A5 is expressed in the liver and small intestine [8, 36, 37], and it plays a key role in the small intestine [15]. The interaction between tacrolimus and AZ is depicted in Fig. 3. In patients with the CYP3A5*1 allele, tacrolimus can be metabolized by CYP3A5 in the intestinal epithelium when oral AZ is given, resulting in inhibition of CYP3A4 activity. In contrast, the metabolism of tacrolimus in the CYP3A5*3/*3 group proceeds only through CYP3A4 in the presence of oral AZ. Since HSCT recipients are at high risk of developing invasive fungal infection [23], antifungal agents are commonly used therapeutically and/or prophylactically. Many factors contribute to variability in the clinical significance of drug interactions between tacrolimus and AZ [27, 34, 38, 39]. Although the strong inhibition of CYP3A4 and P-glycoprotein by itraconazole is well known, many reports suggested that the influence of fluconazole on CYP3A4 may be less than other AZ agents [26–28]. In the present study, 15 patients were given fluconazole and eight of them carried the CYP3A5*3/*3. Four patients who were given fluconazole in the CYP3A5*3/*3 group showed nephrotoxicity (Fig. 2). Kuypers et al. [40] reported similar results, in that the CYP3A5*3/*3 patients who were given fluconazole were more frequently exposed to supra-therapeutic tacrolimus C0. Our study suggests that co-administration of fluconazole with Tac-QD in the CYP3A5*3/*3 may cause not only elevation of tacrolimus blood concentrations but also kidney injury.\n\nTacrolimus has a narrow therapeutic window in HSCT, and Yano et al. [41] reported that the modification of Tac-QD to maintain a whole tacrolimus C0 above 7.5 ng/mL may be as effective as Tac-BID, and no patient developed grade III–IV acute GVHD. On the other hand, we demonstrated that nephrotoxicity of tacrolimus may increase when tacrolimus C0 was above 10.1 ng/mL (Fig. 2). By maintaining the tacrolimus C0 under 10 ng/mL, we may prevent nephrotoxicity in patients who are given Tac-QD with AZ. As Ram et al. reported [1], a higher mean blood concentration of tacrolimus during the second week following HSCT was also correlated with protection against grade III–IV acute GVHD (Supplementary Fig. 2). The number of subjects was quite small, and we could not identify the clinical significance of the blood concentration of tacrolimus and CYP3A5 genotype. Studies consisting of a large number of subjects will be needed.\n\nUnlike kidney transplantation, the administration of antifungal agents is usually required for allogeneic HSCT. CYP3A5 genotyping may be useful for determination of the appropriate dose of Tac-QD and the selection of AZ, in order to avoid AKI as well as severe acute GVHD. We need further prospective study to determine whether appropriate therapeutic drug monitoring based on stratified doses of tacrolimus in the setting of CYP3A5 polymorphism can prevent AKI.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary Fig. 1. Cumulative incidence of AKI after co-administration of AZ in the CYP3A5*1*1 + *1/*3 group and the *3/*3 group with AZ. Solid line, the CYP3A5*1*1 + *1/*3 group; dotted line, the CYP3A5*3/*3 group. AZ: azole antifungal agent, AKI: acute kidney injury (TIFF 25 kb)\n\n Supplementary Fig. 2. Cumulative incidence of grade III–IV GVHD after hematopoietic stem cell transplantation in the CYP3A5*1*1 + *1/*3 group and the *3/*3 group with AZ. Solid line, the CYP3A5*1*1 + *1/*3 group; dotted line, the CYP3A5*3/*3 group. GVHD: graft-versus-host disease (TIFF 41 kb)\n\n \n\nAuthor contributions\nTY and NF performed the research, designed the study, collected and analyzed the data, and wrote the paper; MM, TN, MH and NT analyzed the data and revised the manuscript; MA, YS, KU, MN, MF, YK and HT collected and analyzed the data, and revised the manuscript. All authors are responsible for the scientific content of this manuscript and approved the manuscript to be published.\n\nCompliance with ethical standards\nConflict of interest\nThe authors reported no potential conflict of interest.\n==== Refs\nReferences\n1. Ram R Storer B Mielcarek M Association between calcineurin inhibitor blood concentrations and outcomes after allogeneic hematopoietic cell transplantation Biol Blood Marrow Transplant 2012 18 414 422 10.1016/j.bbmt.2011.08.016 21875504 \n2. 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Nara M Takahashi N Miura M Effect of itraconazole on the concentrations of tacrolimus and cyclosporine in the blood of recipients receiving allogeneic hematopoietic stem cell transplants Eur J Clin Pharmacol 2013 69 1321 1329 10.1007/s00228-013-1471-2 23354810 \n40. Kuypers DR de Jonge H Naesens M Vanrenterghem Y Effects of CYP3A5 and MDR1 single nucleotide polymorphisms on drug interactions between tacrolimus and fluconazole in renal allograft recipients Pharmacogenet Genomics 2008 18 861 868 10.1097/FPC.0b013e328307c26e 18704002 \n41. Yano S Mori S Saito T Pharmacokinetics for once-daily modified release formulation of tacrolimus hydrate in unrelated hematopoietic stem cell transplantation Ann Hematol 2015 94 491 496 10.1007/s00277-014-2233-7 25325985\n\n", "fulltext_license": "CC BY", "issn_linking": "0344-5704", "issue": "78(1)", "journal": "Cancer chemotherapy and pharmacology", "keywords": "Azole antifungal agent; CYP3A5 polymorphism; Hematopoietic stem cell transplantation; Once-daily tacrolimus formulation; Pharmacokinetics", "medline_ta": "Cancer Chemother Pharmacol", "mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000483:Alleles; D000935:Antifungal Agents; D001393:Azoles; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies; D016559:Tacrolimus; D055815:Young Adult", "nlm_unique_id": "7806519", "other_id": null, "pages": "111-8", "pmc": null, "pmid": "27217047", "pubdate": "2016-07", "publication_types": "D018848:Controlled Clinical Trial; D016428:Journal Article", "references": "20840481;12242601;19258928;12406645;23354810;21875504;20534291;15502717;25801146;20818295;12228187;17125435;20216110;21861541;23955548;20840480;20170205;1385058;17635182;18704002;23733010;25565672;16501005;25325985;16205037;14961555;17049058;26218924;23073468;12966368;21168673;25594874;21158926;25429674;25303300;19142177;17965516;12490779;21102498;21528942;10709776", "title": "Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation.", "title_normalized": "effects of cyp3a5 polymorphism on the pharmacokinetics of a once daily modified release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation" }

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{ "abstract": "Objectives: Cranial neuropathies (CNs) can be due to a wide spectrum of causes, and the differential diagnosis is particularly challenging in patients with positive history of hematological malignancies, when neoplastic meningitis (NM) must be excluded.Patients and Methods: We retrospectively selected a series of twelve haematological patients with isolated cranial neuropathies (ICNs) or multiple cranial neuropathies (MCNs). among 71 patients that developed neurologic symptoms during different stages of the cancer, between 1 January, 2010 and 31 December, 2017. Brain and cauda equina magnetic resonance imaging (MRI) with gadolinium, cerebrospinal fluid (CSF) analysis, including flow cytometry for cell immunophenotyping and microbiological exams were performed in all patients.Results: Patients developed signs and symptoms of involvement of isolated (n = 11) or multiple (n = 1) cranial nerves, at different stages of the primary disease, and, in 5 of these cases in complete remission after hematopoietic stem cell transplantation. Among the 5 cases that eventually were diagnosed as having NM, cerebrospinal fluid was positive for neoplastic cells in 3, and MRI gadolinium-enhancement was present in 3. The other episodes were attributed to heterogeneous pathologies that were unrelated to meningeal infiltration by neoplastic cells.Conclusions: Our observations confirm that NM in haematological malignancies can yield insidious isolated signs of cranial nerves. Only a multidisciplinary approach allows prompt recognition of these conditions through a challenging process of differential diagnosis, and proper therapies.", "affiliations": "IRCCS C. Mondino Foundation, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.;Department of Microbiology and Virology, Molecular Virology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.;Transplantation Unit, Department of Hematology and Oncology, Foundation IRCCS, Policlinico San Matteo, Pavia, Italy.;IRCCS C. Mondino Foundation, Pavia, Italy.", "authors": "Diamanti|Luca|L|;Berzero|Giulia|G|;Franciotta|Diego|D|;Bini|Paola|P|;Furione|Milena|M|;Farina|Lisa Maria|LM|;Bastianello|Stefano|S|;Colombo|Anna Amelia|AA|;Marchioni|Enrico|E|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/00207454.2019.1705810", "fulltext": null, "fulltext_license": null, "issn_linking": "0020-7454", "issue": "130(8)", "journal": "The International journal of neuroscience", "keywords": "Cranial neuropathies; leukemia; lymphoma; neoplastic meningitis", "medline_ta": "Int J Neurosci", "mesh_terms": "D000328:Adult; D001921:Brain; D002420:Cauda Equina; D003389:Cranial Nerve Diseases; D003937:Diagnosis, Differential; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia; D008223:Lymphoma; D008279:Magnetic Resonance Imaging; D008297:Male; D055756:Meningeal Carcinomatosis; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies", "nlm_unique_id": "0270707", "other_id": null, "pages": "777-780", "pmc": null, "pmid": "31906752", "pubdate": "2020-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Cranial nerve palsies in patients with hematological malignancies: a case series.", "title_normalized": "cranial nerve palsies in patients with hematological malignancies a case series" }

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{ "abstract": "Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.", "affiliations": "Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Postgraduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Postgraduate School in Clinical Pharmacology and Toxicology, University of Campania \"L. Vanvitelli\", 80138 Naples, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Postgraduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy.;Postgraduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Postgraduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, 84081 Baronissi, Italy.", "authors": "Conti|Valeria|V|;De Bellis|Emanuela|E|;Manzo|Valentina|V|;Sabbatino|Francesco|F|;Iannello|Francesco|F|;Dal Piaz|Fabrizio|F|;Izzo|Viviana|V|0000-0001-6066-7569;Charlier|Bruno|B|;Stefanelli|Berenice|B|;Torsiello|Martina|M|;Iannaccone|Teresa|T|;Coglianese|Albino|A|;Colucci|Francesca|F|;Pepe|Stefano|S|;Filippelli|Amelia|A|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/jpm10030113", "fulltext": "\n==== Front\nJ Pers Med\nJ Pers Med\njpm\nJournal of Personalized Medicine\n2075-4426 MDPI \n\n32899374\n10.3390/jpm10030113\njpm-10-00113\nReview\nA Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature\nConti Valeria 12 De Bellis Emanuela 3 Manzo Valentina 123* Sabbatino Francesco 14 Iannello Francesco 5 Dal Piaz Fabrizio 12 https://orcid.org/0000-0001-6066-7569Izzo Viviana 12 Charlier Bruno 12 Stefanelli Berenice 3 Torsiello Martina 3 Iannaccone Teresa 1 Coglianese Albino 1 Colucci Francesca 3 Pepe Stefano 14 Filippelli Amelia 12 1 Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; [email protected] (V.C.); [email protected] (F.S.); [email protected] (F.D.P.); [email protected] (V.I.); [email protected] (B.C.); [email protected] (T.I.); [email protected] (A.C.); [email protected] (S.P.); [email protected] (A.F.)\n2 Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy\n3 Postgraduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy; [email protected] (E.D.B.); [email protected] (B.S.); [email protected] (M.T.); [email protected] (F.C.)\n4 Oncology Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy\n5 Postgraduate School in Clinical Pharmacology and Toxicology, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; [email protected]\n* Correspondence: [email protected]; Tel.: +39-089-672-424\n03 9 2020 \n9 2020 \n10 3 11305 8 2020 01 9 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/).Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.\n\nDPDDPYD polymorphismspharmacogeneticsfluoropyrimidinespersonalised medicinetherapeutic drug monitoring\n==== Body\n1. Introduction\nFluoropyrimidines (FP), including 5-fluorouracil (5-FU) and its oral prodrug capecitabine, are cytotoxic antineoplastic agents belonging to the class of antimetabolites. They are commonly used to treat solid cancer types such as gastrointestinal, head-neck and breast cancers associated or not to other chemotherapeutics and both cytotoxic and biologic drugs [1,2]. The administration of the FP may cause severe, even life-threatening, adverse drug reactions (ADR), including myelosuppression, mucositis/stomatitis, diarrhoea and hand–foot syndrome (HFS). Indeed, it has been estimated that an increased risk of severe ADR (grade > 2) involves 10–30% of treated patients, although these data greatly depend on the therapeutic regimen used [1,3,4].\n\nThe rate-limiting step of FP catabolism is the conversion of fluorouracil to dihydrofluorouracil, which is catalysed by an enzyme called dihydropyrimidine dehydrogenase (DPD), encoded by a highly polymorphic gene (i.e., DPYD). Several single-nucleotide polymorphisms (SNPs) have been associated to an alteration of the DPYD sequence, and some of them may determine a partial or complete DPD deficiency, leading to FP severe toxicity [1].\n\nThe Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) [5,6] have published guidelines for FP dosing based on the pharmacogenetic testing of four DPYD polymorphisms that are DPYD*2A (rs3918290), DPYD*13 (rs55886062), DPYD c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182 and HapB3). The latter is the most common variant, with ~4% allelic frequency; the DPYD*2A, c.2846A>T and DPYD*13 are present in ~2.0%, 1.4% and 0.1%, respectively, of Caucasian patients [5]. Recently, a new polymorphism, DPYD*6 (rs1801160), has been associated with both gastrointestinal and haematological FP-ADR [7].\n\nNotably, other DPYD genetic variants may lead to dangerous clinical consequences, although their frequency is very low [5,6,8].\n\nWith the main aim of reducing the risk of severe FP-induced toxicity, the CPIC and DPWG have implemented a gene activity score (DPYD-AS), which ranges from 0 (complete DPD deficiency) to 2 (normal DPD activity). In patients who are homozygous for one or more of the aforementioned SNPs, the recommendation is to avoid the use of FP. However, if alternative drugs are not considered a suitable option, the FP dosage should be markedly reduced while establishing a therapeutic drug-monitoring (TDM) approach. Patients who are heterozygous should receive a 50% dose reduction at the first cycle of chemotherapy, followed by a titration dose, while monitoring the patient’s clinical conditions and possibly performing TDM [5,6].\n\nHowever, it has been estimated that 30–50% of the patients experience severe ADR, despite not having a DPD deficit associated with such DPYD polymorphisms. In fact, there are several factors, including comorbidities, polytherapy, other variants in the DPYD and other genes, that can play an important role [9]. Besides DPYD polymorphisms, two SNPs in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene [10] and a tandem repeat in the thymidylate synthase enhancer region (TYMS-TSER) could concur in predicting FP-related toxicity [11]. Moreover, a SNP in glutathione S-transferase-p1 (GSTP1) has been suggested as a genetic factor able to influence the response to oxaliplatin, a drug frequently administered with FP [12].\n\nSeveral strategies complementing the DPYD pharmacogenetics (DPYD-PGx) have been proposed to prevent FP-related severe ADR associated with DPD deficit. Among others, the measurement of the plasmatic dihydrouracil/uracil ratio (UH2/U) and the monitoring of 5-FU clearance are considered valid approaches [13,14]. Here, we reported clinical cases in whom a combined genotyping/phenotyping approach, together with careful clinical monitoring was used to optimise the FP-based treatment. In addition, we performed a systematic review of the literature concerning the use of DPYD-PGx, together with phenotyping methods to personalise such chemotherapy.\n\n2. Materials and Methods\n2.1. Case Series\nWe describe the cases of eleven oncological patients of the Campania Region (Italy) treated with FP-based chemotherapy. They were enrolled in an ongoing study (ethics committee approval n. 4_r.p.s.o.) whose main aim was to investigate the association between DPYD SNPs and other genetic variants with FP-related severe toxicity. To manage the therapy of these eleven patients, we used a combined genotyping/phenotyping approach with clinical monitoring.\n\nA careful clinical monitoring was carried out by interviewing patients and checking the results of their blood counts at each cycle of chemotherapy. The ADR were recorded and graded according to the Common Terminology Criteria for Adverse Events (CTC-AE) version 5.0 [15]. The Response evaluation criteria in solid tumors (RECIST) were used to assess the treatment response [16].\n\nAll enrolled patients were genotyped for the recommended DPYD SNPs (DPYD*2A, DPYD*13, DPYD 2846A>T and c.1129-5923C>G) as part of the clinical practice. Besides this pharmacogenetic testing (DPYD-PGx) performed by real-time PCR with allelic discrimination, the SNPs MTHFR-C677T and -A1298C were analysed using pyrosequencing technology and the TYMS-TSER variant by classical PCR and agarose gel-based electrophoresis.\n\nA phenotyping analysis was carried out by determining the plasmatic UH2/U ratio, as an indirect measurement of DPD activity, using high-performance liquid chromatography (HPLC) [17]. Moreover, in three patients, a 5-FU pharmacokinetic analysis was also performed to determine the plasmatic 5-FU clearance by using ultra-high-performance liquid chromatography combined with tandem mass spectrometry (UHPLC-MS/MS) [18]. Written informed consent was obtained from the patients for participation in the study, as well as publication of their data.\n\n2.2. Systematic Review\n2.2.1. Search Strategy\nA systematic review was performed using the PubMed, Scopus and Cochrane databases from inception to 3 July 2020. The following keywords and Medical Subject Headings (MeSH) terms were used for the search: DPYD polymorphism, dihydropyrimidine dehydrogenase deficiency, 5-FU clearance and dihydrouracil/uracil ratio.\n\nThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were applied [19]. A total of 1932 studies were retrieved from the searched databases. After the removal of duplicates and then article types such as reviews, metanalyses, case reports, etc., 112 articles were screened. Afterward, considering the inclusion and exclusion criteria, 22 articles were included in the analysis. The flowchart of the literature screening is reported in Figure 1.\n\n2.2.2. Eligibility Criteria\nThe search was limited to studies conducted in human beings and published in the English language. Both observational and randomised clinical studies were eligible. Only the studies enrolling patients treated with FP and showing results of DPYD-PGx, analysing at least one of the four SNPs recommended in the CPIC and DPWG guidelines, have been included in the analysis.\n\n2.2.3. Article Selection\nFirst, articles were selected by reading their titles and abstracts. Then, the full text of all articles considered eligible was read. The authors (Valeria Conti and Berenice Stefanelli) carried out this work independently and discussed when there was a disagreement about the relevance of an article.\n\n2.2.4. Data Extraction\nClinical, genetic and biochemical data were extracted from the articles. The factors considered were: study design, sample size, DPYD genotyping combined with phenotyping methods and/or clinical monitoring.\n\n3. Results\n3.1. Cases Presentation\nCase 1 was a Caucasian 55-year-old male former smoker with a history of hypertension. The patient had stage IV colorectal adenocarcinoma with metastases in the lymph nodes, lungs, liver and kidneys. The tumour mutational profile identified no mutations in the KRAS, NRAS or BRAF genes. The patient was treated with the combination of 5-FU, leucovorin and oxaliplatin (FOLFOX6) regimen, plus cetuximab. After three cycles of chemotherapy, the patient reported grade 1 thrombocytopenia and paraesthesia; grade 2 stomatitis, rash and leukopenia and grade 3 neutropenia and mucositis.\n\nA post-therapeutic DPYD-PGx was performed, revealing that the patient was heterozygous for DPYD*2A. Moreover, the patient was homozygous (TT) for MTHFR-C677T, homozygous TYMS-TSER-2R/2R and homozygous (AA) for GSTP1-A313G. The plasmatic UH2/U ratio was 4.52. Based on these results and the reported toxicity, both the 5-FU and cetuximab doses were reduced. Specifically, the total dosage of 5-FU was reduced to 50%, according to the CPIC and DPWG guidelines.\n\nAt the fourth cycle of therapy, the pharmacokinetic analysis revealed a trough 5-FU plasma concentration of 950 ng/mL. The CT scan demonstrated an overall stable disease, according to the RECIST criteria v1.1. The patient was still treated with the same doses of 5-FU. At the sixth cycle of therapy, the 5-FU plasma concentration was 400 ng/mL. The following cycles (fifth to eighth) of chemotherapy were administered at the same drug doses. A new CT scan demonstrated no evidence of disease progression. The ADR were grade 1 leukopenia, neutropenia, thrombocytopenia and mucositis and grade 2 HFS. Following a further two cycles of therapy, the reported ADR were grade 1 paraesthesia, erythematous maculopapular rash and grade 2 cutaneous and mucous fissures. Lastly, following a further two treatment cycles, a new CT scan showed disease progression. The treatment was stopped, and the administration of a new chemotherapeutic regimen was planned. Sadly, the patient died before starting a second line of treatment.\n\nCase 2 was a Caucasian 48-year-old male with no comorbidity. He had stage IV colorectal adenocarcinoma with metastases in the lymph nodes and liver. The tumour mutational profile highlighted the presence of a KRAS mutation; thus, a treatment with the FOLFOX6 regimen plus bevacizumab was planned. A pretherapeutic DPYD-PGx was requested, and the patient was identified as DPYD*2A heterozygous. In addition, he was wild type for MTHFR-C677T and MTHFR-A1298C, heterozygous TYMS TSER-2R/3R and homozygous (GG) for GSTP1-A313G. The plasmatic UH2/U ratio was 3.22. Based on these results, a 50% dose reduction of 5-FU was planned for the first cycle of FOLFOX administration, according to the CPIC and DPWG guidelines. After the first cycle of treatment, the plasmatic 5-FU clearance was 474 ng/mL. Following three cycles of therapy, a stable disease was found, according to the RECIST criteria v1.1, and no adverse events were reported. The patient was still treated with the same doses of chemotherapeutic agents for an additional seven cycles of therapy. Grade 1 paraesthesia and mucositis and grade 2 HFS but no severe ADR were reported, and the CT scan demonstrated a stable disease. Afterward, the patient was treated up to the twelfth cycle with a FOLFOX regimen plus bevacizumab, still obtaining, at revaluation, a stable disease. Then, he was a candidate for a maintenance therapy with capecitabine plus bevacizumab. Following 16 cycles of this therapy, the patient reported grade 1 paraesthesia and mucositis, and no severe ADR were recorded.\n\nCase 3 was a Caucasian 60-year-old male former smoker with no comorbidities. He had stage IV rectal adenocarcinoma with liver metastases. The tumour mutational profile did not identify mutations in either KRAS, NRAS or BRAF. Based on the tumour profile and stage, the patient was a candidate for a FOLFOX regimen plus cetuximab. A pretherapeutic DPYD-PGx was performed, and the patient was found heterozygous for DPYD c2846A>T SNP. Therefore, according to the CPIC and DPWG guidelines, he started chemotherapy with a 50% dose reduction of 5-FU. Moreover, he was homozygous (TT) for MTHFR-C677T, heterozygous TYMS TSER-2R/3R and heterozygous for GSTP1-A313G. The plasmatic UH2/U ratio was 1.77.\n\nA grade 2 diffuse maculopapular rash was reported, and, based on such an ADR, the dose of cetuximab was also reduced to 50% for the second cycle of therapy. The plasmatic 5-FU clearance was 811 ng/mL—still high, notwithstanding the 5-FU dose reduction. The patient reported no improvement of the skin rash and grade 2 diarrhoea. At the third cycle of therapy with the same drugs doses, the 5-FU plasma level was 1093 ng/mL. Grade 1 nausea and grade 3 diarrhoea were reported. Based on these results, the 5-FU dose was further reduced by an additional 10% at the fourth cycle of therapy. However, the 5-FU plasma concentration was still high (1048 ng/mL), and grade 4 diarrhoea was reported. Hence, it was decided not to administer 5-FU in a continuous infusion, leaving the administration of 5-FU in bolus. Nevertheless, the 5-FU plasma concentration was still high (i.e., 934 ng/mL), and grade 3 diarrhoea was reported.\n\nA CT scan showed a partial response according to the RECIST criteria with a reduction of hepatic lesions. It was decided to carry out a further cycle with oxaliplatin plus cetuximab.\n\nAfter this cycle, the hepatic lesions were resected. After one month from surgery, a CT scan demonstrated the development of a new hepatic lesion. The patient was a candidate to start a new treatment with 5-FU plus irinotecan as a modified 5-FU, leucovorin and irinotecan (FOLFIRI) regimen, since 5-FU was administered with a 50% dose reduction and without continuous infusion. The patient performed six cycles of FOLFIRI plus bevacizumab. Grade 3 diarrhoea was reported. As a consequence, the 5-FU administration was stopped, and only irinotecan and bevacizumab were further administered. After four cycles of this treatment, the CT scan demonstrated a progression of the disease. The patient died after 11.2 months from starting treatment with irinotecan plus bevacizumab.\n\nTable 1 and Table 2 report the main characteristics and the occurrence of grade ≥ 3 ADR of 3/11 and 8/11 clinical cases, respectively. Table 1 describes three clinical cases for whom either pretherapeutic DPYD-PGx or post-therapeutic DPYD-PGx were performed. As phenotypic characteristics, the UH2/U ratio values and plasmatic 5-FU clearance were reported.\n\nA pretherapeutic DPYD-PGx was performed in two out of three cases, while one patient (case 1) had already started chemotherapy before requesting DPYD-PGx. Importantly, the patients were monitored during all treatment cycles.\n\nBesides these three clinical cases, the history of other eight patients is briefly reported below, and their main characteristics are listed in Table 2.\n\nAll subjects were monitored for at least four treatment cycles. In two out of eight subjects, the DPYD-PGx was required after the occurrence of severe toxicity (post-therapeutic DPYD-PGx), while in six out of eight, pharmacogenetic testing was performed before the treatment started (pretherapeutic DPYD-PGx). All patients were identified as carriers of DPYD variants—precisely, four out of eight were DPYD*2A heterozygous, and four out of eight were DPYD c.2846 heterozygous.\n\nThe two patients for whom the DPYD-PGx was performed after 5-FU administration experienced grade 3 ADR with a different timing, and both were then revealed as DPYD-variant carriers. More in detail, one patient with stage III gastric cancer, treated with FOLFOX, suffered from grade 3 vomit after the second cycle; he was then identified as DPYD*2A heterozygous and continued to be treated only with oxaliplatin. Moreover, the patient was homozygous (TT) for MTHFR-C677T, homozygous TYMS TSER-3R/3R and homozygous (AA) for GSTP1-A313G.\n\nThe other one with stage IV colon cancer, treated with FOLFIRI plus bevacizumab, showed grade 3 vomit after the eighth cycle of chemotherapy. The patient was identified as DPYD c.2846 heterozygous, and the 5-FU dosage was halved. With regards to the other SNPs, the patient was homozygous (TT) for MTHFR-C677T, heterozygous TYMS TSER-2R/3R and wild type for UGT1A1*28 SNP. The latter polymorphism is routinely analysed in patients treated with irinotecan.\n\nConversely, in the other patients, a pretherapeutic DPYD-PGx was performed; thus they were treated with a starting halved dose of 5-FU, and no severe ADR were reported.\n\n3.2. Systematic Review\nA systematic review was performed to analyse the studies investigating the variability of responses to FP-based chemotherapy by DPYD genotyping combined with phenotyping methods and/or clinical monitoring.\n\nOf the potential 112 articles assessed for eligibility, after considering the inclusion and exclusion criteria, 22 studies were included in the analysis [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41]. Table 3 shows such studies subdivided with respect to the analysed DPYD polymorphisms (DPYD-PGx), the used phenotyping methods and the presence of clinical monitoring. A DPYD-PGx/clinical monitoring combination was present in 11, and DPYD-PGx/phenotyping in three, surveys. A DPYD-PGx/phenotyping/clinical monitoring combined approach was made in eight studies (Table 3). \n\nAmong the studies with a DPYD-PGx/clinical monitoring combination, five out of eleven studies confirmed the importance of DPYD variants in predicting FP-related toxicity, although a too-short clinical monitoring was performed (only two treatment cycles) [21,23,29,31,39]. Two studies [24,34] analysed only DPYD*2A of the DPYD SNPs currently recommended. The first confirmed a strong association between DPYD*2A and a severe and potentially fatal toxicity [24]. The second did not analyse this type of association because of the too-low DPYD*2A allelic frequency found in the study population [34].\n\nLee et al., by testing 2886 patients, reported a significant association between DPYD*2A and DPYD c.2846A>T and grade ≥3 FP ADR [26]. Similarly, Cremolini et al., in a large cohort of colon cancer patients who were treated with FOLFIRI or FOLFOXIRI plus bevacizumab, demonstrated that DPYD*2A and DPYD c.2846A>T predicted FP-associated clinically relevant ADR [36]. Iachetta et al. analysed 668 out of 1827 patients enrolled in their study. The authors, first, confirmed the clinical relevance of DPYD c.2846A>T and DPYD*13 in predicting FP safety. Second, they found a significant association between DPYD*6 and severe neutropenia. Notably, no patients carrying DPYD*2A (1.7%) had started a FP-based treatment [38]. Negarandeh et al. screened the presence of DPYD c.2846A>T, DPYD*6 and DPYD*2A in a population of 73 Iranian patients. DPYD c.2846A>T and DPYD*6 were not found in the patient population analysed. However, a high allelic frequency for DPYD*2A (5.5%) was reported. Surprisingly, Negarandeh et al. did not find any significant association between DPYD*2A and severe toxicity [40]. \n\nA DPYD-PGx/phenotyping combined approach was performed in three studies that underlined the importance of complementing the DPYD-PGx with a phenotyping analysis. Gentile et al., by measuring the 5-FUDR (degradation rate) in peripheral blood mononuclear cells (PBMCs) utilising HPLC with MS/MS, found a significant correlation between several polymorphisms, including DPYD*2A and DPYD c.2846A>T, and this phenotyping marker [27]. Jacobs et al. determined 5-FU clearance in the plasma of patients treated with capecitabine, finding that the presence of DPYD*2A led to a 21.5% reduction in 5-FU elimination. Pallet et al. evaluated an approach based on the combination of the plasmatic UH2/U ratio and uracil concentration with genotyping of the four recommended DPYD SNPs. The main finding of this study was that complementing the DPYD-PGx with the plasmatic UH2/U ratio increased the possibility to identify patients at higher risks of severe FP-related toxicity [41]. Among the studies that performed a DPYD-PGx/phenotyping approach with clinical monitoring, four out of eight studies reported information about FP-related ADR until a maximum of three treatment cycles. \n\nJoerger et al. confirmed the importance of DPYD genotyping to identify patients at high risks of severe FP-related toxicity. Unfortunately, because of the low sample size of the study, they did not show conclusive results about the usefulness of plasmatic 5-FU clearance determination in improving the predictive potential of DPYD-PGx [28]. \n\nGalarza et al. found that salivary and plasmatic UH2 concentrations were inversely correlated with the ADR grade. However, given the low number of patients enrolled in the study, no DPYD variant allele carriers were identified [30].\n\nBoisdron et al. conducted a phase II study in 85 patients to test the efficacy of a pharmacogenetic-guiding dosing approach combined with the UH2/U ratio measurement. Despite a very large increase in drug dosages, a low incidence of severe ADR was shown in patients who used a guiding dosing approach. However, also in this case, it was not possible to conclude if this phenotyping analysis enhanced the predictability of DPYD genotyping because of the low sample size of the study [32]. Etienne et al. failed to demonstrate a correlation between DPYD variants and the plasmatic UH2/U ratio values. The authors concluded that only an extension of the genetic panel may improve the performance of DPYD-PGx for predicting severe and life-threatening ADR associated with capecitabine [33]. \n\nKuilenburg et al. measured the UH2/U ratio in PBMCs as an indirect assessment of DPYD activity. They demonstrated that patients with a low DPD activity experienced a more rapid onset of toxicity as compared to those with a normal enzymatic activity. Moreover, grade 4 neutropenia occurred in a substantial percentage (55%) of the patients with a decreased DPD activity as compared to that (13%) of subjects with a normal DPD activity. Notably, eleven out of fourteen patients suffering from severe ADR with a decreased enzymatic activity were identified as carriers of DPYD polymorphisms. In particular, six, four and one out of eleven patients carried DPYD*2A, DPYD*9A and DPYD*6 in homozygosis, respectively [20]. Kristensen et al. also showed a significant correlation between the plasmatic UH2/U ratio and the presence of DPYD*2A [22].\n\nFinally, in a prospective study, Henricks et al. analysed all the four recommended DPYD SNPs and performed two phenotyping tests by measuring the UH2/U ratio in PBMCs and plasmatic 5-FU pharmacokinetics (PK) by UHPLC-MS/MS. The patients carrying DPYD c.1236G>A and DPYD c.2846A>T were more likely to manifest FP-related severe toxicity as compared to wild-type subjects. In addition, the mean DPD enzyme activity was significantly lower in patients bearing these two genetic variants, as well as DPYD*2A, as compared to other patients. Only one patient carrying DPYD*13 showed a 60% DPD activity reduction. This patient was treated with a reduced 5-FU dosage for three treatment cycles, and no severe ADR occurred. Based on these results, the authors confirmed that a dose reduction of 50% in DPYD*2A and DPYD*13 carriers is appropriate, as issued in the PGx guidelines [35].\n\n4. Discussion\nFluoropyrimidines (FP) are the most-prescribed antineoplastic drugs in the world and represent the mainstay therapy for colorectal cancer. Unfortunately, 10–30% of the treated patients suffer from severe FP-related ADR [1].\n\nThe association between four DPYD variants and FP toxicity is now widely recognised, and it is also largely accepted that the pretherapeutic guiding dosing model based on the DPYD-PGx is a valid and cost-effective approach to manage FP-based chemotherapy. As a matter of fact, FP are included among the drugs with a pharmacogenetic warning [5], and the CPIC and DPWG guidelines are now followed in several countries, including Italy.\n\nHowever, DPYD-PGx is not yet routinely performed, and one of the aims of these consortia is to overcome the barriers preventing the implementation of the PGx into clinical practice. In March 2019, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommended to perform DPYD-PGx before starting treatment with FP. As in the CPIC and DPWG guidelines, the PRAC stated that 5-FU, capecitabine or tegafur must be avoided in the presence of a complete DPD deficiency. In the case of a partial DPD deficit, a reduced starting dose of FP should be considered [42].The PRAC recommendation was transferred to the Committee for Medicinal Products for Human Use (CHMP), and, on 7 July 2020, the EMA Commission raised a final decision that the DPYD-PGx should be performed in naïve oncological patients prior to starting a treatment with FP [43].\n\nA substantial percentage of patients with a DPYD variant associated with a deficit of DPD activity show grade > 2 toxicity [9]. For instance, it has been estimated that 73% of the patients who are carriers of DPYD*2A suffer from grade ≥ 3 toxicity [24]. Therefore, the upfront DPYD-PGx has a crucial impact on the management of chemotherapy given that it may prevent 20–30% of life-threatening or lethal FP-related toxicity in Caucasian patients, revealing also a cost-effective approach [24,44].\n\nIn this regard, case 1 suffered from grade 3 neutropenia and grade 3 mucositis before the DPYD-PGx was required, which then revealed the presence of DPYD*2A SNP. Notably, once the PGx results were obtained, the patient received 50% of the 5-FU dosage, and at the fourth and following cycles, there was no evidence for severe ADR.\n\nThe importance of performing a pretherapeutic DPYD-PGx is confirmed by the history of two other patients who had experienced grade 3 toxicity, with a different timing, before the test was requested. One of them was identified as DPYD*2A heterozygous and the other one as DPYD c.2846 heterozygous. It is possible to conclude that FP-related severe toxicity may occur anytime during the therapy. The DPYD*2A, which is a no-function variant, could be associated with a more premature ADR when compared with DPYD c.2846A>T SNP, which is classified as reduced-function variant. In fact, the subject bearing the DPYD*2A suffered from grade 3 vomit at the second cycle, while the other patient, who was the carrier of the DPYD c.2846, suffered from the same toxicity but at the eighth cycle of chemotherapy.\n\nNotably, it has been estimated that a 30–50% of the patients treated with FP have no DPD deficit attributable to the four recommended DPYD SNPs, yet suffer from severe ADR [45]. In fact, several factors concur to determine the variability of responses to FP-based treatments. Among them, other polymorphisms in DPYD, and in other genes encoding enzymes involved in the pathway of the FP and, also, FP-associated drugs, may play an important role. In this regard, several studies have shown an association between the TYM-TSER 28-bp variant (in the gene encoding the FP molecular target) and FP-related toxicity [12,46]. Moreover, an increased risk of severe toxicity has been shown in patients carrying rs183205964 in the promoter enhancer region of TYMS [46].\n\nFinding the relationship between FP and specific ADR can be very difficult also, because FP are often administered with both traditional and biologic antineoplastic agents, such as cetuximab and bevacizumab. These drugs, as well as oxaliplatin and irinotecan, can cause diarrhoea and myelosuppression [47,48,49,50] similar to FP, and, as already mentioned, there are several genetic variants that are associated to these ADR and others.\n\nThe MTHFR is a critical enzyme involved in the synthesis of purine and thymidine and, in general, folate homeostasis. Two common SNPs (i.e., MTHFR-C677T and -A1298C), associated with a decrease of the MTHFR enzymatic activity, have been proposed as predictive factors of the response to cytotoxic agents, including FP, raltitrexed and methotrexate [51]. In addition, these two SNPs may exert a synergistic effect on the MTHFR activity [11]. A recent metanalysis failed to recognise the MTHFR polymorphisms (neither MTHFR-C677T nor -A1298C) as predicting factors for the response to FP-based treatment [52]. The data often contrast each other because of several reasons, including the type of cancer, dietary folate levels, therapy regimen and saturation level of the enzyme [51].\n\nOxaliplatin is mainly metabolised by glutathione-S-transferase P1 (GSTP1), and the SNP in this gene (i.e., GSTP1 A313G, Ile105val and rs1695) has been associated with severe ADR. Most of the evidence regards the occurrence of cumulative neuropathy associated with such a polymorphism [12,53], but the presence of at least one variant allele has been associated also with grade 3 or 4 gastrointestinal and haematological toxicity [54].\n\nIn a recent metanalysis, Lv et al. found an association between the GSTP1 rs1695 SNP and granulocytopenia induced by platinum derivatives [55]. Another metanalysis failed to demonstrate that this polymorphism can be considered a reliable predictive factor of oxaliplatin-related severe neurotoxicity [56]. At present, the data are inconclusive; therefore, only large, well-designed clinical trials will be able to clarify this issue.\n\nThe TYMS-TSER 28-bp tandem repeat is one of the more promising candidates as a genetic factor responsible for FP-related ADR. However, as reported in the last CPIC update, its clinical relevance is still debated [5].\n\nLecomte et al. found that patients who were carriers of the double-repeat allele (i.e., TYMS-TSER-2R) had more severe FP-associated ADR than the homozygous -3R/3R. In particular, the authors reported that patients bearing the -2R/2R genotype were 20 times more likely to suffer from severe toxicity compared with those who are carriers of the -3R/3R genotype. This could be related to a decreased TYMS mRNA expression in the normal tissue of subjects bearing a 2R/2R genotype that may lead to increased thymidylate synthase (TS) inhibition by FP treatment [11]. These findings refer to the somatic variant, while the data regarding the same germline polymorphism, which is identifiable by means of a peripheral blood sample, are inconclusive. Obviously, if the germline variant could be considered a predictive parameter like the somatic ones, a less-invasive method would be available to individualise the FP-based treatment in naïve patients. Several recent studies have suggested that the TYMS TSER germline polymorphism may be useful to prevent toxicity [57], such as hand-foot syndrome and other ADR types, including haematological and gastrointestinal ones [58]. With regards to the clinical cases described in Table 1, case 1 was homozygous TYMS TSER-2R/2R and case 2 and 3 were heterozygous 2R/3R.\n\nUndoubtedly, a larger panel of genetic variants is needed. On the other hand, further studies should be performed to support the regulatory authorities to decide whether and which new polymorphisms should be added to the four recommended DPYD SNPs in the PGx guidelines. Researchers’ efforts are addressed to find the best phenotyping methods to complement the DPYD-PGx. Among the different approaches proposed until now, the analysis of the 5-FU pharmacokinetic parameters was evaluated even before the DPYD-PGx introduction. In the eighties, in fact, a high individual variability of the plasmatic 5-FU clearance was demonstrated, and the existence of a correlation between the 5-FU levels and FP-related toxicity had already been highlighted [59].\n\nNowadays, it is possible to determine the 5-FU clearance using sophisticated techniques, such as HPLC coupled with tandem mass spectrometry (LC-MS/MS), which provides the precious opportunity to carry out TDM to adjust the therapy cycle-by-cycle where appropriate. Nonetheless, this approach is not always feasible in hospital settings and is unable to detect a DPD deficit prior to starting the treatment, thus preventing an early severe toxicity. Moreover, a 5-FU pharmacokinetic analysis aims at measuring the area under the curve (AUC) of the 5-FU plasma levels at the steady state (i.e., 2 h after the drug administration) and requires collecting multiple blood samples [14].\n\nThe CPIC and DPWG guidelines recommend to perform the DPYD-PGx and to treat the heterozygous patients with a dose reduction at the first cycle of chemotherapy and then titrate the dosage while performing a careful clinical monitoring and possibly TDM [5,6].\n\nAn ideal management workflow should consent to optimise FP-based therapy before treatment using the least invasive method; therefore, the researchers’ efforts have been addressed in this direction.\n\nThe measure of the plasmatic UH2/U ratio has been proposed as a suitable approach, but its validity is brought up for discussion. Indeed, some studies have demonstrated that this parameter well-correlates with 5-FU clearance and FP-related toxicity [22], while others have suggested that it can be considered a valid predictive factor during 5-FU administration alone [25]. Notably, determining the UH2/U ratio in peripheral blood mononuclear cells (PBMCs) seems to be the best method, but, unfortunately, it is a time-consuming procedure and requires radiolabelled reagents and large volumes of blood [20,35,60].\n\nImportantly, it seems that only a low plasmatic UH2/U ratio is a good predictive factor. For instance, Gamelin et al. suggested that a value less than 1.8 really helps to identify the patients at higher risk of FP-related toxicity [61]. To this line, Kristensen et al. studied 24 patients treated with FP who experienced FP severe-related toxicity, finding that 21 out of 24 subjects had a UH2/U ratio ≤4. They stated that the average UH2/U ratio decreased with the toxicity grade and proposed the value of 4 as the cut-off value [22]. Other authors have fixed the cut-off value at 6, specifying that the patients carrying one functional and one nonfunctional allele of DPYD (i.e., heterozygous) have a UH2/U ratio ranging from 1.5 to 6, while those who are carriers of two nonfunctional alleles (i.e., homozygous) have a value close to 0, corresponding to a complete DPD deficiency [62].\n\nBesides the patients described in Table 1, we have measured the plasmatic UH2/U ratio in another eight subjects who are all heterozygous for DPYD*2A or DPYD c.2846A>T. We did not perform the pharmacokinetic analysis on these patients for several reasons (e.g., unavailability of the patients consents and changes of the therapy). It is important to underline that in six out of eight patients for whom a pretherapeutic DPYD-PGx was performed and the starting 5-FU dosage was halved, no severe toxicity was recorded (Table 2).\n\nIn the 11 patients we examined, the UH2/U ratio ranged between 1.77 and 7.38.\n\nThe fluctuation of the UH2/U ratio values as a predictive factor could reflect the variability of the DPD deficit that may range from 30% to 70% in the heterozygous patients. Nonetheless, the plasmatic UH2/U ratio could contribute to identifying, before beginning treatment, the subjects who are at-risk of severe or life-threatening ADR. Case 3 (reported in Table 1) exemplifies the complexity of the management of FP-based therapy. In fact, he had a very low (i.e., 1.7) plasmatic UH2/U ratio and continued suffering from severe toxicity despite the reduction of the 5-FU dosage. It is mandatory to bear in mind that this ratio remains a surrogate marker of DPD activity, and even if it was a more sensitive and specific parameter, several other variables may influence both the efficacy and tolerability of FP-based chemotherapy.\n\nThis is the reason why a combined genotyping/phenotyping approach, together with careful clinical monitoring, is the best way to personalise and optimise the therapy. Several studies have used this kind of approach, suggesting that phenotyping analyses, especially those based on the plasmatic 5-FU clearance and/or UH2/U ratio measurement, could successfully complement the DPYD-PGx in predicting FP-related toxicity. This is clearly shown by our systematic literature search (Figure 1 and Table 3).\n\nAs shown in Table 3, eight studies have combined DPYD-PGx with phenotyping methods and clinical monitoring, but only two out of eight have provided satisfactory clinical monitoring [28,35]. Indeed, to perform daily careful, clinical monitoring during all patients’ treatment cycles is very arduous. In fact, among these studies, three out of eight reported ADR only for two cycles [22,25,33], one out of eight monitored the toxicity until the third cycle [30] and two out of eight made clinical monitoring for two-to-three months [20,32].\n\nMoreover, as shown in Table 3, three studies have performed a combined DPYD-PGx/phenotyping [27,37,41] approach, and eleven carried out the DPYD-PGx together with clinical monitoring. However, among these, only 2/11 genotyped all the four DPYD SNPs recommended in the CPIC and DPWG guidelines [29,39]; the other studies performed at least one of such SNPs, together with other DPYD genetic variants [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40].\n\nThe main limitations of the studies performed until now are the lack of clinical monitoring throughout the entire course of chemotherapy and the scarce sample size. Moreover, the missing of the screening of one or more of the four DPYD-SNPs now recommended and the heterogeneity in the choice of other polymorphisms potentially useful to implement genotyping do not allow reaching conclusive results.\n\n5. Conclusions\nThe pretherapeutic DPYD-PGx represents an essential approach to personalise FP-based chemotherapy, minimising the risk of severe and life-threatening toxicity. This is confirmed by both the clinical cases here described and the literature data.\n\nNowadays, the regulatory agencies recommend carrying out the DPYD-PGx, including four DPYD polymorphisms (i.e., rs3918290, rs55886062, rs67376798 and rs75017182, HapB3) in patients who need to be treated with FP.\n\nDespite that these DPYD variants are strongly associated with treatment toxicity, other genetic and nongenetic factors concur to determine the variable response to FP-based chemotherapy.\n\nInitiating the FP with a reduced dosage is not a suitable option, because DPD deficits may range from 30% to 70% in the heterozygous patients who would experience a dangerous period of undertreatment.\n\nA pretherapeutic DPYD-PGx offers the possibility to avoid early ADR. Nonetheless, severe and even fatal FP-related toxicity may happen anytime during the therapy also in subjects having no DPD deficit attributable to the four recommended DPYD SNPs.\n\nOn the other hand, measuring the plasmatic 5-FU clearance—currently, the best method to perform TDM—does not permit to diagnose a possible DPD deficit prior to starting the treatment.\n\nTherefore, because both genetic and phenotypic tests show advantages and disadvantages, a combined genotyping/phenotyping approach, together with careful and continuous clinical monitoring, is the best diagnostic method to optimise the therapy with FP (Figure 2).\n\nAn accurate genotypic/phenotypic characterisation of each patient is essential not only to prevent severe toxicity associated with the cytotoxic agents but, also, to determine patients’ benefit-risk profiles to begin early the best therapeutic approach. This is of particular interest considering the current possibility to treat certain patients with anticancer agents, such as immune checkpoint inhibitors, that are changing the cancer therapeutic paradigm.\n\nAcknowledgments\nWe thank the native English-speaker Jan Festa, who revised the manuscript.\n\nAuthor Contributions\nConceptualisation, A.F., V.C., F.S. and S.P.; methodology, V.M., E.D.B., F.D.P., F.I., M.T., B.C. and A.C.; validation, V.C., B.S. and F.C.; investigation, V.C., V.M., E.D.B. and A.F.; resources, A.F. and V.C.; data curation, E.D.B., B.S., V.C., F.I. and T.I.; writing—original draft preparation, V.C., E.D.B., V.M., V.I. and M.T.; writing—review and editing, V.C., A.F., F.S., V.I. and F.D.P.; supervision, V.C. and A.F.; project administration, V.C., V.M. and A.F. and funding acquisition, A.F. and V.C. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nItalian Medicines Agency (AIFA) AVPM/17806/A (Rome, Italy) and Reti Oncologiche, Campania Region (2018) fund to A.F. at University Hospital of Salerno (Salerno, Italy) and University ORSA175354 fund (University of Salerno, Italy) to V.C.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nAbbreviations\nFP\tFluoropyrimidines\t\nDPD\tDihydropyrimidine Dehydrogenase\t\nDPYD-PGx\tDPYD-Pharmacogenomics\t\nPCR\tPolymerase Chain Reaction\t\n5-FU\t5-Fluorouracil\t\nADR\tAdverse Drug Reaction\t\nHFS\tHand-Foot Syndrome\t\nSNPs\tSingle-Nucleotide Polymorphisms\t\nCPIC\tThe Clinical Pharmacogenetics Implementation Consortium\t\nDPWG\tDutch Pharmacogenetics Working Group\t\nDPYD-AS\tDPYD-Activity Score\t\nTDM\tTherapeutic Drug Monitoring\t\nMTHFR\tMethylene-Tetrahydrofolate Reductase\t\nTYMS-TSER\tThymidylate Synthase-Thymidylate Synthase Enhancer Region\t\nGSTP1\tGlutathione S-Trasferase-p1\t\nUH2/U ratio\tDihydrouracil/Uracil Ratio\t\nCTC-AE\tCommon Terminology Criteria for Adverse Events\t\nRECIST \tResponse Evaluation Criteria in Solid Tumours\t\nHPLC\tHigh-Performance Liquid Chromatography\t\nUHPLC-MS/MS\tUltra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry\t\nMeSH\tMedical Subject Heading\t\nPRISMA\tPreferred Reporting Items for Systematic reviews and Meta-Analyses\t\nFOLFOX\t5-FU, Leucovorin and Oxaliplatin\t\nCT scan\tComputed Tomography Scan\t\nFOLFIRI\t5-FU, Leucovorin and Irinotecan\t\nPRAC\tPharmacovigilance Risk Assessment Committee \t\nEMA\tEuropean Medicines Agency\t\nCHMP\tCommittee for Medicinal Products for Human Use \t\nAUC\tArea Under the Curve\t\nLC-MS/MS\tLiquid Chromatography-Tandem Mass Spectrometry\t\nPBMCs\tPeripheral Blood Mononuclear Cells\t\nFigure 1 Flowchart of the databases searched. * Exclusion criteria: (1) studies not including at least one of the four recommended DPYD polymorphisms and (2) other study designs (e.g., allelic frequencies estimation, no patients and methods for genotyping).\n\nFigure 2 This figure illustrates the main enzymatic reactions involved in the fluoropyrimidines (FP) pathway. The importance to perform, together with careful clinical monitoring, a genotyping/phenotyping combined approach is shown by using panels and arrows. The four recommended DPYD-SNPs, including in the DPYD-PGx, are listed, together with the other polymorphisms proposed as potential predictive factors of FP-related toxicity. Phenotyping methods (e.g., UH2/U ratio measured in plasma or PBMCs), which potential in predicting FP safety are currently under evaluation, are also described. An ideal flowchart to manage patients eligible for FP-based therapy is shown at the bottom of the figure. DPYD-PGx and the plasmatic UH2/U ratio have to perform one time (continuous line), while the plasmatic 5-FU clearance is throughout the entire course of the therapy (dotted line). The numbers located on the panels are the same reported in the flowchart in order to underline which genotyping and phenotyping markers may be used together to optimise the diagnosis and management of patients. Abbreviations: DPD, dihydropyrimidine dehydrogenase; DPYD-PGx, DPYD-pharmacogenomics; 5-FU, fluorouracil; DHFU, 5-fluoro-dihydrouracil; TP, thymidine phosphorylase; TK, thymidine kinase; FdUMP, 5-fluorodeoxyuridine monophosphate; TS, thymidylate synthase; dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate; dTTP, deoxythymidine triphosphate; 5,10-methylene-THF, 5,10-methylene-tetrahydrofolate; H2PteGlu(n), dihydrofolic acid; MTHFR, methylene-tetrahydrofolate reductase; 5-methyl-THF, 5,10-methyl-tetrahydrofolate; NADPH, nicotinamide adenine dinucleotide phosphate and TYMS-TSER, thymidylate synthase-thymidylate synthase enhancer region.\n\njpm-10-00113-t001_Table 1Table 1 Reports of the main characteristics of three patients with the occurrence of grade ≥ 3 ADR.\n\nPt\tSex\tAge (years)\tTumor Type and Stage\tChemotherapy Regimen\tPre-Therapeutic\nDPYD-PGx\tPost-Therapeutic\nDPYD-PGx\tDPYD\nGenotype\tUH2/U Ratio\t5-FU Dosage\t5-FU Clearance\tADR ≥ 3\tTotal Toxicity\t\n1\tM\t55\tCRC\n(metastatic)\tFolfox plus cetuximab\t/\tYes (C4)\tHeterozygous for DPYD*2A\t4.52\tC1-C3: 100% C4-C6: 50%\t950 ng/mL (C4)\n400 ng/mL (C6)\tG3 mucositis (C3) G3 neutropenia (C3) (neuthrophils: 830.58 /mm3)\t7\t\n2\tM\t48\tCRC\n(metastatic)\tFolfox plus bevacizumab\tYes\t/\tHeterozygous for DPYD*2A\t3.22\tC1-C8: 50%\t474 ng/mL (C1)\t/\t6\t\n3\tM\t60\tRectal cancer (metastatic)\tFolfox plus cetuximab)\tYes\t/\tHeterozygous for c.2846A>T\t1.77\tC1-C3: 50% C4: 40%\nC5-C6: 40% (only bolus)\t811 ng/mL (C2) 1093 ng/mL (C3) 1048 ng/mL (C4) 934 ng/mL (C5)\tG3 diarrhoea (C3)\nG4 diarrhoea (C4)\nG3 diarrhoea (C5)\t3\t\nPt, patient; M, male; CRC, colorectal cancer; FOLFOX, 5-fluorouracil plus leucovorin plus oxaliplatin; DPYD-PGx, DPYD pharmacogenetics; 5-FU, 5-fluorouracil; C, cycle; plasmatic UH2/U ratio, dihydrouracil/uracil ratio; ADR, adverse drug reaction; G, grade and total toxicity, number of ADR regardless of the grade of severity.\n\njpm-10-00113-t002_Table 2Table 2 Reports of 8 clinical cases for whom either pretherapeutic DPYD-PGx or post-therapeutic DPYD-PGx were performed. As phenotypic characteristics, the UH2/U ratio values were reported.\n\nPt\tSex\tAge\n(Years)\tTumor Type and Stage\tChemotherapy Regimen\tPre-Therapeutic\nDPYD-PGx\tPost-Therapeutic\nDPYD-PGx\tDPYD\nGenotype\tUH2/U Ratio\t5-FU Dosage\tADR ≥3\t\n1\tF\t63\tStomach cancer\n(locally advanced)\tFolfox\t/\tYes (C2)\tHeterozygous for DPYD*2A\t7.09\tC1-C2: 100% C3: 5-FU withdrawal\tG3 vomit (C2)\t\n2\tM\t43\tCRC\n(metastatic)\tFolfiri with bevacizumab\t/\tYes (C8)\tHeterozygous for c.2846A>T\t3.88\tC1-C8: 100% C9: 50%\tG3 vomit (C8)\t\n3\tM\t63\tKidney cancer\n(metastatic)\tXeloda\tyes\t/\tHeterozygous for c.2846A>T\t6.57\tC1-C6: 50%\t/\t\n4\tM\t68\tCRC\n(metastatic)\tXelox\tyes\t/\tHeterozygous for c.2846A>T\t4.4\tC1-C7: 50%\t/\t\n5\tM\t78\tCRC\n(local)\tXelox\tyes\t/\tHeterozygous for c.2846A>T\t3.37\tC1-C2: 50%\t/\t\n6\tM\t72\tCRC\n(locally advanced)\tXelox\tyes\t/\tHeterozygous for DPYD*2A\t5.15\tC1-C8: 50%\t/\t\n7\tF\t52\tVulva carcinoma\n(local)\tXeloda with cisplatin\tyes\t/\tHeterozygous for DPYD*2A\t7.38\tC1-C5: 50%\t/\t\n8\tM\t76\tRectosigmoid cancer (locally advanced)\tFolfox\tyes\t/\tHeterozygous for DPYD*2A\t2.44\tC1-C5: 50%\t/\t\nPt, patient; M, male; F, female; CRC, ColoRectal Cancer; FOLFOX, 5-Fluorouracil plus leucovorin plus oxaliplatin; FOLFIRI, 5-Fluorouracil plus leucovorin plus irinotecan; XELOX, capecitabine plus oxaliplatin; XELODA, Capecitabine; DPYD-PGx, DPYD pharmacogenetics; UH2/U RATIO, dihydrouracil/uracil ratio; ADR, Adverse Drug Reaction; C, cycle; G, Grade.\n\njpm-10-00113-t003_Table 3Table 3 The table reports the studies included in the systematic review and subdivided into three groups: DPYD-PGx/clinical monitoring combination, DPYD-PGx/phenotyping and DPYD-PGx/phenotyping/clinical monitoring. Abbreviations: PBMC, peripheral blood mononuclear cells; HPLC-UV, high-performance liquid chromatography-UV detector; LC-MS/MS, liquid chromatography-tandem mass spectrometry; 5-FUDR, 5-FU degradation rate; UHPLC-MS/MS, ultra-high-performance liquid chromatography-tandem mass spectrometry; PK, pharmacokinetics; FP, fluoropyrimidines; DPD, dihydropyrimidine dehydrogenase; UH2/U ratio, dihydrouracil/uracil ratio and AAS, atomic absorption spectrometry.\n\nFirst Author‘s Name (Published Year)\tEnrolled Patients (n)\tOutcomes\tDPYD-PGx/Clinical Monitoring\tDPYD-PGx/Phenotyping\tDPYD-PGx/Phenotyping/Clinical Monitoring\t\nKuilenburg et al. (2000) [20]\t37\tDPD activity and overall toxicity; DPYD genotyping in patients with reduced DPD activity.\t\n\t\n\tDPYD*2A, c.2846A>T, DPYD*6, DPYD*9A, c.496A>G/ UH2/U ratio in PBMC/ADR until two treatment months.\t\nSchwab et al. (2008) [21]\t683\tOverall toxicity; DPYD, TYMS, MTHFR genotyping; sequencing of DPYD exome; influence of sex and promoter methylation on DPD expression in human liver.\tDPYD*2A, c.2846A>T, c.623G>T, DPYD*4, DPYD*6, and c.2858G>C/ ADR reported until the second cycle of treatment.\t\n\t\n\t\nKristensen et al.(2010) [22]\t68\tRelationship between UH2/U plasma ratio and 5-FU-related early toxicity; relationship between 5-FU concentration and toxicity; IVS14+1G>A mutation screening.\t\n\t\n\tDPYD*2A/ UH2/U ratio in plasma 5-FU clearance by HPLC-UV/ ADR reported until the second cycle of treatment.\t\nDeenen et al. (2011) [23]\t568\tRelationships between SNPs and toxicity, SNPs and dose modification of capecitabine, DPYD haplotypes and toxicity, DPYD SNPs and haplotypes and survival.\tDPYD*2A, c.2846A>T and c.1236G>A [HapB3]/ ADR reported until the second cycle of treatment.\t\n\t\n\t\nDeenen et al. (2016) [24]\t2038\tFeasibility, safety and cost of DPYD*2A genotype-guided dosing.\tDPYD*2A/ADR reported until the sixth cycle of treatment.\t\n\t\n\t\nSistonen et al. (2014) [25]\t28\tRelationship between UH2/U plasma ratio and DPYD genetic variation; plasma concentration of 5-FU and corresponding AUC; toxicity.\t\n\t\n\tc.234-123G>C, c.496A>G, c.775A>G, c.1129-5923C>G [Hap B3], DPYD*13, DPYD*2A and c.2846A>T/ UH2/U ratio in plasma- 5-FU clearance by LC-MS/MS/ ADR reported until the second cycle of treatment.\t\nLee et al.(2014) [26]\t2886\tRelationship between DPYD variants and toxicity.\tDPYD*2A, DPYD*13, c.2846A>T/ ADR until the twelfth cycle of treatment.\t\n\t\n\t\nGentile et al. (2015) [27]\t156\tCorrelation between degradation rate of 5-FU with detected SNPs.\t\n\tDPYD*2A, DPYD*13, c.2846A>T/5-FUDR assay in PBMC by HPLC-MS/MS\t\n\t\nJoerger et al. (2015) [28]\t140\tQuantitative effect of 44 gene polymorphism in 16 drug pathway associated genes on progression free survival (PFS), on chemotherapy toxicity, on objective response rate (ORR), on overall survival (OS).\t\n\t\n\tDPYD*13, DPYD*2A, c.2846A>T, DPYD*9A, c.1896T>C/5-FU clearance by AAS and HPLC/ADR until disease progression.\t\nLunenburg et al. (2016) [29]\t275\tEvaluation of requests of prospective DPYD screening and results with a dose recommendation; estimation of the follow up of the dose recommendations.\tDPYD*2A, DPYD*13, c.2846A>T, c.1236G>A [HapB3]/ ADR reported until the second cycle of treatment.\t\n\t\n\t\nGalarza et al. (2016) [30]\t60\tEstimation of the use of plasma and saliva; Uracil to UH2 metabolic ratio and DPYD genotyping.\t\n\t\n\tDPYD *2A, *13, c.557A>G, DPYD *7/ UH2/U ratio in plasma/ ADR reported until the third cycle of treatment.\t\nMilano et al. (2016) [31]\t243\tSequencing of DPYD exome and frequence of G3, G4 toxicity over cycle 1-2.\tDPYD*2A, DPYD*13, c.2846A>T, c.1774C>T, c.1475C>T, D342G/ ADR reported until the second cycle of treatment.\t\n\t\n\t\nBoisdron-Celle et al.(2017) [32]\t85\tUGT1A1 and DPYD genotyping; UH2/U ratio; follow up of efficacy and tolerance.\t\n\t\n\tDPYD*2A, DPYD*13, c.2846A>T, DPYD*7/ UH2/U ratio in plasma/ADR every two weeks until three months.\t\nEtienne-Grimaldi et al.(2017) [33]\t243\tDPYD sequencing; relationship between toxicity and DPYD variants; DPD phenotyping.\t\n\t\n\tDPYD*2A, DPYD*13, c.2846A>T/ UH2/U ratio in plasma/ ADR reported until the second cycle of treatment.\t\nLiu et al.(2017) [34]\t661\tRelationship between UGT1A1 and DPYD polymorphism and incidence of severe neutropenia and diarrhea; relationship between UGT1A1 and DPYD variants and objective response rate, disease control rate, overall and progression free survival.\tDPYD*5, c.1896 T > C, and DPYD*2A/ ADR reported every two-three cycles or whenever patient’s condition changed.\t\n\t\n\t\nHenricks et al.(2018) [35]\t1181\tFrequency of severe overall FP-related toxicity; pharmacokinetics of fluoropyrimidines in DPYD variant allele carriers; DPD enzyme activity; cost analysis on individualised dosing by upfront DPYD genotyping.\t\n\t\n\tDPYD*2A, c.2846A>T, DPYD*13 and c.1236G>A [Hap B3]/ UH2/U ratio in PBMC/PK data by UHPLC-MS/MS/ADR until toxicity resolution.\t\nCremolini et al. (2018) [36]\t443\tRelationship between DPYD and UGT1A1 genotyping and toxicity.\tDPYD*2A, *13, c.2846A>T/ADR reported until the fourth cycle of treatment.\t\n\t\n\t\nJacobs et al.(2019) [37]\t237\tPharmacokinetics of capecitabine and 5-FU in DPYD variant allele carriers.\t\n\tDPYD*2A, c.2846A>T, c.1236G>A [HapB3]/5-FU clearance by LC MS/MS.\t\n\t\nIachetta et al.(2019) [38]\t1827\tRelationship between DPYD and toxicity.\tDPYD*13, DPYD*2A, c.2846A>T, DPYD*6 /ADR reported until the eleventh cycle of treatment.\t\n\t\n\t\nKleinjan et al. (2019) [39]\t185\tDPYD genotyping and toxicity.\tDPYD*2A, c.2846A>T, DPYD*13 and c.1236G>A [HapB3] /ADR reported until the second cycle of treatment.\t\n\t\n\t\nNegarandeh et al.(2020) [40]\t88\tRelationship between DPYD genotyping and toxicity.\tDPYD*2A, c.2846A>T, DPYD*6/ADR reported following 227 cycles for 88 patients.\t\n\t\n\t\nNicolas Pallet et al.(2020) [41]\t5886\tRelationship between DPYD genotyping and [U] and UH2/U ratio in plasma.\t\n\tDPYD*2A, DPYD*13, c.2846A>T, c.1236G>A [HapB3]/ [U] and UH2/U ratio in plasma.\n==== Refs\nReferences\n1. Longley D.B. Harkin D.P. Johnston P.G. 5-Fluorouracil: Mechanisms of Action and Clinical Strategies Nat. Rev. Cancer 2003 3 330 338 10.1038/nrc1074 12724731 \n2. Venook A.P. Niedzwiecki D. Lenz H.-J. Innocenti F. Fruth B. Meyerhardt J.A. Schrag D. Greene C. O’Neil B.H. Atkins J.N. 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Milano G. Link between Dihydropyrimidine Dehydrogenase Activity in Peripheral Blood Mononuclear Cells and Liver Clin. Cancer Res. 1996 2 507 510 9816197 \n61. Gamelin E. Boisdron-Celle M. Guérin-Meyer V. Delva R. Lortholary A. Genevieve F. Larra F. Ifrah N. Robert J. Correlation between Uracil and Dihydrouracil Plasma Ratio, Fluorouracil (5-FU) Pharmacokinetic Parameters, and Tolerance in Patients with Advanced Colorectal Cancer: A Potential Interest for Predicting 5-FU Toxicity and Determining Optimal 5-FU Dosage J. Clin. Oncol. 1999 17 1105 1110 10.1200/JCO.1999.17.4.1105 10561167 \n62. Thomas F. Hennebelle I. Delmas C. Lochon I. Dhelens C. Tixidre C.G. Bonadona A. Penel N. Goncalves A. Delord J.P. Genotyping of a Family with a Novel Deleterious DPYD Mutation Supports the Pretherapeutic Screening of DPD Deficiency with Dihydrouracil/Uracil Ratio Clin. Pharmacol. Ther. 2016 99 235 241 10.1002/cpt.210 26265035\n\n", "fulltext_license": "CC BY", "issn_linking": "2075-4426", "issue": "10(3)", "journal": "Journal of personalized medicine", "keywords": "DPD; DPYD polymorphisms; fluoropyrimidines; personalised medicine; pharmacogenetics; therapeutic drug monitoring", "medline_ta": "J Pers Med", "mesh_terms": null, "nlm_unique_id": "101602269", "other_id": null, "pages": null, "pmc": null, "pmid": "32899374", "pubdate": "2020-09-03", "publication_types": "D016428:Journal Article; D016454:Review", "references": "16707601;28632865;31745289;29487697;11304782;30238837;23695028;30858516;15355920;29152729;30628914;19097774;27181275;23856855;29906295;28481884;18299612;11156223;26573078;28395759;25555855;20362666;21498394;27399164;31838077;31652031;26099996;27454530;30131855;22454320;28637434;9816197;25677447;17064846;30510603;10561167;8630950;32595208;20926004;26216193;26189437;17115185;12724731;24923815;32546132;30723313;25381393;28024938;18635751;26265035;30348537;18781847;23604281;20530282;25410891", "title": "A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature.", "title_normalized": "a genotyping phenotyping approach with careful clinical monitoring to manage the fluoropyrimidines based therapy clinical cases and systematic review of the literature" }

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"reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Palmar-plantar erythrodysaesthesia syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stomatitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash erythematous", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash maculo-papular", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anal fissure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CONTI V, DE BELLIS E, MANZO V, SABBATINO F, IANNELLO F, PIAZ F. A GENOTYPING/PHENOTYPING APPROACH WITH CAREFUL CLINICAL MONITORING TO MANAGE THE FLUOROPYRIMIDINES-BASED THERAPY: CLINICAL CASES AND SYSTEMATIC REVIEW OF THE LITERATURE. JOURNAL OF PERSONALIZED MEDICINE. 2020?10(113):1-25.", "literaturereference_normalized": "a genotyping phenotyping approach with careful clinical monitoring to manage the fluoropyrimidines based therapy clinical cases and systematic review of the literature", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201111", "receivedate": "20201111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18490304, "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": "IT-TEVA-2020-IT-1849076", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES OF FOLFOX AND THEREAFTER ONE CYCLE WITH CETUXIMAB", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES EACH OF FOLFOX AND FOLFIRI", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES ALONG WITH FOLFOX REGIMEN AND THEREAFTER ONE CYCLE WITH OXALIPLATIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40333", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIATED AT 50% DOSE REDUCTION; RECEIVED 6 CYCLES EACH OF FOLFIRI AND FOLFOX REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5-FLUOROURACIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES OF FOLFIRI AND THEREAFTER CONTINUED WITH BEVACIZUMAB", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES ALONG WITH FOLFIRI AND THEREAFTER CONTINUED WITH IRINOTECAN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL ADENOCARCINOMA", "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": "5", "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash maculo-papular", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CONTI V, DE BELLIS E, MANZO V, SABBATINO F, IANNELLO F, PIAZ FD, ET AL. A GENOTYPING/PHENOTYPING APPROACH WITH CAREFUL CLINICAL MONITORING TO MANAGE THE FLUOROPYRIMIDINES-BASED THERAPY: CLINICAL CASES AND SYSTEMATIC REVIEW OF THE LITERATURE. J-PERS-MED 2020?10(3):1-24.", "literaturereference_normalized": "a genotyping phenotyping approach with careful clinical monitoring to manage the fluoropyrimidines based therapy clinical cases and systematic review of the literature", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201201", "receivedate": "20201201", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18566676, "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": "IT-TEVA-2020-IT-1849073", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "40333", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5?FLUOROURACIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40333", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5?FLUOROURACIL" } ], "patientagegroup": "5", "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Palmar-plantar erythrodysaesthesia syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash erythematous", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin fissures", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash maculo-papular", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stomatitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CONTI V, DE BELLIS E, MANZO V, SABBATINO F, IANNELLO F, PIAZ FD, ET AL. A GENOTYPING/PHENOTYPING APPROACH WITH CAREFUL CLINICAL MONITORING TO MANAGE THE FLUOROPYRIMIDINES?BASED THERAPY: CLINICAL CASES AND SYSTEMATIC REVIEW OF THE LITERATURE. 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A GENOTYPING/PHENOTYPING APPROACH WITH CAREFUL CLINICAL MONITORING TO MANAGE THE FLUOROPYRIMIDINES-BASED THERAPY: CLINICAL CASES AND SYSTEMATIC REVIEW OF THE LITERATURE. JOURNAL OF PERSONALIZED MEDICINE. 2020?10 (3):1-25", "literaturereference_normalized": "a genotyping phenotyping approach with careful clinical monitoring to manage the fluoropyrimidines based therapy clinical cases and systematic review of the literature", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201015", "receivedate": "20201008", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18362215, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]

{ "abstract": "Rituximab has been associated with the development of cytomegalovirus enterocolitis in immunosuppressed patients. A 51-year-old patient with diffuse large B-cell lymphoma who received a conditioning chemotherapy regimen (RCVP and RICE) consisting of rituximab before bone marrow transplantation went on to develop cytomegalovirus enterocolitis. This supports evidence from previously described cases that rituximab may be associated with cytomegalovirus enterocolitis.", "affiliations": null, "authors": "Seewoodhary|Jason|J|", "chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab", "country": "United States", "delete": false, "doi": "10.3748/wjg.v12.i45.7391", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "12(45)", "journal": "World journal of gastroenterology", "keywords": null, "medline_ta": "World J Gastroenterol", "mesh_terms": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003586:Cytomegalovirus Infections; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D016896:Treatment Outcome", "nlm_unique_id": "100883448", "other_id": null, "pages": "7391", "pmc": null, "pmid": "17143963", "pubdate": "2006-12-07", "publication_types": "D002363:Case Reports; D016420:Comment; D016422:Letter", "references": "10458242;16610013", "title": "Cytomegalovirus enterocolitis in a patient with diffuse large B-cell lymphoma after chemotherapy with rituximab.", "title_normalized": "cytomegalovirus enterocolitis in a patient with diffuse large b cell lymphoma after chemotherapy with rituximab" }

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{ "abstract": "Postoperative visual loss is a rare but devastating complication of non-ophthalmic surgery. Its aetiology is poorly understood and multiple associated factors have been proposed. We present a report of a 33-year-old female who developed irreversible diminution of vision on the right eye (non-arteritic-posterior-ischemic-optic-neuropathy) following general anaesthesia for pedicle screw fixation and plating for fracture vertebrae and hip in prone position and then screw placement for fracture calcaneum in supine position. The vision loss, limited to finger count close to face on the right eye, did not improve till follow-up at one-year. The combination of mild intraoperative hypotension, anaemia, prone positioning, prolonged surgery and anaesthesia may have contributed to postoperative visual loss in our patient. Keywords: ischaemic optic neuropathy; postoperative visual loss; spine surgery.", "affiliations": "Department of Anaesthesia and Intensive Care, Kathmandu Medical College, Sinamangal, Kathmandu, Nepal.;Department of Anaesthesia and Intensive Care, Kathmandu Medical College, Sinamangal, Kathmandu, Nepal.;Department of Anaesthesiology and Critical care, B.P. Koirala Insitute of Health Sciences, Dharan, Nepal.", "authors": "Bhandari|Sabin|S|;Pokharel|Krishna|K|;Sah|Birendra Prasad|BP|", "chemical_list": null, "country": "Nepal", "delete": false, "doi": null, "fulltext": "\n==== Front\nJNMA J Nepal Med Assoc\nJNMA J Nepal Med Assoc\nJ Nepal Med Assoc\nJNMA\nJNMA: Journal of the Nepal Medical Association\n0028-2715\n1815-672X\nJournal of the Nepal Medical Association\n\n10.31729/jnma.4539\nCase Report\nPostoperative Visual Loss Following Spine Surgery: A Case Report\nBhandari Sabin 1\nPokharel Krishna 1\nSah Birendra Prasad 1\n1 Department of Anaesthesiology and Critical Care, B.P. Koirala Institute of Health Sciences, Dharan, Nepal\nCorrespondence: Dr. Sabin Bhandari, Department of Anaesthesiology and Critical Care, B. P. Koirala Institute of Health Sciences, Dharan, Nepal. Email: [email protected], Phone: +9779851161225.\n8 2019\n31 8 2019\n57 218 269271\n© The Author(s) 2018.\n2018\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open-Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nABSTRACT\n\nPostoperative visual loss is a rare but devastating complication of non-ophthalmic surgery. Its aetiology is poorly understood and multiple associated factors have been proposed. We present a report of a 33-year-old female who developed irreversible diminution of vision on the right eye (non-arteritic-posterior-ischemic-optic-neuropathy) following general anaesthesia for pedicle screw fixation and plating for fracture vertebrae and hip in prone position and then screw placement for fracture calcaneum in supine position. The vision loss, limited to finger count close to face on the right eye, did not improve till follow-up at one-year. The combination of mild intraoperative hypotension, anaemia, prone positioning, prolonged surgery and anaesthesia may have contributed to postoperative visual loss in our patient.\n\nKeywords\n\nischaemic optic neuropathy\npostoperative visual loss\nspine surgery\n==== Body\npmcINTRODUCTION\n\nPostoperative visual loss (POVL) is a rare, devastating complication of non-ophthalmic surgery. Its incidence is variable from 0.05 to 1.3% and mostly reported after cardiac (incidence 0.09%) and spinal (incidence 0.03%) surgery.1,2 However, the exact incidence and aetiology remains unknown as most cases of postoperative vision loss following spine surgery are mentioned as case reports, which are difficult to obtain as the cases are often subject to malpractice claims, resulting in a lack of public access to case reports.\n\nCASE REPORT\n\nA 33-year-old female, weighing 70 kg, was scheduled for pedicle screw fixation at T11-L3, open reduction internal fixation for fracture hip and closed reduction and cortico-cancellous screw for calcaneum fracture for a five-day-old traumatic anterior wedge compression fracture L1 vertebrae without neurological deficit, fracture left iliac blade and fracture calcaneum without distal neurovascular damage.\n\nHer pre-anaesthetic check-up revealed anaemia (hemoglobin 9.4 gm/dl). After induction of general anaesthesia, her eyes were padded with cotton gauze and she was placed prone. The head was placed on a horse shoe in a neutral position. We ensured that pressure was not exerted on the eyes. The abdomen was also checked for free movement. After three and half hours of prone positioning, she was made supine for surgery on the hip and calcaneum. We followed the routine departmental anaesthesia protocol for induction, maintenance and reversal of anaesthesia. We maintained mean arterial pressure (MAP) from 60 to 70 mmHg (20% below baseline) during the manipulation of spine with IV esmolol 5 mg boluses and IV nitroglycerin 50 -100 mcg boluses for two hours. MAP was maintained close to baseline for the remaining period. Heart rate was maintained at 100-120/min. Estimated blood loss was 700 ml. One unit of packed red cells was transfused after the hemostasis was secured. Urine output was 75–100 ml/h. The surgery lasted for four and half hours.\n\nIn the orthopaedics in-patient unit, the patient complained of painless diminution of vision in the right eye. An ophthalmologist was consulted. In the right eye, vision was limited to finger count close to face. Intraocular pressure was normal. A dense apparent pupillary defect was present. Anterior segments were normal. Fundal examination showed normal discs and maculae without swelling or pallor or retinal hemorrhage. Visual evoked potential showed perception of light with absent visual evoked response. There was no abnormality on the left eye. A diagnosis of non-arteritic posterior ischemic optic neuropathy of right eye was made. IV methylprednisolone 250 mg four times a day for three days followed by tapering dose of tab prednisolone over 15 days was administered. Other aspects of recovery from surgery was unremarkable. On regular follow-up for one year in the ophthalmology out-patient-service, her visual acuity did not improve.\n\nDISCUSSION\n\nThe aetiology of post-operative visual loss is poorly understood. Proposed risk factors include obesity, cardiovascular disease, hyper-lipidemia, diabetes, smoking, male gender, intraoperative hypotension, prone positioning, less usage of colloids, prolonged procedures and anaesthesia.3\n\nThe American Society of Anaesthesiologists (ASA) closed claim database analysis of 93 patients with postoperative visual loss after spine surgery from 1999 to June 2005 revealed 89% had ischaemic optic neuropathy (ION) while 10% had central retinal arterial occlusion. Among the patients developing ION, majority (60%) had posterior ischaemic optic neuropathy (PION).4\n\nOur patient was anaemic. We also induced deliberate hypotension (MAP 20 % below baseline but around 60 – 70 mm Hg) for two hours. Although these two are the most commonly blamed risk factors, the ASA report does not suggest any independent effect of anaemia or intraoperative mean arterial pressure drop of more than 40% below baseline for 30 congruent or additive minutes on postoperative blindness.5 Our patient did not have decreased urine output or ECG changes that may reflect reduced end organ perfusion due to hypotension.\n\nAnother risk factor for postoperative visual loss is increased intraocular tension by direct pressure on the globe or raised central venous pressure (CVP) due to head-down position, rotation of head or direct pressure on the abdomen during prone positioning. We had ensured that these factors were absent. However, the prone position itself can significantly increase intraocular pressure which could be normalized by 10° reverse trendelenberg position.6,7 We did not take this precaution. An analysis of the reports of spine procedures obtained from the Anaesthesia Closed Claims Project database (2000 to 2014) found that prone positioning and surgical duration of ≥4 hours were associated with permanent disabling injuries to nerves, spinal cord, and eyes or visual pathways.8 The duration of surgery in our patient was four and a half hours.\n\nIt is likely that the combination of preoperative anaemia, intraoperative mild to moderate hypotension, prone positioning, prolonged surgery and anaesthesia resulted in a reduced perfusion pressure to the optic nerve and hence, visual loss in our patient. We strongly feel that we should have corrected the preoperative anaemia and also staged the last part of surgery after a few days instead of performing it in a single setting. The practice of deliberate hypotension for all spine surgery in prone position also warrants some caution.\n\nIn conclusion, both anaesthesiologist and surgeon need to be aware that a number of risk factors which, when combined, can cumulatively increase the risk of postoperative visual loss. A thorough preoperative evaluation to identify high risk patients should be performed and they should be informed about the risk of POVL. Whenever possible, staged procedure to reduce surgical duration should be considered. During surgery, a 10° reverse trendelenburg position should be maintained with the neck in a neutral forward position. Direct ocular pressure must be prevented, and the anaesthesiologist should have unobstructed access to the patient's eyes for repeat positioning checks. Normocarbia should be maintained, prolonged decrease in blood pressure should be corrected and deliberate hypotension should only be used with extreme caution at high risk patients. Monitoring the haemoglobin values frequently and avoiding anaemia are other preventive measures. Postoperatively, the vision of a high-risk patient should be assessed once the patient becomes alert and if there is concern regarding potential visual loss, an urgent ophthalmologic consultation should be obtained. Also, maintaining 30–45° head-up position postoperatively, if feasible, to limit orbital oedema is another preventive measure.1,2,6,7,8,9,10\n\nConsent:\n\nJNMA Case Report Consent Formwas signed by the patient and the original is attached with the patient's chart.\n\nConflict of Interest:\n\nNone.\n==== Refs\nREFERENCES\n\n1. Kitaba A Martin DP Gopalakrishnan S Tobias JD Perioperative visual loss after nonocular surgery J Anesth 2013 Dec 27 6 919 26 10.1007/s00540-013-1648-y 23775280\n2. Chwalisz B Gilbert AL Gittinger JW Jr Perioperative Vision Loss after Non-Ocular Surgery Semin Ophthalmol 2018 33 1 17 22 10.1080/08820538.2017.1353807 28881162\n3. Mendel E Stoicea N Rao R Niermeyer W Revilla S Cluse M et al Revisiting Postoperative Vision Loss following Non-Ocular Surgery: A Short Review of Etiology and Legal Considerations Front Surg 2017 4 34 10.3389/fsurg.2017.00034 28695122\n4. Lee LA Roth S Posner KL Cheney FW Caplan RA Newman NJ et al The American Society of Anesthesiologists Postoperative Visual Loss Registry: analysis of 93 spine surgery cases with postoperative visual loss Anesthesiology 2006 Oct 105 4 652 9 10.1097/00000542-200610000-00007 17006060\n5. Postoperative Visual Loss Study Group Risk factors associated with ischemic optic neuropathy after spinal fusion surgery Anesthesiology 2012 Jan 116 1 15 24 10.1097/ALN.0b013e31823d012a 22185873\n6. Hunt K Bajekal R Calder I Meacher R Eliahoo J Acheson JF Changes in intraocular pressure in anaesthetised prone patients J Neurosurg Anesthesiol 2004 Oct 16 4 287 90 15557832\n7. Ozcan MS Praetel C Bhatti MT Gavenstein N Mahla ME Seubert CN The effect of body inclination during prone positioning on intraocular pressure in awake volunteers: a comparison of two operating tables Anesth Analg 2004 Oct 99 4 1152 8 10.1213/01.ANE.0000130851.37039.50 15385367\n8. Kutteruf R Wells D Stephens L Posner KL Lee LA Domino KB Injury and liability associated with spine surgery J Neurosurg Anesthesiol 2018 Apr 30 2 156 62 10.1097/ANA.0000000000000448 28763433\n9. American Society of Anesthesiologists Task Force on Perioperative Vision loss Practice advisory for perioperative vision loss associated with spine surgery: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Vision loss Anesthesiology 2012 Feb 116 2 274 85 10.1097/ALN.0b013e31823c104d 22227790\n10. Practice Advisory for Perioperative Visual Loss Associated with Spine Surgery 2019 An Updated Report by the American Society of Anesthesiologists Task Force on Perioperative Visual Loss, the North American Neuro-Ophthalmology Society, and the Society for Neuroscience in Anesthesiology and Critical Care Anesthesiology 2019 Jan 130 12 30 10.1097/ALN.0000000000002503 30531555\n\n", "fulltext_license": "CC BY", "issn_linking": "0028-2715", "issue": "57(218)", "journal": "JNMA; journal of the Nepal Medical Association", "keywords": null, "medline_ta": "JNMA J Nepal Med Assoc", "mesh_terms": "D000328:Adult; D000740:Anemia; D000768:Anesthesia, General; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018917:Optic Neuropathy, Ischemic; D056888:Patient Positioning; D065289:Pedicle Screws; D011183:Postoperative Complications; D013131:Spine; D014786:Vision Disorders", "nlm_unique_id": "0045233", "other_id": null, "pages": "269-271", "pmc": null, "pmid": "32323661", "pubdate": "2019", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Postoperative Visual Loss Following Spine Surgery: A Case Report.", "title_normalized": "postoperative visual loss following spine surgery a case report" }

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{ "abstract": "Immunotherapy for cancer treatment continues to evolve, and immune checkpoints have proven successful therapeutic targets. With success has come the challenge of managing the commonly associated immune-related toxicities. Arthralgias and arthritis are a common immune-related adverse event (IrAE), well described in the literature (Pardoll Nat Rev Cancer 12:252-264, 2012; Diesendruck and Benhar Drug Resist Updat 30:39-47, 2017; Cappelli et al. Arthritis Care Res 69:1751-1763, 2017; Brahmer et al. J Clin Oncol 36:1714-1768, 2018; Smith and Bass (2017). The optimal management of immune checkpoint inhibitor (ICI)-induced arthritis remains unclear. We describe the first series using hydroxychloroquine as a first-line disease-modifying antirheumatic drug (DMARD) for patients without pre-existing autoimmune disease, who developed arthritis secondary to ICI's. This was a single-center retrospective observational study reporting all patients evaluated by rheumatologists affiliated with the University of Alberta, a large tertiary health care center in Northern Alberta, Canada, deemed to have inflammatory arthritis (IA) following ICIs. We identified 11 patients, without pre-existing autoimmune disease, who developed IA following ICIs. Most patients presented with a symmetrical polyarthritis with both large and small joint involvement. All patients were treated according to the outlined treatment protocol with hydroxychloroquine as a first-line steroid-sparing agent: either as monotherapy or in combination with tapering doses of systemic corticosteroids (3) or intra-articular steroid injections (6). One patient required the addition of methotrexate to control symptoms and none required biologic therapy. There were no reported adverse effects from hydroxychloroquine. Inflammatory arthritis is an important complication of ICIs leading to significant impact on patient quality of life. In our experience, in patients without pre-existing autoimmune disease, hydroxychloroquine is an effective first-line therapy for IA secondary to ICI therapy.", "affiliations": "Division of Rheumatology, Department of Medicine, Dalhousie University, Suite 245 Nova Scotia Rehabilitation Building, 1341 Summer Street, Halifax, NS, B3H 4K4, Canada. [email protected].;Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.;Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.;Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.;Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.;Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.;Division of Rheumatology, Department of Medicine, University of Alberta, 8-120 Clinical Sciences Building, 8440 112 St NW, Edmonton, AB, T6G 2G3, Canada.;Division of Rheumatology, Department of Medicine, University of Alberta, 8-120 Clinical Sciences Building, 8440 112 St NW, Edmonton, AB, T6G 2G3, Canada.", "authors": "Roberts|Janet|J|http://orcid.org/0000-0002-3787-8541;Smylie|Michael|M|;Walker|John|J|;Basappa|Naveen S|NS|;Chu|Quincy|Q|;Kolinsky|Michael|M|;Lyddell|Christopher|C|;Ye|Carrie|C|", "chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor; D006886:Hydroxychloroquine", "country": "Germany", "delete": false, "doi": "10.1007/s10067-019-04451-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0770-3198", "issue": "38(5)", "journal": "Clinical rheumatology", "keywords": "Autoimmune disease; Hydroxychloroquine; Immunotherapy; Inflammation; Neoplasms", "medline_ta": "Clin Rheumatol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000416:Alberta; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D060908:CTLA-4 Antigen; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D061026:Programmed Cell Death 1 Receptor; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D016896:Treatment Outcome", "nlm_unique_id": "8211469", "other_id": null, "pages": "1513-1519", "pmc": null, "pmid": "30701346", "pubdate": "2019-05", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": "4856023;28363334;29442540;27307501;28830882;29162153;28405474;28600350;21398612;22343096;26687632;26282644;29146737;28514612", "title": "Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor-induced inflammatory arthritis.", "title_normalized": "hydroxychloroquine is a safe and effective steroid sparing agent for immune checkpoint inhibitor induced inflammatory arthritis" }

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HYDROXYCHLOROQUINE IS A SAFE AND EFFECTIVE STEROID-SPARING AGENT FOR IMMUNE CHECKPOINT INHIBITOR?INDUCED INFLAMMATORY ARTHRITIS. CLINICAL RHEUMATOLOGY. 2019?38(5):1513-9", "literaturereference_normalized": "hydroxychloroquine is a safe and effective steroid sparing agent for immune checkpoint inhibitor induced inflammatory arthritis", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190614", "receivedate": "20190614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16429439, "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": "CA-009507513-1906CAN004863", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PEMBROLIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "125514", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "UNK", "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": "KEYTRUDA" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune-mediated adverse reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Polyarthritis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ROBERTS J, SMYLIE M, WALKER J, BASAPPA NS, CHU Q, KOLINSKY M, ET AL.. HYDROXYCHLOROQUINE IS A SAFE AND EFFECTIVE STEROID-SPARING AGENT FOR IMMUNE CHECKPOINT INHIBITOR?INDUCED INFLAMMATORY ARTHRITIS. CLINICAL RHEUMATOLOGY. 2019?38(5):1513-9", "literaturereference_normalized": "hydroxychloroquine is a safe and effective steroid sparing agent for immune checkpoint inhibitor induced inflammatory arthritis", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190614", "receivedate": "20190614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16429280, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]

{ "abstract": "The efficacy and safety of rituximab against B-cell lymphomas is well established. However, there has been an increased incidence of infectious complications after rituximab treatment, mostly hepatitis B reactivation and progressive multifocal leukoencephalopathy. This is the case of a 67-year-old patient with primary central nervous system lymphoma, who developed cytomegalovirus meningoencephalitis after receiving high-dose chemotherapy and rituximab. As there was no evidence of lymphoma relapse or additional immunosuppression, besides his previous treatment, an association between rituximab and cytomegalovirus meningoencephalitis cannot be ruled out.", "affiliations": "*1st Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School †Immunology and HLA Histocompatibility Laboratory ‡Department of Neurology, Laiko General Hospital §Department of Hematology, Athens Medical Center-Psychikon Branch, Athens, Greece.", "authors": "Siakantaris|Marina P|MP|;Argyropoulos|Kimon V|KV|;Ioannou|Savvas|S|;Papadopoulou|Vasiliki|V|;Tzeletas|George|G|;Tsonis|John|J|;Dimitrakopoulou|Aglaia|A|;Yiannopoulou|Konstantina G|KG|;Pangalis|Gerassimos A|GA|;Vaiopoulos|George|G|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab", "country": "United States", "delete": false, "doi": "10.1097/NRL.0b013e318287fde0", "fulltext": null, "fulltext_license": null, "issn_linking": "1074-7931", "issue": "19(2)", "journal": "The neurologist", "keywords": null, "medline_ta": "Neurologist", "mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D016543:Central Nervous System Neoplasms; D003586:Cytomegalovirus Infections; D006801:Humans; D008223:Lymphoma; D008297:Male; D008590:Meningoencephalitis; D000069283:Rituximab", "nlm_unique_id": "9503763", "other_id": null, "pages": "35-7", "pmc": null, "pmid": "25607329", "pubdate": "2015-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cytomegalovirus meningoencephalitis after rituximab treatment for primary central nervous system lymphoma.", "title_normalized": "cytomegalovirus meningoencephalitis after rituximab treatment for primary central nervous system lymphoma" }

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CYTOMEGALOVIRUS MENINGOENCEPHALITIS AFTER RITUXIMAB TREATMENT FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA. NEUROLOGIST. 2015?19(2):35-37. DOI:10.1097/NRL.0B013E318287FDE0.", "literaturereference_normalized": "cytomegalovirus meningoencephalitis after rituximab treatment for primary central nervous system lymphoma", "qualification": "1", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20181103", "receivedate": "20181103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15582998, "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": "GR-PFIZER INC-2018413657", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (2 CYCLES OF HIGH-DOSE METHOTREXATE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CENTRAL NERVOUS SYSTEM LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071868", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (HIGH-DOSE CYTARABINE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CENTRAL NERVOUS SYSTEM LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, WEEKLY (ADDITIONAL 6 CYCLES, WEEKLY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CENTRAL NERVOUS SYSTEM LYMPHOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalitis cytomegalovirus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SIAKANTARIS, M.. 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{ "abstract": "BACKGROUND\nIn our previous study, colorectal cancer (CRC) patients with active Mycobacterium tuberculosis (MTB) tolerated concurrent anti-cancer chemotherapy (anti-CCT) and anti-MTB chemotherapy. In this study, we retrospectively confirmed the efficacy and safety of concurrent chemotherapy in a greater number of patients with different types of malignancies.\n\n\nMETHODS\nWe enrolled 30 patients who were treated concurrently with anti-CCT and anti-MTB regimens between January 2006 and February 2016. Cancer and MTB treatments were administered according to the approved guidelines.\n\n\nRESULTS\nPatient demographics included: men/woman: 24/6; median age: 66.5 years; Eastern Cooperative Oncology Group performance status 0-1/2/3-4: 24/4/2; Stage IIB-IIIC/IV/recurrence: 6/22/2; lung cancer (LC)/CRC/other: 15/10/5; and MTB diagnosis (before or during anti-CCT): 20/10 (LC: 8/7; CRC: 8/2; other: 4/1). For anti-CCT, 23 patients received two cytotoxic agents with or without targeted agents and 7 patients received a single cytotoxic or targeted agent. The overall response rate was 36.7%. Regarding anti-MTB chemotherapy, 22 patients received a daily drug combination containing isoniazid, rifampicin, and ethambutol, plus pyrazinamide in 15 of the 22 patients, followed by daily isoniazid and rifampicin; the remaining 8 patients received other combinations. Hematological adverse events of Grade ≥ 3 were observed in 19 (67.9%) of 28 patients; laboratory data were lost for the remaining 2. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies (P < 0.005). Non-hematological adverse events of Grade ≥ 3 were observed in 5 (16.7%) of 30 patients. One CRC patient experienced Grade 3 hemoptysis and another 2 experienced Grade 3 anaphylaxis. One patient with cholangiocellular carcinoma and gastric cancer experienced Grade 3 pseudomembranous colitis as a result of a Clostridium difficile infection. One patient (3.3%) died of pemetrexed-induced pneumonitis. The success of the anti-MTB chemotherapy was 70.0%. There were no MTB-related treatment failures. The median overall survival (months, 95.0% confidence interval) was 10.5 (8.7-36.7), 8.7 (4.7-10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) for all patients combined, LC, CRC, and Other malignancies, respectively. LC patients experienced delayed MTB diagnosis and shorter overall survival.\n\n\nCONCLUSIONS\nConcurrent chemotherapy is effective and safe for treating cancer patients with active MTB.", "affiliations": "Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan. [email protected].;Departments of Clinical Laboratory, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Infectious Diseases, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Infectious Diseases, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Gynecology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Breast Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Thoracic Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Gastroenterological Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Gastroenterological Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Gastroenterological Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.;Departments of Infectious Diseases, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583-8588, Japan.", "authors": "Hirashima|Tomonori|T|;Tamura|Yoshitaka|Y|;Han|Yuki|Y|;Hashimoto|Shoji|S|;Tanaka|Ayako|A|;Shiroyama|Takayuki|T|;Morishita|Naoko|N|;Suzuki|Hidekazu|H|;Okamoto|Norio|N|;Akada|Shinobu|S|;Fujishima|Makoto|M|;Kadota|Yoshihisa|Y|;Sakata|Kazuya|K|;Nishitani|Akiko|A|;Miyazaki|Satoru|S|;Nagai|Takayuki|T|", "chemical_list": "D000970:Antineoplastic Agents; D000995:Antitubercular Agents", "country": "England", "delete": false, "doi": "10.1186/s12885-018-4889-1", "fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 488910.1186/s12885-018-4889-1Research ArticleEfficacy and safety of concurrent anti-Cancer and anti-tuberculosis chemotherapy in Cancer patients with active Mycobacterium tuberculosis: a retrospective study Hirashima Tomonori [email protected] 1Tamura Yoshitaka [email protected] 2Han Yuki [email protected] 3Hashimoto Shoji [email protected] 3Tanaka Ayako [email protected] 1Shiroyama Takayuki [email protected] 1Morishita Naoko [email protected] 1Suzuki Hidekazu [email protected] 1Okamoto Norio [email protected] 1Akada Shinobu [email protected] 4Fujishima Makoto [email protected] 5Kadota Yoshihisa [email protected] 6Sakata Kazuya [email protected] 7Nishitani Akiko [email protected] 7Miyazaki Satoru [email protected] 7Nagai Takayuki [email protected] 31 Department of Thoracic Oncology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 2 Departments of Clinical Laboratory, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 3 Departments of Infectious Diseases, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 4 Departments of Gynecology, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 5 Departments of Breast Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 6 Departments of Thoracic Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 7 Departments of Gastroenterological Surgery, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka 583-8588 Japan 12 10 2018 12 10 2018 2018 18 97519 8 2017 2 10 2018 © The Author(s). 2018Open 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\nIn our previous study, colorectal cancer (CRC) patients with active Mycobacterium tuberculosis (MTB) tolerated concurrent anti-cancer chemotherapy (anti-CCT) and anti-MTB chemotherapy. In this study, we retrospectively confirmed the efficacy and safety of concurrent chemotherapy in a greater number of patients with different types of malignancies.\n\nMethods\nWe enrolled 30 patients who were treated concurrently with anti-CCT and anti-MTB regimens between January 2006 and February 2016. Cancer and MTB treatments were administered according to the approved guidelines.\n\nResults\nPatient demographics included: men/woman: 24/6; median age: 66.5 years; Eastern Cooperative Oncology Group performance status 0–1/2/3–4: 24/4/2; Stage IIB–IIIC/IV/recurrence: 6/22/2; lung cancer (LC)/CRC/other: 15/10/5; and MTB diagnosis (before or during anti-CCT): 20/10 (LC: 8/7; CRC: 8/2; other: 4/1). For anti-CCT, 23 patients received two cytotoxic agents with or without targeted agents and 7 patients received a single cytotoxic or targeted agent. The overall response rate was 36.7%. Regarding anti-MTB chemotherapy, 22 patients received a daily drug combination containing isoniazid, rifampicin, and ethambutol, plus pyrazinamide in 15 of the 22 patients, followed by daily isoniazid and rifampicin; the remaining 8 patients received other combinations. Hematological adverse events of Grade ≥ 3 were observed in 19 (67.9%) of 28 patients; laboratory data were lost for the remaining 2. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies (P < 0.005). Non-hematological adverse events of Grade ≥ 3 were observed in 5 (16.7%) of 30 patients. One CRC patient experienced Grade 3 hemoptysis and another 2 experienced Grade 3 anaphylaxis. One patient with cholangiocellular carcinoma and gastric cancer experienced Grade 3 pseudomembranous colitis as a result of a Clostridium difficile infection. One patient (3.3%) died of pemetrexed-induced pneumonitis. The success of the anti-MTB chemotherapy was 70.0%. There were no MTB-related treatment failures. The median overall survival (months, 95.0% confidence interval) was 10.5 (8.7–36.7), 8.7 (4.7–10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) for all patients combined, LC, CRC, and Other malignancies, respectively. LC patients experienced delayed MTB diagnosis and shorter overall survival.\n\nConclusions\nConcurrent chemotherapy is effective and safe for treating cancer patients with active MTB.\n\nKeywords\nConcurrent chemotherapyTuberculosisBreast cancerColorectal cancerEfficacyGastric cancerLung cancerSafetyissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nMycobacterium tuberculosis (MTB) represents the leading cause of death from an infectious disease worldwide [1], with the majority of cases occurring in Asia (61.0%) and Africa (26.0%). Incidence and mortality rates are noticeably higher in Japan than other developed countries [1].\n\nAlthough active MTB infections may be present in cancer patients, our previous preliminarily report [2] is the only study to discuss the clinical course and chemotherapy outcomes of concurrent anti-cancer chemotherapy (anti-CCT) and anti-MTB chemotherapy, revealing that patients with metastatic colorectal cancer (CRC) and active MTB could safely and effectively continue anti-CCT, and achieve comparable survival to those without the infection, upon receiving appropriate MTB treatment [2].\n\nIn this study, we retrospectively examined the clinical course and chemotherapy outcomes of a larger number of patients treated concurrently with anti-CCT and anti-MTB chemotherapy.\n\nMethods\nStudy approval\nThe present retrospective study was approved by the Institutional Review Board (IRB) of the Osaka Habikino Medical center on 30 January 2017 (approval number: 808–1). The board waived the requirement for informed written consent due to the anonymous nature of the data, and no risk of exposure to subjects.\n\nPatient selection\nWe enrolled 30 cancer patients with active MTB who were treated concurrently with anti-CCT and anti-MTB chemotherapy at our institution between January 1, 2006 and February 29, 2016. The 6 metastatic CRC patients with active MTB from our previous study [2] were also included.\n\nClinical review\nAs described previously, [2] the clinical history of eligible patients was retrospectively reviewed. We collected baseline demographic data and anti-CCT data, which were also collected from clinical records or pharmacy database. Complete history and physical examinations; surgical reports; findings of flexible bronchoscopy, colonoscopy, and esophagogastroduodenoscopy; imaging investigations; pathological reports, and blood test results were available for all patients at the time of anti-MTB chemotherapy.\n\nMTB diagnosis\nAs described previously [2], MTB diagnosis was performed by smears and cultures of various patients’ specimens or chest computed tomography (CT) image in patients without microbiological evaluation. The method of choice for confirming MTB infection was Ziehl-Neelsen staining of sputum smear samples [3]. Polymerase chain reaction (PCR) or loop-mediated isothermal amplification (LAMP) [4] was performed for patients with positive sputum smears to distinguish MTB from other mycobacteria. If the sputum smears were negative or specimens other than sputum were obtained, the diagnosis of MTB was confirmed by culturing mycobacterial organisms. Drug sensitivity was determined for all cases with positive culture. Liquid media with the Mycobacteria Growth Indicator Tube (MGIT) [5] and solid media with the Ogawa-Kudoh method [6] were both used for culturing mycobacteria. Drug sensitivity was determined for all cases. Quantitative drug susceptibility testing for MTB was performed using the MTB-I® (Kyokuto Pharmaceutical Industrial Co., Ltd., Tokyo, Japan) modified Minimum Inhibitory Concentration method [7].\n\nTreatment of MTB infection\nAs described previously [2], in cancer patients with active MTB, appropriate anti-MTB agents were administered for approximately 1.5 months prior to anti-CCT, according to the American Thoracic Society and Infectious Diseases Society of America guidelines [8] A multi-drug resistant MTB, based on the sensitivity test, negated the initiation of anti-CCT. Since MTB patients with severe complications often require longer courses of treatment than those without such complications, patients treated with anti-CCT also received long-term treatment for MTB. Thus, the patients received 2 months of isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z), followed by HR for 7 months, or 6 months of HRE, followed by HR for 6 months as standard anti-MTB chemotherapy. The majority of patients who could not be treated with standard anti-MTB chemotherapy, due to side effects or drug resistance, were treated with a levofloxacin (X)-based regimen.\n\nFollow-up MTB culture\nAfter commencing anti-MTB chemotherapy, sputum specimens were cultured every other week for the first 3 months. Once two consecutive sputum cultures were negative, cultures were done monthly until the course of MTB treatment was completed.\n\nDefinition of MTB treatment outcomes\nMTB treatment outcomes were based on the World Health Organization’s definitions [9]. Treatment success included “cure” and “treatment completed”. A “cured” patient was defined as one who had completed the planned treatment and had two consecutive negative cultures. Patients with treatment failure had positive cultures ≥5 months into MTB treatment.\n\nCancer staging and treatment\nCancer staging and treatment were performed according to the guidelines of the respective lung cancer (LC) [10], CRC [11], gastric cancer (GC) [12], breast cancer, [13], and cholangiocellular carcinoma (CCA) [14] societies.\n\nThe policy of our institution was to commence anti-CCT immediately if patients were sensitive to anti-MTB agents. However, if patients were resistant or had experienced intolerable side effects while awaiting sensitivity test, anti-CCT was suspended until a decision could be reached concerning the appropriate drug combination and duration of anti-MTB chemotherapy. Additionally, when MTB cultures could not be obtained, due to a number of reasons, or the physician could not await the results of the sensitivity test due to rapid tumor progression, anti-CCT was commenced, following informed patient consent.\n\nAssessment of anti-cancer chemotherapy outcomes\nPatients’ best response to chemotherapy was collected from the records of weekly meetings at our institution and clinical summaries. Based on the Response Evaluation Criteria in Solid Tumors [15], the responses of tumors to cytotoxic agents were categorized as complete or partial responses and stable or progressive disease. Tumor responses that could not be assessed were recorded as “not evaluable”. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0 [16].\n\nStatistical analyses\nOverall survival (OS) was measured from the date of commencing concurrent chemotherapy (for both cancer and MTB) to the date of death or last follow-up (February 28, 2017). OS rates were estimated using the Kaplan-Meier method [17]. The duration of concurrent chemotherapy was defined as the time from commencing concurrent chemotherapy to the end date. All statistical analyses were conducted using R statistical software (version 3.2.0). Patient background data were analyzed using chi-square and Fisher’s exact test for categorical variables. A P < 0.05 was considered statistically significant.\n\nResults\nPatient demographics\nIn total, 30 cancer patients with active MTB who were treated concurrently with anti-CCT and anti-MTB chemotherapy between January 1, 2006 and February 29, 2016 at our institution, were enrolled in this study. Fifteen patients were diagnosed with LC (non-small cell LC [NSCLC, n = 10] and small cell LC [SCLC, n = 5]), 10 patients were diagnosed with CRC (rectal cancer [n = 7], sigmoid cancer [n = 2], and transverse colon cancer [n = 1]), and 5 patients were diagnosed with other malignancies (GC [n = 1], Breast Cancer [n = 1], LC with GC [n = 1], CRC with GC [n = 1], and CCA with GC [n = 1]). The patient demographics are summarized in Table 1. No significant differences in patient demographics were observed among LC, CRC, and other malignancy groups. However, LC patients tended to be more frequently diagnosed with active MTB during anti-CCT in comparison to those with CRC or other malignancy.Table 1 Patient Characteristics\n\nCharacteristic\tPatients\t\nAll\tLC\tCRC\tOther\t\n(n = 30)\t(n = 15)\t(n = 10)\t(n = 5)\t\nSex, n (%)\t\n M\t24 (80.0)\t12 (80.0)\t8 (80.0)\t4 (80.0)\t\n F\t6 (20.0)\t3 (20.0)\t2 (20.0)\t1 (20.0)\t\nAge (years), median (range)\t66.5 (39–79)\t68.0 (43–79)\t62.5 (43–75)\t56.0 (39–75)\t\nECOG PS, n (%)\t\n 0–1\t24 (80.0)\t12 (80.0)\t8 (80.0)\t4 (80.0)\t\n 2\t4 (13.3)\t3 (20.0)\t0 (0.0)\t1 (20.0)\t\n 3\t2 (6.7)\t0 (0.0)\t2 (20.0)\t0 (0.0)\t\nStage, n (%)\t\n IIB-IIIA\t3 (10.0)\t2 (13.3)\t0 (0.0)\t1 (20.0)\t\n IIIB-ΙΙΙC\t3 (10.0)\t2 (13.3)\t0 (0.0)\t1 (20.0)\t\n IV\t22 (73.3)\t10 (66.7)\t9 (90.0)\t3 (60.0)\t\nPostoperative recurrence, n (%)\t2 (6.7)\t1 (6.7)\t1 (10.0)\t0 (0.0)\t\nLine of cancer chemotherapy at the commencement of concurrent chemotherapy, n (%)\t\n Adjuvant\t1 (3.3)\t0 (0.0)\t0 (0.0)\t1 (20.0)\t\n First\t21 (70.0)\t9 (60.0)\t8 (80.0)\t4 (80.0)\t\n Second\t3 (10.0)\t3 (20.0)\t0 (0.0)\t0 (0.0)\t\n Third or higher\t5 (16.7)\t3 (20.0)\t2 (20.0)\t0 (0.0)\t\nDiabetes mellitus, n (%)\t\n Y\t7 (20.7)\t3 (20.0)\t2 (20.0)\t2 (40.0)\t\n N\t23 (79.3)\t12 (80.0)\t8 (80.0)\t3 (60.0)\t\nMTB diagnosis, n (%)\t\n Before anti-CCT\t20 (66.7)\t8 (53.3)\t8 (80.0)\t4 (80.0)\t\n During anti-CCT\t10 (33.3)\t7 (46.7)\t2 (20.0)\t1 (20.0)\t\nAbbreviations CCT cancer chemotherapy, CRC colorectal cancer, ECOG Eastern Cooperative Oncology Group, F female, LC lung cancer, M male, MTB Mycobacterium tuberculosis, N no, PS performance status, Y yes\n\n\n\nChest CT imaging\nThoracic CT findings at the time of MTB diagnosis is presented in Fig. 1 (a-d). These CT images present a combination of thick and thin walled lung cavities, infiltration shadows, and multiple nodules. There were no consistent findings on CT imaging based on the type of malignancy.Fig. 1 Thoracic computed tomography findings in 4 cancer patients with active Mycobacterium tuberculosis. a Non-small cell lung cancer patient with a thick wall cavity in the left lung with an infiltration shadow in the right upper lobe. b Colorectal cancer patient with multiple nodules in both lungs. c Breast cancer patient with a small cavity with an infiltration shadow in the right upper lobe. d Non-small cell lung cancer patient with multiple small nodules with partial patty follicular spot in the both lungs and cavity formation in the S6 segment of the right lung and lingular segment of the left lung\n\n\n\nBacteriological examinations\nThe findings of bacteriological examinations are summarized in Table 2. Twenty (66.7%) patients had MTB-positive sputum smears. In 25 (83.3%) cultures were positive for MTB and negative cultures were reported in 5 (16.7%). Cultures were negative for MTB in 3 LC and 2 CRC patients. In the former, active MTB was diagnosed by PCR of sputum in 2 cases and LAMP of sputum in 1, alongside CT results, while in the latter, the diagnosis was confirmed by PCR of sputum in one, and the results of the CT scan and clinical course in the other.Table 2 Bacteriological Examinations\n\nCharacteristic\tPatients\t\nAll\tLC\tCRC\tOther\t\n(n = 30)\t(n = 15)\t(n = 10)\t(n = 5)\t\nSputum smear, n (%)\t\n Negative\t10 (33.3)\t5 (33.3)\t3 (30.0)\t2 (40.0)\t\n Positive\t20 (66.7)\t10 (66.7)\t7 (70.0)\t3 (60.0)\t\nPCR/LAMP, n (%)\t\n Negative\t1 (3.3)\t1 (6.7)\t0 (0.0)\t0 (0.0)\t\n Positive\t15 (50.0)\t10 (66.7)\t3 (30.0)\t2 (40.0)\t\n Unknown\t14 (46.7)\t4 (26.7)\t7 (70.0)\t3 (60.0)\t\nCulture, n (%)\t\n Negative\t5 (16.7)\t3 (20.0)\t2 (20.0)\t0 (0.0)\t\n Positive\t25 (83.3)\t12 (80.0)\t8 (80.0)\t5 (100.0)\t\nSensitivity to anti-MTB agents, n (%)\t\n Sensitive\t22 (88.0)\t12 (100.0)\t6 (75.0)\t4 (80.0)\t\n Resistant\t2 (8.0)a\t0 (0.0)\t2 (25.0)\t0 (0.0)\t\n Unknown\t1 (4.0)b\t0 (0.0)\t0 (0.0)\t1 (20.0)b\t\nTime until the result of Bacteriological Examination come out\t\n\tOverall\tOgawa-Kudoh\tMGIT\t\nTime to MTB-positive culture (days), mean ± SD, n\t20.9 ± 12.4\n(n=23c)\t37.6 ± 8.4\n(n = 5)\t16.2 ± 8.7*\n(n = 18)\t\nTime to sensitivity testing (days), mean ± SD, n\t12.6 ± 3.5\n(n=22d)\t\t\t\nAbbreviations CRC colorectal cancer, LAMP loop-mediated isothermal amplification, LC lung cancer, MGIT Mycobacteria Growth Inhibitor Tube, MTB = Mycobacterium tuberculosis, PCR polymerase chain reaction, NTM Nontuberculous Mycobacteriosis\n\n*P < 0.0005\n\naOne MTB strain was resistant to isoniazid and streptomycin, another was isoniazid and pyrazinamide\n\nbOne specimen with MTB-positive cultures and concomitant NTM was not used for sensitivity testing\n\ncIn two specimens, measure of the time to MTB-positive cultures were not possible because the culture specimens were obtained in other institutes\n\ndTwenty-two cultures except one which was concomitant NTM and two which was obtained in other institute\n\n\n\nIn the 25 cases positive for MTB, 22 (88.0%) were sensitive, 2 (8.0%) were resistant (one MTB strain was resistant to H and streptomycin, another to H and Z), and 1 (4.0%) was not tested for sensitivity because of concomitant Nontuberculous Mycobacteriosis. In 2 of 25 patients with MTB-positive cultures, the time to MTB-positive culture could not be confirmed because the culture specimens were obtained in other institutes. Therefore, the time to MTB-positive culture in 23 patients was demonstrated by MGIT (n = 18) and Ogawa-Kudoh method (n = 5). The time (days: mean ± SD) to MTB-positive cultures was significantly shorter for MGIT than for the Ogawa-Kudoh method (16.2 ± 8.7 vs 37.6 ± 8.4; P < 0.0005). Furthermore, the time (days: mean ± SD) to sensitivity testing in 22 patients except one with concomitant Nontuberculous Mycobacteriosi was 12.6 ± 3.5.\n\nMTB treatment until concurrent chemotherapy\nOf the 30 patients enrolled in this study, 4 received X-based regimen from the start of MTB treatment due to resistant to INH (n = 2), past history of RFP-induced systemic eruption (n = 1), and preventing the drug interaction between erlotinib and RFP via CYP3A4 (n = 1).\n\nIn 2 of 4 patients the X-based regimen was changed to a different regimen due to renal dysfunction in one and liver dysfunction in the other.\n\nIn 4 patients the planned HREZ or HRE regimen was changed to X-based regimen due to drug eruption (n = 1), drug eruption and liver dysfunction (n = 1), thrombocytopenia (n = 1), and preventing the drug interaction between Paclitaxel and RFP via CYP3A4 and CYP2C8 (n = 1). Subsequently, 8 patients received concurrently X-based regimens and anti-CCT. The remaining 22 patients received concurrent HREZ or HRE and anti-CCT as planned, without many adverse events except in one patient who experienced a paradoxical response on day 23 after starting HREZ and was kept on HREZ while taking prednisolone. Thus, until concurrent chemotherapy, 6 (20.0%) of the 30 patients experienced adverse events with MTB treatment alone, and in 5 the planned MTB treatment was changed to other regimens.\n\nOutcomes of concurrent chemotherapy\nDetails of the initial concurrent anti-CCT regimens are listed in Table 3. Twenty-three patients (76.7%) received intensive anti-CCT regimens with or without targeted agents, 5 patients (16.7%) received a single cytotoxic agent, and 2 patients (6.7%) received a single targeted agent. The overall response rates (ORRs) were 36.7, 33.3 40.0, and 40.0% for all patients combined, LC patients, CRC patients, and patients with other malignancies, respectively. In 15 LC patients, all 5 patients with SCLC received intensive cytotoxic treatment (carboplatin plus etoposide) as first line chemotherapy (Table 3) with a high response rate (80%). Of 10 NSCLC patients, 4 (40%) received platinum doublets as intensive first regimen, and one of them achieved partial response. In the remaining 6 patients (60%), one received platinum doublets, three were administered single cytotoxic agent, and two received erlotinib as re-challenge regimen. They received those regimens as second-line or later anti-CTT and there was no responder.Table 3 Outcomes of Anti-Cancer Chemotherapy (Anti-CCT) and Anti-MTB Chemotherapy\n\nCharacteristic\tPatients\t\nAll\tLC (SCLC/NSCLC)\tCRC\tOther\t\n(n = 30)\t(n = 15, 5/10)\t(n = 10)\t(n = 5)\t\nInitial concurrent anti-CCT regimen, n\t\n Intensive cytotoxic regimen and targeted agenta\t4\t0\t3\t1\t\n Intensive cytotoxic regimenb\t19\t10 (5/5)\t6\t3\t\n Single targeted agentc\t2\t2 (0/2)\t0\t0\t\n Single cytotoxic agentd\t5\t3 (0/3)\t1\t1\t\nBest response on anti-CCT after commencing concurrent chemotherapy, n\t\n CR\t1\t0\t1\t0\t\n PR\t10\t5 (4/1)\t3\t2\t\n SD\t5\t2 (0/2)\t3\t0\t\n PD\t6\t4 (0/4)\t2\t0\t\n NE\t8\t4 (1/3)\t1\t3\t\nORR (%)e\t36.7\t33.3 (80.0/10.0)\t40.0\t40.0\t\nMain anti-MTB chemotherapy, n\t\n 2HREZ/7HRf\t15\t8 (3/5)\t4\t3\t\n 6HRE/6HRg\t7\t2 (0/2)\t4\t1\t\n Levofloxacin-based\t8\t5 (2/3)\t2\t1\t\nDuration of anti-MTB treatment (days), median (range)\t275.0 (72–637)\t274.0 (90–469) [274 (183–469)/255 (90–310)]\t259.0 (72–539)\t368.0 (273–637)\t\nDuration of concurrent chemotherapy (days), median (range)\t157.5 (13–408)\t117.0 (20–245) [93 (20–207)/121 (48–245)]\t168.5 (13–408)\t155.0 (51–376)\t\nMTB treatment outcomes, n (%)\tAll\tLC\tCRC\tOther\t\n Cured\t20 (66.7)\t10 (66.7)\t6 (60.0)\t4 (80.0)\t\n Completed\t1 (3.3)\t0\t1 (10.0)\t0\t\n Died\t9 (30)\t5 (33.3)\t3 (30.0)\t1 (20.0)\t\n Failed\t0\t0\t0\t0\t\n Not evaluated\t0\t0\t0\t0\t\nSuccess (%)h\t70.0\t66.7\t70.0\t80.0\t\nAbbreviations CI confidence interval, CR complete response, CRC colorectal cancer, E ethambutol, EGFR-TKI epidermal growth factor receptor-tyrosine kinase inhibitor, H isoniazid, LC lung cancer, MTB Mycobacterium tuberculosis, NE not evaluable, ORR overall response rate, PD progressive disease, PR partial response, R rifampicin, SD stable disease, Z pyrazinamide\n\naTwo cytotoxic agents combined with targeted therapy (bevacizumab or trastuzumab)\n\nbTwo cytoxic agents\n\ncErlotinib\n\ndSingle cytoxic agent (S-1, vinorelbine, or pemetrexed)\n\neCR + PR\n\nfDaily drug combination containing HREZ for 2 months, followed by daily HR for 7 months\n\ngDaily drug combination containing HRE for 6 months, followed by HR for 6 months\n\nhCured + completed\n\n\n\nThe main anti-MTB regimens were as follows: HREZ/HR (n = 15 patients; LC [n = 8], CRC [n = 4], other [n = 3]); HRE/HR (n = 7 patients; LC [n = 2], CRC [n = 4], other [n = 1]); and X-based (n = 8 patients; LC [n = 5]. and CRC [n = 2], other [n = 1]). The median duration (range) of MTB treatment was 275.0 (72–637), 274.0 (90–469), 259.0 (72–539), and 368.0 (273–637) days for all patients combined, those with LC, CRC, and other malignancies, respectively. The success of anti-MTB chemotherapy in each of the above groups was 70.0, 66.7, 70.0, and 80.0%, respectively. There were no MTB-related treatment failures. The median duration (range) of concurrent chemotherapy was 157.5 (13–408), 117.0 (20–245), 168.5 (13–408), and 155.0 (51–376) days for all patients combined, those with LC, CRC, and other malignancies, respectively.\n\nIn 20 (66.7%) patients MTB was cured, one (3.3%) completed the course for MTB treatment, and 9 (30%) died while receiving MTB treatment. Among the 9 patients who died, one died of pemetrexed-induced pneumonitis and 8 died of cancer.\n\nIn 2 CRC patients with performance status of 3, anti-CCT was started because of patients’ insistence and after the approval of the Cancer Board. In one of these patients, MTB was resistant to H and Z. Hence, X + Streptomycin was administered, alongside Folnic acid, fluorouracil and irinotecan for 1 cycle. The patient died 54 days after treatment withdrawal. Regular MTB cultures performed every other week were negative for six consecutive times. The other patient received modified regimen of Folinic acid, fluorouracil and oxaliplatin for 4 cycles and died 57 days after treatment withdrawal.\n\nEpidermal growth factor receptor sensitive mutation was found in 2 MTB-positive patients with lung adenocarcinoma. They received erlotinib as re-challenge regimen alongside HRE regimen in one patient and X-based regimen without rifampicin in the other. Both died because of cancer progression, 140 and 90 days after the initiation of erlotinib, respectively. Regular MTB cultures were performed for both patients every other week. Cultures were negative in each patient two and three consecutive times, respectively. None of the 30 patients enrolled in this study experienced recurrence of MTB through their clinical course.\n\nAdverse events of concurrent chemotherapy\nHematological adverse events of Grade ≥ 3 were observed in 19 (67.9%) of 28 patients; the laboratory data for 2 patients were lost. Non-hematological adverse events of Grade ≥ 3 were observed in 5 (17.9%) of 28 patients.\n\nNumber of cases in concurrent chemotherapy-related adverse events are shown in Table 4. There were no significant differences in the occurrence of adverse events between different cancer types, except for lymphopenia and neutropenia. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies (P < 0.005). Grade 3 Neutropenia and higher tended to be more frequent in LC compared to other malignancies. In non-hematological adverse events, Grade 1–2 liver dysfunction was frequently observed in each malignancies.Table 4 Concurrent Chemotherapy-Related Adverse Events\n\nNCI-CTCa (Grade)\tPatients\t\nAll\tLC\tCRC\tOther\t\n(n = 28)\t(n = 13b)\t(n = 10)\t(n = 5)\t\nAdverse event\t1–2\t≥3\t1–2\t≥3\t1–2\t≥3\t1–2\t≥3\t\nHematological toxicity, number of cases\t\n Leukocytopenia\t7\t8\t4\t6\t3\t1\t2\t1\t\n Neutropenia\t5\t14\t1\t9\t2\t3\t2\t2\t\n Anemia\t20\t2\t9\t2\t8\t0\t3\t0\t\n Thrombocytopenia\t3\t3\t1\t2\t1\t1\t1\t0\t\n Lymphopenia\t13\t10\t4\t8*\t7\t1\t2\t1\t\nNon-hematological toxicity, number of cases\t\n AST/ALT elevation\t12\t0\t4\t0\t6\t0\t2\t0\t\n Interstitial pneumonitis\t0\t1c\t0\t1c\t0\t0\t0\t0\t\n Colitis\t0\t1d\t0\t0\t0\t0\t0\t1d\t\n Anaphylaxis\t0\t2e\t0\t0\t0\t2e\t0\t0\t\n Hemorrhage\t1f\t1g\t1f\t0\t0\t1g\t0\t0\t\nAbbreviations CRC colorectal cancer, LC lung cancer\n\naNCI-CTC: National Cancer Institute Common Toxicity Criteria\n\nbIn two of 15 patients, laboratory data was lost\n\ncDeath caused by pemetrexed-induced pneumonitis\n\ndPseudomembranous colitis due to Clostridium difficile infection\n\neOxaliplatin- and cetuximab-induced anaphylaxis\n\nfNasal bleeding\n\ngHemoptysis\n\n*: P < 0.005\n\n\n\nOne CRC patient experienced Grade 3 hemoptysis and another 2 experienced Grade 3 anaphylaxis (oxaliplatin-induced [n = 1] and cetuximab-induced [n = 1]). One patient with CCA and GC experienced Grade 3 pseudomembranous colitis as a result of a Clostridium difficile infection. One LC patient died of pemetrexed-induced pneumonitis (Grade 5).\n\nOverall survival\nThe median OS in all patients was 10.5 (8.7–36.7; 95.0% confidence interval) months (Fig. 2a). The median OS according to the type of malignancy were 8.7 (4.7–10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) months for LC, CRC, and other malignancies, respectively (Fig. 2b).Fig. 2 (a) Kaplan-Meier curve of overall survival for 30 cancer patients with active Mycobacterium tuberculosis who received concurrent chemotherapy between January 1, 2006 and February 29, 2016. The median OS in all patients was 10.5 (8.7–36.7; 95.0% confidence interval) months (b) Kaplan-Meier curves of overall survival according to cancer type. Lung Cancer patients are represented by the thick solid line, Colorectal Cancer patients are represented by the thin solid line, and patients with Other malignancies, are represented by the dashed line. The median OS according to the type of malignancy were 8.7 (4.7–10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) months for Lung Cancer, Colorectal Cancer, and Other malignancies, respectively\n\n\n\nDiscussion\nThis study demonstrates the efficacy and safety of concurrent anti-CCT and anti-MTB chemotherapy for cancer patients with active MTB, confirming the findings of our previous preliminary study [2] in a bigger sample size with a variety of cancer types.\n\nIn Japan, the national rates for success, failed, died, and lost to follow-up of anti-MTB chemotherapy in 2015 were 52.8, 0.4, 17.0, and 5.6%, respectively [18]. In Nagoya which is almost similar to Osaka, where our institution is located, the rates of success, failed, died, and the others were 52.0, 0.7, 20.8, and 26.5%, respectively. [19] The success rate of anti-MTB chemotherapy in this study may have been higher than previous studies [18, 19], possibly because of no loss to follow-up and no unevaluated patient in the present study. However, it is important that there were no MTB-related treatment failures in our study, suggesting that cancer patients with active MTB would be able to tolerate anti-MTB chemotherapy while receiving anti-CCT as well as non-cancer patients with active MTB.\n\nConversely, the ORRs for all patients combined, LC patients, CRC patients, and other malignancy patients were 36.7, 33.3, 40.0, and 40.0%, respectively.\n\nIn 15 LC patients, all 5 patients with SCLC received intensive cytotoxic treatment (carboplatin plus etoposide) as first line chemotherapy (Table 3) with a high response rate (80%), which is similar to the response rate (73%) of similar treatment regimen in the elderly patient or those at poor risk with extensive disease [20]. On the other hand, 10% of response rate in 10 NSCLC patients seems to be low. This may be because 6 (60.0%) of 10 NSCLC patients had received second-line or later anti-CCT after starting anti-MTB chemotherapy.\n\nORR in CRC patients with MTB was 40% which was similar to other 1st line combined chemotherapy regimens without molecular targeted therapy in previous reports [21, 22].\n\nAlthough there were no significant differences in patient characteristics between the LC, CRC, and other malignancy groups, the diagnosis of MTB was more frequently reached during chemotherapy in LC patients when compared to patients with other types of malignancies. If LC and pulmonary MTB coexist in the lungs, a diagnosis of MTB becomes more difficult. Therefore, MTB diagnosis tends to be delayed in these patients.\n\nIn a Japanese retrospective study, [23] 247 (28.7%) of 861 patients who received MTB treatment experienced adverse events. The frequency of adverse events with MTB treatment alone, prior to the initiation of concurrent chemotherapy, in our study was equal to that of the a previous study. [23] Besides, upon starting concurrent chemotherapy in LC and CRC, we did not expect any differences in the prevalence of adverse events between this study and previous studies [20–22] except for liver dysfunction which may be correlated with MTB treatment.\n\nConcurrent chemotherapy-related toxicities were generally acceptable except death caused by pemetrexed-induced pneumonitis. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies. The treatment related lymphopenia may affect poor prognosis in LC patients through decreased immune system shown in previous study [24].\n\nIncreased multi-drug resistance and extensive drug resistance among strains of MTB is becoming a serious problem worldwide. Hattori et al. reported that 171 patients (0.2%) in Japan were diagnosed with multi-drug resistant MTB, and 48 of these (28.1%) were foreigners [25]. Although the number of multi-drug resistant MTB cases in Japan is low, Osaka city and Osaka prefecture have the highest prevalence of tuberculosis in Japan (34.4 and 18.2 per 100,000 individuals in 2015, respectively) [26]. Hence, we are exceedingly cautious of an increase in multi-drug resistant MTB. In our institution, anti-CCT was suspended as far as possible until the results of the sensitivity test were known.\n\nGiven the benefits of a short duration from MTB diagnosis to the turnaround of results from sensitivity test, MGIT [5] is recommended for culturing mycobacterial organisms.\n\nIn this study, 2 (8.0%) of 25 patients had resistant MTB to H and streptomycin and H and Z, respectively, but there was no patient with multi-drug resistant MTB. In National-wide survey in Japan [27], the frequencies of drug-resistant isolates from new cases were as follows 8.5% to any drug which was similar to this study.\n\nPoor PS, extensively drug-resistant MTB (XDR), and severe organ dysfunction were the basic contra-indications for concurrent chemotherapy. However, targeted therapy including EGFR-TKI may be used in selected patients despite a poor PS. Furthermore, concurrent chemotherapy may be initiated in patients with rapidly progressive cancer without waiting the results of MTB sensitivity test, even if the MTB is later categorized as XDR. Therefore, there may be no strict contra-indications for concurrent chemotherapy. However, since 6 (20%) of 30 patients experienced adverse events while receiving MTB treatment alone until concurrent chemotherapy, awaiting the result of sensitivity test will be important not only for excluding XDR but also to evaluate the adverse events of MTB treatment alone.\n\nConcurrent use of R, which induces CYP3A4 and CYP2C8 [28, 29], may weaken the clinical efficacy of some anti-CCT agents. In clinical practice, we attempt to not administer concurrent chemotherapy along with Erlotinib, Irinotecan, or Pclitaxel and HRE regimen as much as possible. Therefore, a better choice would be X-based regimen or other regimens without rifampicin.\n\nThe limitations of this study include its retrospective design and relatively small sample size. It remains unclear whether the findings of this study could be generalized for hematological malignancies or solid malignancies except LC and CRC, or expanded to other institutions. Therefore, a prospective multi-institutional study to evaluate the efficacy and safety of concurrent anti-CCT and anti-MTB chemotherapy in patients with various types of solid tumors and an active MTB infection is warranted.\n\nConclusions\nConcurrent anti-CCT and anti-MTB chemotherapy is effective and safe for treating cancer patients with active MTB.\n\nAbbreviations\nAnti-CCTAnti-cancer chemotherapy\n\nATSAmerican Thoracic Society\n\nCCConcurrent chemotherapy\n\nCCACholangiocellular carcinoma\n\nCCTCancer chemotherapy\n\nCIConfidence interval\n\nCRComplete response\n\nCRCColorectal cancer\n\nCTComputed tomography\n\nEEthambutol\n\nGCGastric cancer\n\nHIsoniazid\n\nIDSAInfectious Diseases Society of America\n\nLAMPLoop-mediated isothermal amplification\n\nLCLung cancer\n\nMDR-TBMulti-drug resistant Mycobacterium Tuberculosis\n\nMGITMycobacteria Growth Indicator Tube\n\nMSTMedian survival time\n\nMTB\nMycobacterium tuberculosis\n\n\nNENot evaluable\n\nNSCLCNon-small cell lung carcinoma\n\nPCRPolymerase chain reaction\n\nPDProgressive disease\n\nPRPartial response\n\nXDRExtensively drug-resistant MTB\n\nZPyrazinamide\n\nAcknowledgements\nThe authors thank Editage (www.editage.jp) for English language editing and a part donation to the Osaka Prefectural Hospital Organization (Osaka, Japan) for writing our manuscript.\n\nFunding\nThis study had no funding source.\n\nAvailability of data and materials\nWe cannot share the detailed data, because the Institutional Review Board of the Osaka Habikino Medical Center has not approved it.\n\nAuthors’ contributions\nTH, HS, NO, YT, and TN planned and designed the study. TH, YT, YH, SH and TN collected data of Bacteriological Examinations, and adverse effects and outcomes of MTB treatment; TH, AT, TS, NM, HS, NO, SA, MF, YK, KS, AN, and SM collected data of adverse effects and outcomes of cancer treatment. TH and HS performed the statistical analyses. All authors have been involved in drafting the manuscript or revising it critically for important intellectual content and approved the final manuscript.\n\nEthics approval and consent to participate\nEthics and publication of this study was approved by the Institutional Review Board of the Osaka Habikino Medical Center (formerly the Osaka Prefectural Medical Center for Respiratory and Allergic Diseases) (Osaka, Japan) on January 30, 2017 (approval no.: 808–1). The board waived the requirement for informed written consent due to the anonymous nature of the data and the fact that this research presented no risk of exposure to the subjects. Research was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nT.H. has received honoraria and research funding from Ono Pharmaceutical Co. Ltd. (Osaka, Japan), Lilly Japan Co. Ltd. (Hyogo, Japan), AstraZeneca Co. Ltd. (Osaka, Japan), Taiho Pharmaceutical Co. Ltd. (Tokyo, Japan), Chugai Pharmaceutical Co. Ltd. (Tokyo, Japan), and MSD Oncology Co. Ltd. (Tokyo, Japan). T.H. received honoraria from Kyowa-Hakko Kirin and Boehringer Ingelheim. T.H. received research funding from Merck Serono Co. Ltd. (Tokyo, Japan). The remaining authors (Y.T., Y.H., S.H., A.T., T.S., N.M., H.S., N.O., S.A., M.F., Y.K., K.S., A.N., S.M., and T.N.) declare 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. WHO: Global tuberculosis report 2017. [http://www.who.int/tb/country/data/download/en/]. Accessed 1 Aug 2018.\n2. Hirashima T Nagai T Shigeoka H Tamura Y Yoshida H Kawahara K Comparison of the clinical courses and chemotherapy outcomes in metastatic colorectal cancer patients with and without active Mycobacterium tuberculosis or Mycobacterium kansasii infection: a retrospective study BMC Cancer 2014 14 770 10.1186/1471-2407-14-770 25326267 \n3. Steingart KR Henry M Ng V Hopewell PC Ramsay A Cunningham J Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review Lancet Infect Dis 2006 6 570 581 10.1016/S1473-3099(06)70578-3 16931408 \n4. Notomi T Okayama H Masubuchi H Yonekawa T Watanabe K Amino N Loop-mediated isothermal amplification of DNA Nucleic Acids Res 2000 28 E63 10.1093/nar/28.12.e63 10871386 \n5. Bemer P Palicova F Rusch-Gerdes S Drugeon HB Pfyffer GE Multicenter evaluation of fully automated BACTEC mycobacteria growth Indicator tube 960 system for susceptibility testing of Mycobacterium tuberculosis J Clin Microbiol 2002 40 150 154 10.1128/JCM.40.1.150-154.2002 11773109 \n6. Kudoh S Kudoh T A simple technique for culturing tubercle bacilli Bull World Health Organ 1974 51 71 82 4218139 \n7. Yajko DM Madej JJ Lancaster MV Sanders CA Cawthon VL Gee B Colorimetric method for determining MICs of antimicrobial agents for Mycobacterium tuberculosis J Clin Microbiol 1995 33 2324 2327 7494021 \n8. Blumberg HM Burman WJ Chaisson RE Daley CL Etkind SC Friedman LN American thoracic society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis Am J Respir Crit Care Med 2003 167 603 662 10.1164/rccm.167.4.603 12588714 \n9. WHO: Definitions and reporting framework for tuberculosis – 2013 revision (updated December 2014) A.2.1 Treatment outcomes for TB patients [http://apps.who.int/iris/bitstream/handle/10665/79199/9789241505345_eng.pdf;jsessionid]. Accessed 1 Aug 2018.\n10. JLCS Guidelines 2015 for the Treatment of Lung Cancer [https://www.haigan.gr.jp/modules/guideline/]. Accessed 1 Aug 2018.\n11. Watanabe T Itabashi M Shimada Y Tanaka S Ito Y Ajioka Y Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2014 for treatment of colorectal cancer Int J Clin Oncol 2015 20 207 239 10.1007/s10147-015-0801-z 25782566 \n12. Japanese gastric cancer treatment guidelines [http://www.jgca.jp/guideline.html]. Accessed 1 Aug 2018.\n13. Tozaki M Kuroki Y Kikuchi M Kojima Y Kubota K Nakahara H The Japanese breast Cancer society clinical practice guidelines for screening and imaging diagnosis of breast cancer, 2015 edition Breast Cancer 2016 23 357 366 10.1007/s12282-016-0674-7 27052720 \n14. Furuse J Takada T Miyazaki M Miyakawa S Tsukada K Nagino M Guidelines for chemotherapy of biliary tract and ampullary carcinomas J Hepato-Biliary-Pancreat Surg 2008 15 55 62 10.1007/s00534-007-1280-z \n15. Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L New guidelines to evaluate the response to treatment in solid tumors J Natl Cancer Inst 2000 92 205 216 10.1093/jnci/92.3.205 10655437 \n16. Trotti A Colevas AD Setser A Rusch V Jaques D Budach V CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment Semin Radiat Oncol 2003 13 176 181 10.1016/S1053-4296(03)00031-6 12903007 \n17. Kaplan E Meier P Nonparametric estimation from incomplete observations J Am Stat Assoc 1958 53 457 481 10.1080/01621459.1958.10501452 \n18. WHO; Download treatment outcomes [http://www.who.int/tb/country/data/download/en/]. Accessed 1 Aug 2018.\n19. Katsuda N Hirosawa T Reyer JA Hamajima N Roles of public health centers (Hokenjo) in tuberculosis control in Japan Nagoya J Med Sci 2015 77 19 28 25797967 \n20. Okamoto H Watanabe K Kunikane H Yokoyama A Kudoh S Asakawa T Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702 Br J Cancer 2007 97 162 169 10.1038/sj.bjc.6603810 17579629 \n21. Van Cutsem E Kohne CH Hitre E Zaluski J Chang Chien CR Makhson A Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer N Engl J Med 2009 360 1408 1417 10.1056/NEJMoa0805019 19339720 \n22. Douillard JY Siena S Cassidy J Tabernero J Burkes R Barugel M Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study J Clin Oncol 2010 28 4697 4705 10.1200/JCO.2009.27.4860 20921465 \n23. Yamamoto Y Hasegawa Y Ogawa K Retrospective cohort study of risk factors for adverse effects of antituberculous therapy Kekkaku 2011 86 499 507 21735857 \n24. Grossman SA Ellsworth S Campian J Wild AT Herman JM Laheru D Survival in patients with severe lymphopenia following treatment with radiation and chemotherapy for newly diagnosed solid tumors J Natl Compr Cancer Netw 2015 13 1225 1231 10.6004/jnccn.2015.0151 \n25. Hattori T Kobayashi N Nagai H Chagan-Yasutan H Telan E Solante MB Nationwide HIV-, MDR-TB survey in Japan and collaborative study in the Philippines Int J Mycobacteriol 2016 5 Suppl 1 S18 S19 10.1016/j.ijmyco.2016.09.009 28043540 \n26. Statistic of TB 2015 [http://www.jata.or.jp/rit/ekigaku/en/statistics-of-tb/]. Accessed 1 Aug 2018\n27. Tuberculosis Research Committee TJ Nationwide survey of anti-tuberculosis drug resistance in Japan Int J Tuberc Lung Dis 2015 19 157 162 10.5588/ijtld.13.0905 25574913 \n28. Rakhit A Pantze MP Fettner S Jones HM Charoin JE Riek M The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition Eur J Clin Pharmacol 2008 64 31 41 10.1007/s00228-007-0396-z 18000659 \n29. Kajosaari LI Laitila J Neuvonen PJ Backman JT Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin Basic Clin Pharmacol Toxicol 2005 97 249 256 10.1111/j.1742-7843.2005.pto_157.x 16176562\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2407", "issue": "18(1)", "journal": "BMC cancer", "keywords": "Breast cancer; Colorectal cancer; Concurrent chemotherapy; Efficacy; Gastric cancer; Lung cancer; Safety; Tuberculosis", "medline_ta": "BMC Cancer", "mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D015897:Comorbidity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D009369:Neoplasms; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D014376:Tuberculosis", "nlm_unique_id": "100967800", "other_id": null, "pages": "975", "pmc": null, "pmid": "30314434", "pubdate": "2018-10-12", "publication_types": "D016428:Journal Article", "references": "25797967;4218139;10871386;27052720;10655437;25326267;18000659;26483062;12588714;25782566;7494021;17579629;11773109;16176562;18274844;12903007;20921465;16931408;28043540;19339720;21735857;25574913", "title": "Efficacy and safety of concurrent anti-Cancer and anti-tuberculosis chemotherapy in Cancer patients with active Mycobacterium tuberculosis: a retrospective study.", "title_normalized": "efficacy and safety of concurrent anti cancer and anti tuberculosis chemotherapy in cancer patients with active mycobacterium tuberculosis a retrospective study" }

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{ "abstract": "BACKGROUND\nPatients with pulmonary arterial hypertension (PAH) who develop hyperthyroidism are at risk for acute cardiopulmonary decompensation and death.\nWe present a series of eight idiopathic PAH/heritable PAH pediatric patients who developed hyperthyroidism between 1999 and 2011. Institutional Review Board approval was obtained; informed consent was waived due to the retrospective nature of the series. All eight patients were receiving iv epoprostenol; five of the eight patients presented with acute cardiopulmonary decompensation in the setting of hyperthyroidism. In the remaining three patients, hyperthyroidism was detected during routine screening of thyroid function tests. The one patient who underwent emergency thyroidectomy was the only survivor of those who presented in cardiopulmonary decline.\n\n\nRESULTS\nAggressive treatment of the hyperthyroid state, including emergency total thyroidectomy and escalation of targeted PAH therapy and β-blockade when warranted, may prove lifesaving in these patients. Prompt thyroidectomy or radioactive iodine ablation should be considered for clinically stable PAH patients with early and/or mild hyperthyroidism to avoid potentially life-threatening cardiopulmonary decompensation.\n\n\nCONCLUSIONS\nAlthough the association between hyperthyroidism and PAH remains poorly understood, the potential impact of hyperthyroidism on the cardiopulmonary status of PAH patients must not be ignored. Hyperthyroidism must be identified early in this patient population to optimize intervention before acute decompensation. Thyroid function tests should be checked routinely in patients with PAH, particularly those on iv epoprostenol, and urgently in patients with acute decompensation or symptoms of hyperthyroidism.", "affiliations": "Division of Pediatric Endocrinology, Children’s Hospital of New York Presbyterian, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.", "authors": "Trapp|Christine M|CM|;Elder|Robert W|RW|;Gerken|Adrienne T|AT|;Sopher|Aviva B|AB|;Lerner|Shulamit|S|;Aranoff|Gaya S|GS|;Rosenzweig|Erika B|EB|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1210/jc.2012-1109", "fulltext": null, "fulltext_license": null, "issn_linking": "0021-972X", "issue": "97(7)", "journal": "The Journal of clinical endocrinology and metabolism", "keywords": null, "medline_ta": "J Clin Endocrinol Metab", "mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D065627:Familial Primary Pulmonary Hypertension; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D006980:Hyperthyroidism; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "0375362", "other_id": null, "pages": "2217-22", "pmc": null, "pmid": "22622024", "pubdate": "2012-07", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "16507873;15289375;11399743;12426269;19555858;19555857;16889843;19506387;11344172;11999999;20411253;21329849;9814445;17341574;19015610;4622570;21394427;12084741;2493228;19389575;17389704;19289321;21700562;3341864;16373874;164339;19470885;20180281;18811892;20009390;20924158", "title": "Pediatric pulmonary arterial hypertension and hyperthyroidism: a potentially fatal combination.", "title_normalized": "pediatric pulmonary arterial hypertension and hyperthyroidism a potentially fatal combination" }

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{ "abstract": "Small cell carcinomas (SCCs) are aggressive neoplasms commonly associated with a pulmonary origin. However, albeit rare, extrapulmonary SCC can occur in a variety of sites with an incidence in North America approximated to be 0.1% to 0.4%. Among these sites, approximately 10% of extrapulmonary SCC cases occur in the prostate and are associated with a poor mortality with a median survival of 10 months. Because of the rarity of the prostatic SCC, there is no formal treatment protocol. In this case report, we present a patient who was diagnosed with SCC in the prostate as primary origin. Adjuvant concurrent chemoradiotherapy was started, which he is tolerating so far. While the management of metastatic disease is well documented with the use of chemotherapy, specific data on nonmetastatic disease is lacking. As some studies suggest, a combined surgical and chemotherapeutic approach is helpful in localized disease. In our case, this approach has led to a good clinical outcome in a disease that does not usually allow such results.", "affiliations": "Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, USA.;Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, USA.;Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, USA.;Department of Hematology/Oncology, Joan C. Edwards School of Medicine, Marshall University, USA.", "authors": "Abusnina|Waiel|W|https://orcid.org/0000-0003-2617-8483;Auyoung|Eric Yiman|EY|;Megri|Mohammed|M|;Pacioles|Toni|T|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/2324709618760644", "fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961876064410.1177_2324709618760644Case ReportSmall Cell Carcinoma of Prostate: A Case Report of a Patient With Concomitant Transitional Cell Cancer of the Bladder https://orcid.org/0000-0003-2617-8483Abusnina Waiel MD1Auyoung Eric Yiman MD1Megri Mohammed MD1Pacioles Toni MD21 Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, USA2 Department of Hematology/Oncology, Joan C. Edwards School of Medicine, Marshall University, USAWaiel Abusnina, Internal Medicine, Joan C Edwards School of Medicine at Marshall University, 1600 Medical Center Drive, Huntington, WV 25701-3655, USA. Email: [email protected] 3 2018 Jan-Dec 2018 6 232470961876064423 12 2017 10 1 2018 13 1 2018 © 2018 American Federation for Medical Research2018American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Small cell carcinomas (SCCs) are aggressive neoplasms commonly associated with a pulmonary origin. However, albeit rare, extrapulmonary SCC can occur in a variety of sites with an incidence in North America approximated to be 0.1% to 0.4%. Among these sites, approximately 10% of extrapulmonary SCC cases occur in the prostate and are associated with a poor mortality with a median survival of 10 months. Because of the rarity of the prostatic SCC, there is no formal treatment protocol. In this case report, we present a patient who was diagnosed with SCC in the prostate as primary origin. Adjuvant concurrent chemoradiotherapy was started, which he is tolerating so far. While the management of metastatic disease is well documented with the use of chemotherapy, specific data on nonmetastatic disease is lacking. As some studies suggest, a combined surgical and chemotherapeutic approach is helpful in localized disease. In our case, this approach has led to a good clinical outcome in a disease that does not usually allow such results.\n\nsmall cell cancerprostate cancercover-dateJanuary-December 2018\n==== Body\nIntroduction\nSmall cell carcinomas (SCCs) are aggressive neoplasms commonly associated with a pulmonary origin. However, albeit rare, extrapulmonary SCC (EPSCC) can occur in a variety of sites with an incidence in North America approximated to be 0.1% to 0.4%.1 Among these sites, approximately 10% of EPSCC cases occur in the prostate2,3 and are associated with a poor survival, with a median survival of 10 months.3,4 Because of the rarity of the prostatic SCC, there is no formal treatment protocol. Current treatment is based on studies of pulmonary SCC, using a combined chemoradiotherapeutic approach with radical prostatectomy as an adjunct in only a few selected cases.5-8 With the poor outcome of this aggressive subtype of prostate cancer, further studies can help improve treatment outcomes. Here, we present a case of limited-stage pure SCC of the prostate treated with a total cystoprostatectomy and adjuvant chemoradiotherapy.\n\nCase Report\nA 60-year-old Caucasian male presented with episodes of urinary retention, a normal digital rectal examination, and no other urinary symptoms. His past medical history was significant for a high-grade T1 transitional cell carcinoma of the bladder 1 year prior, as well as another T1 transitional cell carcinoma of the bladder 7 months after the first tumor was diagnosed. For the first tumor, he successfully underwent transurethral resection of the tumor and 6 cycles of intravesical bacillus Calmette-Guerin (BCG) immunotherapy. The same treatment plan was given for his second tumor, but he developed BCG-osis after the fourth cycle. He underwent close follow-up by his urologist with abdominal/pelvic computed tomography (CT) scans and urine cytology. Three months later, around the onset of his urinary retention, imaging showed thickening of his bladder wall, and urine cytology was positive for malignancy. Furthermore, on bimanual examination, a firm, but moveable mass was palpated. With these new findings, the patient was recommended cystoscopy with transurethral resection of the prostate to investigate a suspected recurrence of bladder cancer and to provide relief of his obstructive symptoms. The procedure relieved not only the patient’s urinary retention but also revealed a fleshy mass occupying the right lobe of the prostate and no bladder masses. The pathologist reported the transrectal ultrasound-guided prostate biopsy to be consistent with a small cell neuroendocrine carcinoma. High-power evaluation (400×) demonstrated tumor cells with hyperchromatic nuclei, no nucleoli, scant cytoplasm, and nuclear molding, with numerous mitoses (Figure 1). The tumor has neuroendocrine features as shown by positivity with antibodies to CD5 (Figure 2) and synaptophysin (Figure 3).\n\nFigure 1. The tumor is composed of cells with hyperchromatic nuclei, no nucleoli, scant cytoplasm, and nuclear molding, with numerous mitoses (hematoxylin-eosin, 400×).\n\nFigure 2. The tumor has neuroendocrine features as shown by positivity with antibodies to CD56 (400×).\n\nFigure 3. The tumor has neuroendocrine features as shown by positivity with antibodies to synaptophysin (400×).\n\nImmunohistochemical stains were found to be positive for P53, CK7, and AE1/AE3 (Figures 4-6) but negative for staining with antibodies to chromogranin A, CK20, PSA, uroplakin III, GATA-3, and LCA (data not shown).\n\nFigure 4. p53 mutation is shown by positive nuclear staining with antibody to p53 (400×).\n\nFigure 5. The tumor is a carcinoma as evidenced by positivity with antibodies to CK7 (400×).\n\nFigure 6. The tumor is a carcinoma as evidenced by positivity with antibodies to cytokeratin AE1/AE3 (400×).\n\nThe specimen was also compared with the patient’s previous bladder biopsy and determined to be morphologically dissimilar. Further staging workup was obtained with positron emission tomography (PET)/CT scan and with magnetic resonance imaging of the pelvis–neither of which revealed obvious lymphadenopathy or extraprostatic spread. Considering the localized nature of the tumor, the patient underwent a robotic-assisted total cyst prostatectomy with lymph node sampling of the right and left obturator lymph nodes. Final pathology report confirmed a submucosal small cell neuroendocrine carcinoma in the prostatic base, 3.5 cm at its greatest dimension, with involvement of the bladder neck and trigone area. One of the 2 lymph nodes were positive for metastatic carcinoma, and final pathologic staging was determined to be T3aN1M0. He underwent adjuvant concurrent chemoradiotherapy with cisplatin/etoposide. The patient completed 4 cycles and at last follow-up, 12 months after diagnosis, is tolerating the treatment well with negative CT imaging for recurrence.\n\nDiscussion\nAlthough the prostate is one of the common site for EPSCC, it is a rare prostatic malignancy.2,3,9 Of these cases, only about 35% are pure SCC of the prostate, with the rest having concurrent adenocarcinomatous components,5 but it is currently unknown whether this pathological difference affects the management or prognosis. SCC of the prostate is reported to be more prevalent in the elderly with over 70% of patients being over the age of 65.10 Unlike prostate adenocarcinomas, most patients with SCC of the prostate are symptomatic. The most frequently reported symptoms are obstructive symptoms, pressure-related neurological symptoms, or constitutional symptoms, with 10% of cases present with paraneoplastic symptoms.9,11 Depending on the tumor involvement, other clinical features include bone pain, hydronephrosis, abdominal pain, hematochezia, and hematuria. Imaging of the pelvis is generally nonspecific and serum prostate-specific antigen levels often remain within normal ranges.5 Ultimately, SCC of the prostate is diagnosed by pathological analysis of morphology and immunohistochemistry.3,5,11\n\nMuch of our current treatment approach to prostatic SCC are extrapolated from studies on the management of pulmonary SCC. In the limited studies available on the management of prostatic SCC, the recommended first-line treatment is chemotherapy with a combined use of cisplatin and etoposide because of its comparatively higher efficacy rate.5,6,11 However, most of these cases are patients with metastatic or extensive-stage prostatic SCC, the more common presentation of the tumor. With respect to nonmetastatic or limited-stage prostatic SCC, a couple of studies recommend prostatectomy with adjuvant chemotherapy, but this approach is controversial.2,5,12 Most studies report using chemotherapy as the first-line treatment regardless if the tumor is metastatic or not; hence, it is difficult to properly assess the efficacy of a surgical therapy with adjuvant chemotherapy. Several studies have reported that prostatectomy alone is not effective.5,8,13 In these localized tumors, as in our case, it would be logical to remove the tumor to potentially prevent possible metastases and use adjuvant chemotherapy to treat possible occult metastases.\n\nConclusion\nSCC of the prostate is an aggressive tumor that is associated with a high mortality. While the management of metastatic disease is well documented with the use of chemotherapy, specific data on nonmetastatic disease are lacking. As some studies suggest, a combined surgical and chemotherapeutic approach is helpful in localized disease. In our case, this approach has led to a good clinical outcome in a disease that does not usually allow such results.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.\n\nORCID iD: Waiel Abusnina \nhttps://orcid.org/0000-0003-2617-8483\n==== Refs\nReferences\n1 \nBrennan SM Gregory DL Stillie A Herschtal A Mac Manus M Ball DL. \nShould extrapulmonary small cell cancer be managed like small cell lung cancer? \nCancer . 2010 ;116 :888 -895 .20052730 \n2 \nWhitaker DA JrMiller DH Jagadesh N et al \nSmall cell carcinoma of the prostate in an elderly patient: a case report and review of the literature . Rare Tumors . 2016 ;8 :6657 .28191295 \n3 \nFurtado P Lima MV Nogueira C Frnaco M Tavora F. \nReview of small cell carcinomas of the prostate . Prostate Cancer . 2011 ;2011 :543272 .22110988 \n4 \nCapizzello A Peponi E Simou N et al \nPure small cell carcinoma of the prostate: a case report and literature review . Case Rep Oncol . 2011 ;4 :88 -95 .21475596 \n5 \nGuo A Wen S Ma Y Wei L Liu A. \nClinicopathological analysis on small cell carcinoma of the prostate in Chinese patients . J Cancer . 2014 ;5 :797 -803 .25520757 \n6 \nCohen A Richards KA Patel S Weiner A Eggener SE Szmulewitz RZ. \nMetastatic small cell carcinoma of the prostate: population-based analysis of patient characteristics and treatment paradigms . Urol Oncol . 2015 ;33 :70 .\n7 \nStein ME Bernstein Z Abacioglu U et al \nSmall cell (neuroendocrine) carcinoma of the prostate: etiology, prognosis, and therapeutic implications—a retrospective study of 30 patients from the rare cancer network . Am J Med Sci . 2008 ;336 :478 -488 .19092321 \n8 \nSpiess PE Pettaway CA Vakar-Lopez F et al \nTreatment outcomes of small cell carcinoma of the prostate: a single-center study . Cancer . 2007 ;110 :1729 -1737 .17786954 \n9 \nPalmgren JS Karavadia SS Wakefield MR. \nUnusual and underappreciated: small cell carcinoma of the prostate . Semin Oncol . 2007 ;34 :22 -29 .17270662 \n10 \nWang J Wang FW. \nImpact of age on clinical presentation, treatment, and cancer-specific survival of patients with small-cell carcinoma of the prostate . Clin Interv Aging . 2013 ;8 :871 -877 .23885169 \n11 \nNadal R Schweizer M Kryvenko ON Epstein JI Eisenberger MA. \nSmall cell carcinoma of the prostate . Nat Rev Urol . 2014 ;11 :213 -219 .24535589 \n12 \nWeiner AB Patel SG Richards KA Szmulewitz RZ Eggener SE. \nPopulation-based analysis of treatment modalities and survival for clinically localized small-cell carcinoma of the prostate . Prostate Cancer Prostatic Dis . 2014 ;17 :286 -291 .25027862 \n13 \nBolton DM Chiu ST Clarke S Angus D. \nPrimary small cell carcinoma of the prostate: unusual modes of presentation . Aust N Z J Surg . 1994 ;64 :91 -94 .7507315\n\n", "fulltext_license": "CC BY", "issn_linking": "2324-7096", "issue": "6()", "journal": "Journal of investigative medicine high impact case reports", "keywords": "prostate cancer; small cell cancer", "medline_ta": "J Investig Med High Impact Case Rep", "mesh_terms": null, "nlm_unique_id": "101624758", "other_id": null, "pages": "2324709618760644", "pmc": null, "pmid": "29536021", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": "25044254;17786954;28191295;25027862;17270662;23885169;21475596;24535589;25520757;22110988;19092321;20052730;7507315", "title": "Small Cell Carcinoma of Prostate: A Case Report of a Patient With Concomitant Transitional Cell Cancer of the Bladder.", "title_normalized": "small cell carcinoma of prostate a case report of a patient with concomitant transitional cell cancer of the bladder" }

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{ "abstract": "Nontuberculous mycobacterial (NTM) genitourinary (GU) infections are relatively rare, and there is frequently a delay in diagnosis. Mycobacterium avium-intracellulare complex (MAC) cases seem to be less frequent than other NTM as a cause of these infections. In addition, there are no set treatment guidelines for these organisms in the GU tract. Given the limitations of data this review summarizes a case presentation of this infection and the literature available on the topic. Many different antimicrobial regimens and durations have been used in the published literature. While the infrequency of these infections suggests that there will not be randomized controlled trials to determine optimal therapy, our case suggests that a brief course of amikacin may play a useful role in those who cannot tolerate other antibiotics.", "affiliations": "School of Medicine, Creighton University, Omaha, NE 68124, USA.;College of Pharmacy, Creighton University, Omaha, NE 68124, USA.;School of Medicine, Creighton University, Omaha, NE 68124, USA.", "authors": "Rajendraprasad|Sanu|S|;Destache|Christopher|C|;Quimby|David|D|0000-0003-3976-9522", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/idr13020045", "fulltext": "\n==== Front\nInfect Dis Rep\nInfect Dis Rep\nidr\nInfectious Disease Reports\n2036-7430\n2036-7449\nMDPI\n\n10.3390/idr13020045\nidr-13-00045\nCase Report\nMycobacterium Avium Complex Genitourinary Infections: Case Report and Literature Review\nRajendraprasad Sanu 1\nDestache Christopher 2\nhttps://orcid.org/0000-0003-3976-9522\nQuimby David 1*\nPetrosillo Nicola Academic Editor\n1 School of Medicine, Creighton University, Omaha, NE 68124, USA; [email protected]\n2 College of Pharmacy, Creighton University, Omaha, NE 68124, USA; [email protected]\n* Correspondence: [email protected]\n24 5 2021\n6 2021\n13 2 454464\n06 5 2021\n20 5 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nNontuberculous mycobacterial (NTM) genitourinary (GU) infections are relatively rare, and there is frequently a delay in diagnosis. Mycobacterium avium-intracellulare complex (MAC) cases seem to be less frequent than other NTM as a cause of these infections. In addition, there are no set treatment guidelines for these organisms in the GU tract. Given the limitations of data this review summarizes a case presentation of this infection and the literature available on the topic. Many different antimicrobial regimens and durations have been used in the published literature. While the infrequency of these infections suggests that there will not be randomized controlled trials to determine optimal therapy, our case suggests that a brief course of amikacin may play a useful role in those who cannot tolerate other antibiotics.\n\nnontuberculous mycobacteria\nmycobacterium avium-intracellulare complex\nurinary tract infections\ngenitourinary infections\n==== Body\n1. Introduction\n\nIn recent decades, the incidence and prevalence of nontuberculous mycobacteria (NTM) causing extrapulmonary infections have greatly increased, becoming a major worldwide public health problem [1,2]. Among numerous NTM species, the Mycobacterium avium complex (MAC) is the most common cause of infection in humans. MAC is recognized as a ubiquitous microorganism, with contaminated water and soil as established sources of infection [3]. MAC consists of multiple species, of which two of the most common are M.avium and M.intracellulare [4,5,6]. There are four main manifestations of MAC infection: (1.) HIV with disseminated disease; (2.) focal lymphadenitis also in predominantly HIV patients; (3.) pulmonary infection in those with structural lung disease; and (4.) skin and soft tissue infections [7,8,9,10]. Genitourinary tract infections secondary to MAC appear to be rare with questionable clinical relevance and no standardized treatment. Here we present a case of MAC-associated urinary tract infection in a woman with an extensive urological history and recurrent urinary tract infections.\n\n2. Case Presentation\n\nPatient is a 79-year-old woman with a complicated urologic history. Three years prior to her presentation in the infectious disease clinic, she had issues with urinary retention and frequent urinary tract infections, for which she would receive antibiotics. She required an indwelling urinary catheter for several months due to urinary retention, but voiding trials after initiation of tamsulosin were effective, and she was catheter-free for over 2 years prior to infectious disease clinic presentation. Recurrent infections were treated with methenamine and she had no symptoms of infection between November 2016 and June 2017. Starting in June 2017, she had more issues with urinary tract infection (UTI) symptoms, which improved with thrice-weekly vaginal estrogen cream and intermittent antibiotics.\n\nBeginning in January 2019, however, her symptoms became near-constant. Repeated urine cultures were positive for methicillin-sensitive Staphylococcus aureus (Table 1); she was found to have some kidney stones, which were removed in February of 2019. Unfortunately, despite this intervention, she remained with constant symptoms, significantly affecting her quality of life. She underwent cystoscopy in August 2019 showing inflammation but no mass lesions; biopsies were not performed. Urine cytology showed no malignancy, abundant inflammation, and significant Candida. CT imaging of the abdomen and pelvis was significant only for a thickened bladder wall, consistent with cystitis. Given the persistent symptoms, pyuria, and relatively negative urine cultures (Table 1), she was treated with antifungal medication for the possibility of a true candida cystitis and had a urine sample sent for AFB culture. Given no improvement, she was started on silver nitrate bladder instillations by urology for symptomatic relief. The first treatment of silver nitrate bladder instillation led to an improvement in discomfort which was regrettably short-lived.\n\nPrior to the second planned instillation of silver nitrate, her urine AFB culture was positive for Mycobacterium avium complex via the nucleic acid DNA probe (AccuProbe Mycobacterium avium complex culture identification test, Hologic). In October 2019, she was started on an antimicrobial regimen of clarithromycin 500 mg BID, rifampin (RIF) 600 mg/day, and ethambutol 1200 mg/day based on susceptibilities (Table 2) and continued with the silver nitrate instillations for about a month given a little improvement after starting them. The instillations were discontinued due to intolerable bladder spasms. Unfortunately, despite antimicrobial therapy, she remained quite symptomatic and was having increasing nausea from the medications.\n\nIn January 2020, due to gastrointestinal symptoms from medications, lack of improvement in pyuria, and lack of improvement in her dysuria, the antimicrobial regimen was changed to rifampin 600 mg/day, linezolid 600 mg/day, and three-times-weekly amikacin. After the first week of this regimen, she had significant improvement in her urinary symptoms. By the end of the second week, she was completely asymptomatic. She completed three weeks of the amikacin and was then maintained on linezolid and rifampin alone. Follow-up urinalysis showed marked improvement in pyuria, and she remained asymptomatic. For the next ten months, she remained symptom-free from a urinary standpoint and tolerated the linezolid/rifampin combination with no ill effects. She completed twelve months of therapy from initiation of the amikacin with a follow-up urine analysis demonstrating no pyuria. A second urine analysis a few weeks the first was also negative. Interestingly, a second urinary AFB culture obtained prior to any antimycobacterial therapy (but after the first silver nitrate instillation) was ultimately negative.\n\n3. Nontuberculous Mycobacteria: An Overview\n\nAmong numerous NTM species, MAC is the most predominant group causing disease in humans. Originally not recognized as pathogenic, in the 1950s, the isolation of acid-fast bacilli with atypical cultural characteristics was noted at Battey State hospital, Rome, Georgia USA. At this time there developed evidence of direct causation of disease [11,12]. In 1959, Runyon proposed the first classification of NTM into four groups, the first three comprising “Slowly Growing Mycobacteria” (SGM) and the fourth of “Rapidly Growing Mycobacteria” [5]. MAC is part of group III or Battey type NTM in the Runyon classification [13]. With advances in the systematic analysis we are able to identify and classify new (sub) species within MAC at the molecular level. The most common SGM is the species belonging to the Mycobacterium avium complex (MAC), comprising especially Mycobacterium avium and Mycobacterium intracellulare.\n\nThe incidence of MAC infections is increasing in most industrialized countries, possibly because of the increase in immunocompromised and/or older patients [1,2]. In addition, improvement in testing methods to culture and identify have spurred increases in MAC have likely led to increased diagnoses. The use of fluorescent stain and fluorescent microscope appears to be superior to Ziehl-Neelson stain for AFB smear [14]. AFB culture in liquid Mycobacteria Growth Indicator Tube (MGIT) has replaced the Lowenstein-Jensen slant in isolating NTM and DNA probes and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) allows for precise identification in hours compared to the traditional biochemical and phenotypic methods that can take weeks [15,16].\n\n4. Mycobacterial Genitourinary (GU) Infections: Clinical Presentation\n\nMycobacterial genitourinary (GU) tract infections are a not-uncommon event, and genitourinary tract tuberculosis is a common manifestation of extrapulmonary TB. In genitourinary tuberculosis, men are more frequently infected than women, and HIV-infected men are at the highest risk [17]. Initial presentation is not always associated with specific symptoms; pyuria and/or microscopic hematuria may be observed as incidental findings. Involvement of the bladder may cause symptoms of frequency, dysuria, urgency, and nocturia in approximately half of the cases; gross hematuria and low back pain develop in 1/3 of cases. Systemic symptoms (fever, weight loss) are relatively rare [18]. While there are good data on prevalence and therapeutic options for tubercular GU infections, non-tubercular (NTM) infections of the GU tract are much less common, and there is currently no standard approach to therapy.\n\nMost cases that have been documented of genitourinary NTM showed increased prevalence in women. Infections are more common in the elderly population, although a case of genitourinary MAC associated with disseminated infection has been reported in a child as young as 14 years [19]. Genitourinary infection does not appear to be isolated to the immunocompromised, as only one infection in a transplant recipient has been documented [20]. Most patients appear immunocompetent. It is unclear if race is a factor; of the published cases, most patients are Caucasian, but lack of diagnosis and publication bias could play a role in this.\n\nPrimary complaints of UTI appear to be present in all those that have been diagnosed with MAC as the etiology of their symptoms. Duration of symptoms varies from 1 week to 3 years. Several patients appear to have been treated with antibiotics for suspected bacterial urinary tract infections in the past. Sterile pyuria in routine urine culture with dysuria appears to be a common presenting sign. Of interest is the duration of symptoms and persistence of symptoms after routine treatment with antibiotics. In our patient, she has grown multiple bacterial organisms in the urine cultures over the years including Candida species with some improvement in symptoms until the next recurrence. Other NTM (M. abscessus, M. fortuitum, M. gordonae) causing genitourinary infection do not have a similar presentation [21,22,23,24,25,26,27].\n\nThe most common species of rapidly growing mycobacteria of clinical relevance are M.fortuitum, M.abscessus, M.marinum, and M.chelonae. While predominantly known to cause skin and soft tissue infections, these pathogens can cause disease in other parts of the body, including the GU tract, and there are increasing published reports of these organisms leading to infection in this organ system. M. fortuitum has been associated with prolonged urinary tract elimination in patients with AIDS as well as hemodialysis patients [23,25]. While it is not always clear that the presence of these pathogens in a urine culture is necessarily reflective of true infection, in several cases there has been clinical evidence of true disease, and antimicrobial treatment led to culture sterilization and clinical improvement (Table 3) [20,28,29,30,31,32].\n\nUrinary involvement with disseminated spread has been associated with underlining cell-mediated immune deficiencies or serum interferon-Y-neutralizing autoantibodies [19,28]. None of the patients appear to have any history of HIV which has been associated with disseminated MAC. One of the patients that completed treatment and had sterilization of urine was found to have a recurrence after undergoing orthotopic liver and kidney transplant and being placed on immunosuppression. It is unclear if immunosuppression definitively increases the risk of isolated GU infection secondary to MAC as noted in Obeid et al. [20].\n\nStudies question the clinical significance of MAC in the urine as some patients are not treated with antibiotics and managed conservatively [33,34,35]. Like other potential pathogens isolated on cultures, the presence of a positive culture does not necessarily mean true infection: in one large New York hospital over a 3-year period, there were 422 HIV-negative patients with cultures positive for MAC from various body sites. Of these, 375 had clinical data available to determine true mycobacterial infection or not, of which only 119 felt to have a true infection. One patient had repeated positive urine cultures for MAC but was not categorized as having NTM disease since the patient was asymptomatic [36]. Additionally, it has been suggested that about 43% (12/28 tested) of HIV+ individuals with disseminated MAC infection will have positive urine cultures for this organism [37]. Two reported patients continued to be symptomatic, despite achieving urine sterilization, which raises the question if treatment was beneficial or necessary [31,32]. Two patients had renal involvement requiring surgical management in addition to antibiotic therapy which led to symptomatic improvement and urine sterilization [29,30]. Thus, proper source control may have provided a similar effect. Given the lack of susceptibility information or standardization of care with antibiotics and duration of treatment, it is difficult to form a firm conclusion.\n\n5. Mycobacterial GU Infections: Diagnosis\n\nGeneral practice for patients with ongoing culture-negative urinary symptoms often involves cultures for atypical organisms (such as Chlamydia, Gonorrhoea, Mycoplasma, Ureaplasma, and mycobacterial organisms). Molecular techniques have been explored, and one study used nucleic acid probes of tissue from bladder wall biopsy of patients with interstitial cystitis to look for missed mycobacterial pathogens; of the eight tested, none were positive suggesting that this may not be a common cause of ongoing culture-negative urinary symptoms in this small study [38]. However, there are clear cases where MAC has been implicated in true GU tract infections (Table 3) with consistent symptoms, positive cultures, and clinical benefit from antimicrobial therapy. However, the optimal treatment of medications and duration is not clear at this time.\n\nOur patient exemplifies the difficulty in making a diagnosis of NTM GU tract infection. She had ongoing symptoms for years, constant pyuria on cultures, and was treated repeatedly for small-quantity colonizing bacteria with no clinical improvement. In addition, like many patients with recurrent GU issues, she had more than one problem along the way: initially she had urinary retention, and later developed colonized/infected kidney stones. AFB culture was sent after evaluation by infectious diseases clinic and returned positive after four weeks of incubation. Prior to starting therapy, the culture was repeated, but ultimately reported as negative perhaps as a result of the intermittent intravesicular silver nitrate installations for symptomatic relief. Studies have shown silver nanoparticles (AgNPs) demonstrate antimycobacterial effect in bacterial cultures and within macrophages [39]. The use of monthly silver nitrate installations in conjunction with antibiotic management may have been the key to the eradication of the infection in this patient.\n\n6. Mycobacterial GU Infections: Treatment\n\nTreatment for genitourinary mycobacterial infection has not been standardized. Initial regimens appeared to favor isoniazid (INH), ethambutol (EMB), RIF, and streptomycin [29,30,31,32]. All except Faber et al. used three drug regimens to initiate treatment with modifications as needed for each patient, despite which urine sterilization was achieved. Recent case reports show a shift to macrolide (azithromycin or clarithromycin) based treatment with the use of Clinical and Laboratory Standards Institute (CLSI) published guidelines for drug susceptibility testing (DST) of NTM in 2011 and updated in 2018. Along with macrolides, RIF, EMB, fluoroquinolones, and aminoglycosides have been used as additional medications for three drug antibiotic therapy [20,28].\n\nTreatment for genitourinary MAC does appear to be extrapolating from pulmonary MAC treatment which is based on macrolides combined with a rifamycin (rifampin or rifabutin) and ethambutol. The use of amikacin can be parenteral or inhaled in for severe cases of pulmonary MAC [7,40], although older case reports show streptomycin (600 mg-1g) as the most common addition in 5 out of 7 cases [28,29,30,31,32]. Moxifloxacin, bedaquiline, linezolid, and clofazimine are alternative drugs proposed mainly for the treatment of infections caused by macrolide-resistant pulmonary MAC [41].\n\nIn NTM lung disease, CLSI and the British Thoracic Society (BTS) recommend testing the isolate for clarithromycin and amikacin susceptibility prior to the initiation of therapy. It is reasonable to assume that genitourinary infections would benefit from similar testing. In cases of resistance to clarithromycin, CLSI recommends DST of moxifloxacin and linezolid, whereas BTS recommends testing a wider panel of antibiotics to guide treatment regimens [42,43,44]. Ethambutol and rifamycins, unfortunately, have no clinical breakpoints defined for treatment of MAC infections [41].\n\nThe use of these antimicrobials does require further evaluation regarding pharmacokinetics with special consideration of urine concentration achieved by each. Linezolid, clarithromycin, clofazimine, and aminoglycosides (streptomycin and amikacin) achieve the highest levels in urine as noted in Table 4. It is not certain how relevant urine antimicrobial concentrations are, as the use of oral medications with lower urinary concentration often leads to urinary sterilization.\n\nBased on the minimal amount of published data on Mycobacterium avium complex genitourinary infections, optimal therapy and duration are unclear at this time. Patients have been treated with several regimens with varying duration of treatment ranging from 6 weeks to 18 months. While likely rare enough to make randomized trials of different therapeutic options impossible, this case suggests that relatively brief therapy with amikacin may be of benefit. The practice of confirming pathogen clearance with repeat sputum culture in pulmonary MAC could be transitioned to genitourinary MAC infection with the determination of duration of treatment after urine sterilization. While the ideal duration of both aminoglycoside therapy and total therapy is unclear, patient symptoms and degree of pyuria may be of benefit in measuring disease activity even in the face of negative follow-up cultures.\n\n7. Conclusions\n\nGenitourinary Mycobacterium avium complex infection appears to be rare. Patients commonly have symptoms with dysuria and sterile pyuria for prolonged periods prior to proper diagnosis. Concern of clinical relevance despite urine culture positivity is present although our case in addition to prior reports of similar patients confirms the need for aggressive and prolonged management to provide symptomatic relief when true infection, and not just colonization, is present. Based on data from the more-common pulmonary infections, beginning with three-drug therapy and evaluation of sensitivity to macrolides and aminoglycosides is recommended. A short course of aminoglycoside for genitourinary MAC may be beneficial in some patients. Overall duration of therapy is unclear, as literature review shows a wide range of therapy, ranging from six weeks to 18 months. Optimal medication choice and antibiotic duration may require tailoring to each individual patient.\n\nAuthor Contributions\n\nWriting manuscript, original draft: S.R., D.Q. Writing manuscript, revisions: S.R., C.D., D.Q. Literature search: S.R., D.Q. Table preparation: S.R., C.D. Manuscript submission: D.Q. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nWritten consent has been obtained from the patient to publish this paper.\n\nData Availability Statement\n\nNot applicable.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nAbbreviations\n\nAFB\tAcid-fast bacillus\t\nAgNPs\tsilver nanoparticles\t\nAIDS\tAcquired immunodeficiency syndrome\t\nBTS\tBritish Thoracic Society\t\nCLSI\tClinical and Laboratory Standards Institute\t\nDST\tDrug susceptibility testing\t\nEMB\tethambutol\t\nGU\tGenitourinary\t\nHIV\tHuman immunodeficiency virus\t\nINH\tisoniazid\t\nMAC\tMycobacterium avium complex\t\nMAI\tMycobacterium Avium-Intracellulare\t\nMALDI-TOF\tmatrix-assisted laser desorption ionization-time of flight mass spectrometry\t\nMGIT\tMycobacteria growth indicator tube\t\nNTM\tNontuberculous mycobacteria\t\nRIF\tRifampin\t\nSGM\tSlowly growing mycobacteria\t\nUTI\tUrinary tract infection\t\n\nidr-13-00045-t001_Table 1 Table 1 Urine culture results 2016 to present.\n\nDate\tLeucocyte Esterase\tWBC/HPF\tCulture\t\n1/9/16\tLarge\t>100\t>100K Pseudomonas aeruginosa, 20K MSSA\t\n2/15/16\tSmall\t10–20\t50K MSSA\t\n5/6/16\tLarge\t>100\t>100K MSSA\t\n5/10/16\tLarge\t\t60K MSSA\t\n5/21/16\tLarge\t>100\t50K Candida albicans\t\n6/18/16\tLarge\t>100\t>100K Citrobacter freundii, >100K Enterococcus faecalis, 10K mixed gram-positive flora\t\n6/19/16\tLarge\t50–100\t>100K Candida albicans\t\n6/28/16\t\t\t40K Candida albicans\t\n8/31/16\tSmall\t10–20\t>100K Proteus mirabilis\t\n9/4/16\tLarge\tPacked field\t>100K Candida albicans\t\n6/19/17\t\t\t>100K MSSA\t\n9/1/17\tLarge\t\t>100K MSSA\t\n9/15/17\tLarge\t\t50K MSSA\t\n9/20/17\tLarge\t>100\t40K MSSA\t\n2/6/18\tLarge\t\t5K mixed Gram-positive flora\t\n7/16/18\tLarge\t\t40K MSSA\t\n8/21/18\tLarge\t\t30K MSSA, 6K mixed Gram-positive flora\t\n11/16/18\tModerate\t\t>100K MSSA\t\n1/7/19\tModerate\t\t20K MSSA\t\n1/19/19\tSmall\t20–50\t400 CFU yeast\t\n3/9/19\tModerate\t>100\t2K yeast\t\n8/19/19\tModerate\tPacked field\t4K yeast\t\n9/5/19\t\t\tMycobacterium avium complex\t\n10/15/19\tLarge\t\tAFB culture negative\t\n11/5/19\tModerate\t\t30K Enterococcus faecalis, 20K yeast\t\n12/8/19\tModerate\t>100\t20K normal urogenital flora\t\n12/23/19\tLarge\t\t20K yeast, 10K Enterococcus faecalis\t\n1/3/20\tLarge\tPacked field\t50K yeast\t\n9/20/20\tNegative\t<5\tNo growth\t\n2/25/2021\tNegative\t<5\tNo growth\t\nWBC/HPF—white blood cells/high power field, MSSA—methicillin-susceptible Staphylococcus aureus, AFB—acid-fast bacillus, CFU—colony forming unit.\n\nidr-13-00045-t002_Table 2 Table 2 Mycobacterium avium complex susceptibility.\n\nAntimicrobial\tMIC\tInterpretation\t\nAmikacin IV\t2\tSensitive\t\nAmikacin—Liposomal, Inhaled\t2\tSensitive\t\nClarithromycin\t0.25\tSensitive\t\nLinezolid\t≤1\tSensitive\t\nMoxifloxacin\t0.25\tSensitive\t\nAbbreviation: MIC, minimum inhibitory concentration.\n\nidr-13-00045-t003_Table 3 Table 3 MAC case reports.\n\nYear\tReference\tAge/Sex\tRace\tClinical Findings\tDuration of Symptoms\tOrganism in Urine\tSusceptibility\tTreatment\tOutcome\t\n1963\tFaber et al. [29]\t27/F\tJapanese—American\tGross hematuria. Left renal mass\t1 week\tAtypical AFB (Battey type)\tN/A\tEmpirically started Streptomycin 1 g/day, INH 250 mg/day. One month in decrease streptomycin to twice a week. Total duration 4 months\tRemoval of left renal mass (pathology showed no AFB) after surgery pt was asymptomatic\t\n1966\tNewman, H. [30]\t52/F\tCaucasian\tPyuria and dysuria\t10 days, Intermittent dysuria since teenager, similar symptoms after 2 years\t2 cultures grew 3 atypical mycobacteria and one group 4 rapid growers\tN/A\tStreptomycin 1 g twice a week, INH 300 mg/day + PAS 12 g daily for 12 months, after which INH and PAS were continued for another 6 months\tSymptomatic improvement. Had left nephroureterectomy which showed granulomatosis changes consistent with tuberculosis. Urine sterilization after procedure.\t\n1973\tPergament et al. [31]\t62/F\tPresumed Caucasian\tFrequency, urgency, nocturia, suprapubic pain and right lower quadrant pain with gross hematuria\t6 months\tBattey-avian complex\tSensitive: INH, RIF, EMB\tINH 300 mg/day, RIF 600 mg/day, EMB 15 mg/kg/day and Streptomycin 1 g 3 times a week for total of 6 weeks\tPatient continued to have symptoms but achieved urine sterilization\t\n1986\tMikolich et al. [32]\t75/M\tPresumed Caucasian\tGranulomatous Prostatitis, Difficulty urinating with hematuria and pyuria\t1 year\tMAC\tInitial culture: Sensitive: PZA; Resistant: INH, EMB, streptomycin and RIF. CDC sensitivities to initial culture: Sensitive: ansamycin Resistant: Capreomycin, streptomycin, INH, PAS, RIF, EMB, kanamycin, PZA, cycloserine and ethionamide\tINH 300 mg/day, RIF 600 mg/day × 4 months, EMB 1 g/day + PZA 1.5 g/day. No change, 6 weeks of ansamycin 300 mg/day, INH 300 mg/day, EMB 1 g/day + 1 g of streptomycin IM 3 times a week for 1 week then twice weekly for total of 6 weeks\tNo improvement with treatment. Some improvement with NSAIDs\t\n2015\tObeid et al. [20]\t61/F\tSomali born\tLiver cirrhosis with chronic dysuria, s/p transplant with recurrence\tUnclear duration\tMAI\tSensitive to Clarithromycin, Moxifloxacin, Linezolid\tAzithromycin 250 mg/day, EMB 1200 mg/day, RIF 600 mg/day (substituted rifabutin), Moxifloxacin 400 mg/day—17 months total\tUrine sterilization in 5 months and completed 17 months of treatment. With 1 year of therapy after first negative mycobacterial urine culture. Recurrence after 8 months of orthotopic liver and kidney transplant. Refused treatment and pt died unrelated to MAI\t\n2018\tMiyashita et al. [28]\t63/F\tPresumed Japanese\tDisseminated MAC initially presented with fever, eruption and sterile pyuria\tUnclear duration\tMAC\tN/A\tClarithromycin 800 mg/day, RIF 450 mg/day, EMB 750 mg/day, (streptomycin 600 mg/day × 3 days—2 months)\t1 month after treatment afebrile, resolution of urinary incontinence—Regression of multiple organ involvement except splenic lesions—Over 20 months of therapy\t\n2019\tPresent case\t79/F\tCaucasian\tRecurrent symptomatic UTI\t3 years\tMAC\tSensitive: Amikacin, Clarithromycin, Linezolid and Moxifloxacin\tClarithromycin 500 mg po BID, RIF 600 mg po daily and EMB 1200 mg po daily changed treatment after 4 months to continue RIF 600 mg/day, linezolid 600 mg/day, and three-times-weekly amikacin for 3 weeks.\tAsymptomatic after 12 months of treatment. Urine sterilization.\t\nAFB—acid-fast Bacillus, N/A—not available, INH—isoniazid, PAS—para-aminosalicylic acid, RIF—rifampin, EMB—ethambutol, PZA—pyrazinamide, MAI—Mycobacterium Avium-Intracellulare, MAC—Mycobacterium avium complex, UTI—urinary tract infection, NSAIDs—nonsteroidal anti-inflammatory drugs.\n\nidr-13-00045-t004_Table 4 Table 4 Pharmacokinetics of antimycobacterial drugs with urine concentration.\n\nDrug\tDose\tUrinary Drug Level (μg/mL)\t\nClarithromycin [45]\t500 mg BID\t~1.24\t\nAzithromycin [46]\t500 mg qd\t~148\t\nRifampin [47]\t600 mg qd\t400–600\t\nEthambutol [48]\t25 mg/kg/d\t7–9\t\nStreptomycin [49]\t600 mg IM qd\t174–534\t\nAmikacin [50]\t500 mg IM qd\t600–832\t\nLinezolid [51]\t600 mg BID po\t192–61\t\nMoxifloxacin [52]\t400 mg qd po\t~137.6\t\nBedaquiline [53]\t400 mg po qd\t~4\t\nClofazimine [54]\t100 mg 3 times/wk\t156–456\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Genitourinary Tract Infection Due to Mycobacterium avium intracellulare Complex Infection in Pretransplant Setting With Recurrence Following Transplant: A Case Report Transpl. Proc. 2018 50 3937 3939 10.1016/j.transproceed.2018.09.007\n21. Hochman I. Siegman-Igra Y. Goor Y. Cabili S. A case of prolonged urinary tract infection caused by Mycobacterium fortuitum Eur. J. Clin. Microbiol. Infect. Dis. 1992 11 725 727 10.1007/BF01989978 1425732\n22. Traore B. Fongoro S. Timbine L.G. Diallo D. Toure A. Djigulba K. Yattara H. Kouriba B. Diallo S. Mycobacterium abscessus urinary infection in a hypertensive patient: A case report Mycobact. Dis. 2016 6 224 10.4172/2161-1068.1000224\n23. Serra C. Loi G. Saddi B. Pautasso M. Manzin A. Unusual clinical presentation of Mycobacterium fortuitum infection in an immunocompetent woman J. Clin. Microbiol. 2007 45 1663 1665 10.1128/JCM.00119-07 17360837\n24. Laudelino J.S. Farias Filho F.T. Costa A.F.P. Santos V.M. 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Haworth C.S. Banks J. Capstick T. Fisher A.J. Gorsuch T. Laurenson I.F. British thoracic society guideline for the management of non-tuberculous Mycobacterial pulmonary disease (NTM-PD) BMJ Open Respir. Res. 2017 4 e000242 10.1136/bmjresp-2017-000242\n45. Ferrero J.L. Bopp B.A. Marsh K.C. Metabolism and disposition of clarithromycin in man Drug Metab. Dispos. 1990 18 441 446 1976065\n46. Foulds G. Shepard R.M. Johnson R.B. The pharmacokinetics of azithromycin in human serum and tissues J. Antimicrob. Chemother. 1990 25 Suppl. A 73 82 10.1093/jac/25.suppl_A.73\n47. Acocella G. Clinical pharmacokinetics of rifampicin Clin. Pharm. 1978 3 108 127 10.2165/00003088-197803020-00002 346286\n48. Lee C.S. Brater D.C. Gambertoglio J.G. Benet L.Z. Disposition kinetics of ethambutol in man J. Pharm. Biopharm. 1980 8 335 346 10.1007/BF01059382\n49. 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Hoetelmans R.M. Bedaquiline: A review of human pharmacokinetics and drug-drug interactions J. Antimicrob. Chemother. 2014 69 2310 2318 10.1093/jac/dku171 24860154\n54. Holdiness M.R. Clinical pharmacokinetics of clofazimine. A review Clin. Pharm. 1989 16 74 85 10.2165/00003088-198916020-00002\n\n", "fulltext_license": "CC BY", "issn_linking": "2036-7430", "issue": "13(2)", "journal": "Infectious disease reports", "keywords": "genitourinary infections; mycobacterium avium-intracellulare complex; nontuberculous mycobacteria; urinary tract infections", "medline_ta": "Infect Dis Rep", "mesh_terms": null, "nlm_unique_id": "101537203", "other_id": null, "pages": "454-464", "pmc": null, "pmid": "34073729", "pubdate": "2021-05-24", "publication_types": "D002363:Case Reports", "references": "1554847;24578959;31173040;9003597;1425732;29897938;32280217;29449949;4407865;5437741;18325252;5433907;26225805;19228258;23804379;8220991;27790302;19305349;19845702;13962814;14136624;3729201;2656045;17277290;14197717;19680441;14638484;29780147;17360837;11125907;9687407;30216086;17428883;346286;7431225;24860154;24624285;19468477;13403152;30577290;30231956;2154441;7452814;4971875;1976065;32140138;14276196", "title": "Mycobacterium Avium Complex Genitourinary Infections: Case Report and Literature Review.", "title_normalized": "mycobacterium avium complex genitourinary infections case report and literature review" }

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"610", "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Genitourinary tract infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SILVER NITRATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2019", "drugenddateformat": "602", "drugindication": "Candida infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2019", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SILVER NITRATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SILVER NITRATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Mycobacterium avium complex infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SILVER NITRATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SILVER NITRATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Genitourinary tract infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SILVER NITRATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SILVER NITRATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Cystitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SILVER NITRATE" } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20190101" } }, "primarysource": { "literaturereference": "Rajendraprasad S, Destache C, Quimby D. Mycobacterium avium complex genitourinary infections: Case report and literature review. Infectious Disease Reports. 2021;13(2):454-464", "literaturereference_normalized": "mycobacterium avium complex genitourinary infections case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211124", "receivedate": "20210921", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19865323, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "BACKGROUND\nPost-transplant lymphoproliferative disease (PTLD), a lymphoid proliferation observed after the solid organ transplantation or allogeneic stem cell transplant, is an important and mortal complication that can occur during the post-transplant period. Classical Hodgkin lymphoma-like PTLD is the least form of PTLD. We are presenting an adult case of classical Hodgkin lymphoma-like PTLD which was successfully treated with nivolumab.\n\n\nMETHODS\nA 31-year-old female was diagnosed with primary myelofibrosis and we performed allogeneic stem cell transplantation from her HLA fully matched brother in 2015. Two years after transplant, classical Hodgkin lymphoma-like PTLD was diagnosed. The patient was resistant to six cycles of ABVD chemotherapy and four cycles of brentuximab vedotin.\nAfter the failure of ABVD and brentuximab vedotin, we started nivolumab therapy at a dose of 3 mg/kg every 2 weeks. After six cycles, we achieved a PET negative complete remission. After 10 cycles of nivolumab, the patient is still followed with a complete remission. Still, there is no evidence of acute or chronic GvHD, and therefore no need for immunosuppressive treatment. No auto-immune complication was observed. It is planned to give nivolumab treatment to the patient until the progression.\n\n\nCONCLUSIONS\nOur case has depicted that the classical Hodgkin lymphoma type PTLD may be resistant to the conventional treatments and anti-CD30 brentuximab vedotine. In such cases, nivolumab may be an effective and worth assessing agent in terms of both activity and safety profile.", "affiliations": "Department of Hematology, Ankara City Hospital, Ankara, Turkey.;Department of Internal Medicine, Gaziantep University School of Medicine, Gaziantep, Turkey.;Department of Hematology, Gaziantep University School of Medicine, Gaziantep, Turkey.", "authors": "Gunes|Ahmet K|AK|https://orcid.org/0000-0001-5522-8342;Demir|Ilknur|I|;Pehlivan|Mustafa|M|", "chemical_list": "D000074322:Antineoplastic Agents, Immunological; D001761:Bleomycin; D000077594:Nivolumab; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin", "country": "England", "delete": false, "doi": "10.1177/1078155220946462", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "27(2)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Nivolumab; allogeneic stem cell transplant; classical Hodgkin lymphoma-Like PTLD; post-transplant lymphoproliferative disease", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003606:Dacarbazine; D004317:Doxorubicin; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008232:Lymphoproliferative Disorders; D000077594:Nivolumab; D049268:Positron-Emission Tomography; D055728:Primary Myelofibrosis; D033581:Stem Cell Transplantation; D016896:Treatment Outcome; D014747:Vinblastine", "nlm_unique_id": "9511372", "other_id": null, "pages": "509-512", "pmc": null, "pmid": "32762294", "pubdate": "2021-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Classical Hodgkin lymphoma-like post-transplant lymphoproliferative disease after allogeneic stem cell transplantation for primary myelofibrosis is successfully treated with nivolumab: A case report.", "title_normalized": "classical hodgkin lymphoma like post transplant lymphoproliferative disease after allogeneic stem cell transplantation for primary myelofibrosis is successfully treated with nivolumab a case report" }

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CLASSICAL HODGKIN LYMPHOMA?LIKE POST?TRANSPLANT LYMPHOPROLIFERATIVE DISEASE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION FOR PRIMARY MYELOFIBROSIS IS SUCCESSFULLY TREATED WITH NIVOLUMAB: A CASE REPORT. J ONCOL PHARM PRACT. 2021?27:(2):509?512", "literaturereference_normalized": "classical hodgkin lymphoma like post transplant lymphoproliferative disease after allogeneic stem cell transplantation for primary myelofibrosis is successfully treated with nivolumab a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20210527", "receivedate": "20210527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19313334, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "BACKGROUND\nSusac syndrome (SuS) is a rare condition characterized by a clinical triad of sensorineural hearing loss, branch artery occlusion and encephalopathy. This study reports an increased incidence of SuS in Israel. We describe the clinical characteristics of these patients, diagnostic procedures and the use and subsequent outcomes of newly published treatment guidelines.\n\n\nMETHODS\nThis is a single center retrospective study. Patients who were diagnosed with SuS between July 2017 and August 2018 were enrolled in this study.\n\n\nRESULTS\nSeven patients were diagnosed with SuS according to the diagnostic criteria in a time period of 13 months. The annual incidence was recently evaluated in Austria to be 0.024/100000, therefore, our case series represent at least a 5.4- fold increase in the annual incidence of SuS expected in Israel and a 7-fold increase in the annual incidence expected in our medical center. Mean time from the onset of the symptoms to diagnosis was three weeks and follow-up time was twenty four months. Recent exposure to cytomegalovirus was serologically evident in three patients and one patient had high titer of anti-streptolysin antibody. All patients underwent brain MRI, fluorescein angiography and audiometry. All patients were treated according to the newly recommended guidelines. All patients achieved clinical and radiological stability.\n\n\nCONCLUSIONS\nWe report of an increased incidence of SuS in Israel. Infectious serological findings may imply a post infectious mechanism. The use of the recommended diagnostic procedures reduced the time to diagnosis. Newly published treatment guidelines led to favorable clinical outcomes.", "affiliations": "Neuro-Immunology Service and Department of Neurology Rabin Medical Center, 4941492, Petach Tikva, Israel. [email protected].;Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Neuroradiology unit, Department of Radiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Department of ENT, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Neuroimmunology and Multiple Sclerosis Unit of the Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Neuroimmunology and Multiple Sclerosis Unit of the Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.", "authors": "Wilf-Yarkoni|A|A|http://orcid.org/0000-0002-2584-5793;Elkayam|O|O|;Aizenstein|O|O|;Oron|Y|Y|;Furer|V|V|;Zur|D|D|;Goldstein|M|M|;Barequet|D|D|;Hallevi|H|H|;Karni|A|A|;Habot-Wilner|Z|Z|;Regev|K|K|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12883-020-01892-0", "fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377 BioMed Central London \n\n1892\n10.1186/s12883-020-01892-0\nResearch Article\nIncreased incidence of Susac syndrome: a case series study\nhttp://orcid.org/0000-0002-2584-5793Wilf-Yarkoni A. [email protected] 1 Elkayam O. 23 Aizenstein O. 4 Oron Y. 5 Furer V. 23 Zur D. 36 Goldstein M. 36 Barequet D. 36 Hallevi H. 7 Karni A. 378 Habot-Wilner Z. 36 Regev K. 7 1 grid.413156.40000 0004 0575 344XNeuro-Immunology Service and Department of Neurology Rabin Medical Center, 4941492 Petach Tikva, Israel \n2 grid.413449.f0000 0001 0518 6922Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel \n3 grid.12136.370000 0004 1937 0546Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel \n4 grid.413449.f0000 0001 0518 6922Neuroradiology unit, Department of Radiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel \n5 grid.413449.f0000 0001 0518 6922Department of ENT, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel \n6 grid.413449.f0000 0001 0518 6922Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel \n7 grid.413449.f0000 0001 0518 6922Neuroimmunology and Multiple Sclerosis Unit of the Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel \n8 grid.12136.370000 0004 1937 0546Sagol School of Neuroscience Tel Aviv University, Tel Aviv, Israel \n2 9 2020 \n2 9 2020 \n2020 \n20 33225 5 2020 18 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nSusac syndrome (SuS) is a rare condition characterized by a clinical triad of sensorineural hearing loss, branch artery occlusion and encephalopathy. This study reports an increased incidence of SuS in Israel. We describe the clinical characteristics of these patients, diagnostic procedures and the use and subsequent outcomes of newly published treatment guidelines.\n\nMethods\nThis is a single center retrospective study. Patients who were diagnosed with SuS between July 2017 and August 2018 were enrolled in this study.\n\nResults\nSeven patients were diagnosed with SuS according to the diagnostic criteria in a time period of 13 months. The annual incidence was recently evaluated in Austria to be 0.024/100000, therefore, our case series represent at least a 5.4- fold increase in the annual incidence of SuS expected in Israel and a 7-fold increase in the annual incidence expected in our medical center. Mean time from the onset of the symptoms to diagnosis was three weeks and follow-up time was twenty four months.\n\nRecent exposure to cytomegalovirus was serologically evident in three patients and one patient had high titer of anti-streptolysin antibody. All patients underwent brain MRI, fluorescein angiography and audiometry.\n\nAll patients were treated according to the newly recommended guidelines. All patients achieved clinical and radiological stability.\n\nConclusions\nWe report of an increased incidence of SuS in Israel. Infectious serological findings may imply a post infectious mechanism. The use of the recommended diagnostic procedures reduced the time to diagnosis. Newly published treatment guidelines led to favorable clinical outcomes.\n\nKeywords\nSusac syndromeTreatmentcmv post infectiousBranch retinal artery occlusionissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nSusac syndrome (SuS) is a rare immune-mediated occlusive microvascular disease. It is characterized by a typical clinical triad of encephalopathy, visual disturbances and hearing loss [1–5]. However, there is a great variability in clinical manifestations and the complete triad is present in less than 20% of patients at disease onset [4–9]. Treatment of SuS is particularly challenging, owning to its rarity, and the great variability in presentation, there are no randomized control trials to evaluate treatment strategies. Optimal outcome requires rapid and aggressive treatment, and acute treatments limited to glucocorticoids and/or IVIg appears to be insufficient to halt the progression of disease [10–15]. Recent treatment guidelines have been published based on disease severity [10].\n\nThe available data regarding the prevalence and incidence of SuS is limited. The annual incidence was recently evaluated in Austria to be 0.024/100000 [16]. The largest case series from Israel comprises 10 patients who were diagnosed over a period of 26 years [17].\n\nIn this retrospective case series, we report seven newly diagnosed cases of SuS in a single referral center over a time period of thirteen months. For a reference, from 2013 to 2016 only two patients were diagnosed with SuS in our institute. We hereby describe the clinical features, diagnostic procedures employed, treatment approach and outcome of this cohort.\n\nMethods\nStudy design and data collection\nThis is a retrospective case series of patients treated at a single tertiary medical center. The study was approved by the Tel Aviv Sourasky Medical Center Institutional Review Board (Helsinki Committee). (0435-15-TLV).\n\nAll patients diagnosed with SuS, between July 2017 and August 2018 were included. The European Susac consortium criteria were used for diagnosis. According to these criteria, patients with involvement of all three main organs (brain, eye and ear) who fulfill the typical clinical triad were defined as definite SuS and patients with involvement of two main organs were defined as probable SuS (Supplementary Table 1) [18].\n\nAll patients were hospitalized in the neurological department in Tel Aviv Sourasky Medical Center and were examined by ophthalmologist and ear, nose and throat specialist. Data regarding the following parameters were collected: patient demographics, medical history, and medications. Clinical presentation including history, neurological assessment, treatment protocol, evidence of relapse and response to treatment were recorded. Detailed personal and occupational history was obtained together with possible environmental, toxic, chemical exposures according to the exposure survey.\n\nAll patients underwent extensive medical investigations to establish the diagnosis of SuS: blood tests and screening tests for infectious diseases; cerebrospinal fluid (CSF) analysis and diagnostic procedures including brain MRI, auditory evaluation, and Fluorescein angiogram (FA). Spectral-domain optical coherence tomography (OCT) was done in all cases since it is an emerging diagnostic tool in SuS [19, 20]. Macular OCT scans were evaluated for (1) areas of hyperreflective thickening of retinal nerve fiber layer to the outer plexiform layer which is indicative for tissue swelling due to acute branch retinal artery occlusion (BRAO), and (2) areas of thinning of these layers indicative for previous ischemic damage. Cerebral angiography was performed in two patients and brain biopsy was performed in one patient.\n\nCNS involvement was characterized by both clinical and radiological evidence. Clinical symptoms included new cognitive impairment and/or behavioral changes and/or new focal neurological symptoms and/or new headache. MRI findings included typical findings on cranial MRI—hyperintense, multifocal, small round lesions; at least one of them in the corpus callosum (‘snowball’) in T2 (or FLAIR) weighted sequences [18]. Cervical spine MRI was done in one patient.\n\nIn order to evaluate treatment response, a special follow-up clinic was created with a multi-disciplinary team including a neurologist, rheumatologist and an ophthalmologist as well as continuing monitoring by MRI scans and FA. New or worsening of neurological, ocular or auditory symptoms and/or new lesions on brain MRI and/or evidence of new BRAO’s on FA determined a relapse. Clinical stability was defined as no evidence of clinical relapse, no new lesion on brain MRI and no evidence of BRAOs on FA study. Outcome measures included adverse events and clinical and para-clinical evidence of disease sequelae.\n\nResults\nClinical characteristics\nTable 1 summarizes the demographic data, signs and symptoms upon presentation. Seven patients (4 females, 3 males) were diagnosed with SuS. There is no available data on the incidence of SuS in Israel. Two patients were diagnosed with SuS in Tel-Aviv Medical Center from 2013 to 2016 (Supplementary figure 1). We calculated the expected number of patients per year in Israel, based on annual incidence evaluation in Austria of 0.024/100000 (age over 19), to be 1.3. Therefore, our case series represent at least a 5.4-fold increase in the annual incidence of SuS compared to a published registry and a 7-fold increase in the annual incidence expected in our medical center.\nTable 1 Demographic and clinical presentation\n\n\tTime to diagnosis\tDisease severity\tLumber Puncture\tCNS involvment\tEye involvment\tEar involvment\tComplete triad***\tSerology\tNon-neurological symptoms\t\n\t\t\tOpening Pressure (mm H2o)\tWBC (cells/μl)\tProtein (mg/dl)\tCognitive/ Psychiatric\tFocal signs\tHeadache\tS*\tA-S**\tS*\tA-S**\t\t\t\t\n1.M/20\tTwo weeks\tSevere\t260\t1\t110\tCognitive + psychiatric\tAphasia and sensory disturbance\t+\t\tBL\tBL\t\t+\tCMV IgM\tGI symptoms\t\n2.F/34\tTwo weeks\tModerate\t80\t14\t125\tModerate encephalopathy\t–\t–\t\tBL\tUL+\n\nVertigo\n\n\t\t+\t\t\t\n3.F/20\tThree weeks\tMild\t–\t–\t–\tCognitive + psychiatric\t–\t+\tUL\t\t\t\t–\t\tGI symptoms\t\n4.F/38\tTwo weeks\tModerate\t165\t3\t61\tCognitive + psychiatric\t–\t–\tBL\t\t\tBL\t+\tCMV IgM\tGI symptoms\t\n5.M/35\tNine weeks\tSevere\tN/A\t9\t140\tCognitive impairment\t–\t+\tBL\t\tUL\t\t+\t\t\t\n6.M/33\tThree weeks\textremely severe\t205\t3\t109\tSevere encephalopathy\tLeft hemiparesis\t+\t\tBL\t\tBL\t+\tCMV IgM\t\t\n7.F/30\tTwo weeks\tModerate\t220\t4\t99\tCognitive impairment\tLeft hemihypoesthesia\t+\tBL\t\t–\t–\t–\tAnti Streptolysin\t\t\nNote: *S – symptomatic, **A-S – A-symptomatic. *** complete triad – evidence for CNS, retinal and Vestibulocochlear involvement; UN – unilateral, bilateral, Abbreviations: CMV – cytomegalovirus, GI – gastrointestinal, WBC –white blood cells\n\n\n\nFive patients fulfilled the criteria for definite SuS and two patients for probable SuS. Their mean age at presentation was 30 years (range 20-38 years). All cases were diagnosed during the summer-autumn seasons (July-October). One women was pregnant in her 7th gestational week. The mean duration from the onset of the symptoms to diagnosis was three weeks (2-9 weeks). Mean duration of follow-up was 24 months and one patient was lost to follow after 2 months. No patient had previous neurological disease. Based on the detailed personal history, no common demographic characteristics were found among patients. Toxic environmental exposure was not reported.\n\nAt clinical onset, the most common manifestations were CNS symptoms. Disease severity was determined according to the extent of CNS involvement; one patient was defined as extremely severe SuS, two patients as severe SuS, three patients as moderate SuS and one as mild SuS. All patients suffered from different severity of encephalopathy characterized by cognitive impairment (mainly deficits in executive function, language and memory) or confusion. Three patients had a psychiatric manifestation of depression and anxiety. Three patients presented with focal neurological signs; sensory disturbance (two patients) and severe hemiparesis (one patient). Five patients had severe migrainous or oppressive headache. Visual disturbances were described as flashing lights in one patient, and visual field defects in three patients. Vestibulocochlear involvement was the least common presentation; three patients suffered from acute sensorineural hearing loss, one of these patients also suffered from vertigo. Gastrointestinal (GI) symptoms, i.e. abdominal pain and diarrhea were reported in three patients.\n\nDiagnostic procedures\nCharacteristic brain MRI findings included: 1. All patients presented with Flair/T2 hyperintense lesions located in the supratentorial white and gray matter areas. Three patients had additional infratentorial lesions. 2. Typical corpus callosum “snow ball” lesions that are considered a characteristic sign of SuS (Fig. 1a1) [21–23] were detected in all of our patients although was not evident on the initial imaging upon presentation in one patient. 3. Punctuate DWI hyperintense lesions with corresponding ADC hypointensity (restricted diffusion) were associated with disease activity in all of our patients (Fig. 1a) [9]. 4. Leptomeningeal enhancement was demonstrated in four patients (Fig. 1a6), three of these patients suffered from severe headache. 5. Corpus callosum hypointense T1 lesions were found in all our patients and corpus callosum atrophy was evident in five patients [24]. One of our patients (patient number 6) had a cervical spinal cord MRI done at disease onset. No evidence of cervical spine involvement was detected.\nFig. 1 Typical diagnostic procedures findings. a Brain MRI. Sagittal and axial T2 FLAIR sequence, showing hyperintense lesions in the corpus callosum (“snow balls”). A1. Periventricular and subcortical areas. A2-3. Sagittal T1 sequence corpus callosum (“black holes”). A4. Axial DWI sequence which show restricted diffusion A5. Leptomeningeal enhancement with gadolinium A6. b Wide field Fluorescein angiogram demonstrating right eye peripheral (superior, temporal and inferior) branch artery occlusions and focal arterial leakage in an inferior branch artery. c. A bilateral low-tone and middle-tone sensorineural hearing loss is seen, with abnormal low scores in speech audiometry\n\n\n\nFA was pathological in all our patients, even though three patients had no ocular symptoms. Abnormalities included BRAOs and arterial wall hyperfluorescence (AWH) (Fig. 1b) [21, 22, 25]. One case had both arterial and venous occlusions. Audiometry showed low-frequency sensorineural hearing loss in five cases (Fig. 1c) [1, 6, 9, 18, 26], three were bilateral and two were unilateral. Of note, two patients had SNHL on audiometry with no auditory symptoms. All our patients performed OCT. Three patients showed signs of acute retinal hypoxia indicating an acute macular BRAO. Additionally, five patients showed signs of macular retinal thinning, compatible with previous events of macular ischemia. Two patients had normal OCT.\n\nSerology for cytomegalovirus (CMV) was available in four patients. Three patients had IgM antibodies for CMV. CMV serology was retested in two patients; in one patient (Patient number one) there was sero-conversion from IgM to IgG and in the second patient (Patient number four) both IgG and IgM levels remained high during follow-up, this patient showed clinical and laboratory evidence of CMV reactivation. CMV PCR in the serum was done in two patients; patient number one had 543 IU/ml and patient number four had 70,635 IU/ml. CMV IgM antibody in the CSF were not measured. CMV immune-stain was done on tissue obtained from brain biopsy. One patient had high titer of anti-streptolysin antibodies. Anti-streptolysin titer in the CSF was not measured.\n\nCSF analysis was performed in six patients (Table 1). Elevated protein levels were observed in all these patients (mean levels 107 mg/dl; 61- 140 mg/dl) and mean CSF cell count was 6 cells/μl (1-14 cells/μl). The presence of oligoclonal bands (OCB) in the CSF was examined in four patients and were all negative providing no evidence of intrathecal synthesis of OCB. Brain angiography was performed in two patients and was unremarkable. One of our patients (patient number 6) who presented with severe encephalopathy underwent stereotactic brain biopsy from an active lesion on his right parietal lobe. The samples include fragments of cortex, white matter and some vessels from subarachnoid space. There was no evidence of vasculitis or inflammatory reaction. CMV immune-stain was negative.\n\nFigure 1 demonstrates typical diagnostic findings.\n\nTreatment regimen and clinical outcomes\nTable 2 summarizes treatment regimens, major side effects and patient outcomes. Patients were treated according to disease course and the severity of CNS involvement based on the recently published treatment guidelines (Supplementary Table 2) [10]. IV Methyprednisolone (IVMP), intravenous immune globulin (IVIG) and mycophenolate mofetil were used for mild cases. An addition of Cyclophosphamide (CPM) and Rituximab (RTX) is optional for the treatment of moderate cases and is recommended to use in severe CNS involvement. All seven patients were treated with IV Methyprednisolone (IVMP) within the first month following the onset of symptoms and during relapses, followed by very slow tapering of prednisone. In addition, all patients received mycophenolate mofetil (MMF) or azathioprine. Six patients were treated with intravenous immune globulin (IVIG) 2 g/kg every 3-4 weeks or 1 g/mg every 2 weeks until clinical stability achieved. Cyclophosphamide (CPM; after fertility preservation) was administered in one patient with moderate SuS and in four patients with severe or extremely severe SuS. Three patients were treated with rituximab. Anti- aggregation is not included in the treatment guidelines and evidence for its efficiency in SuS in lacking [14, 15, 27], nevertheless, all seven patients were treated with an anti- aggregation agent.\nTable 2 Treatment regimens, major side effects and patient outcomes\n\n\t\t\tTreatment\toutcome\tSide effects\tMaintenece treatment\t\nPatient\tDisease Severity\tFollwup time (months)\tAnti aggregation drugs\tIVMP\tIVIG\tCPM\tMMF\tRTX\tAuditory\tVision\tCNS\t\t\t\n1\tSevere\t33\tAcetylsalicylic acid (+Clopidogrel)\t+\t+\t+\t+\t+\tSevere bilateral SNHL\t\tNo evidence for neurological residual\tCMV reactivation\tAspirin, Prednisone, IVIG (1 g/kg), Rituximab,MMF\t\n2\tModerate\t33\tAcetylsalicylic acid\t+\t–\t+\t+\t–\tSNHL\tBilateral VF deficient\tNo evidence for neurological residual\t\tAspirin,MMF\t\n3\tMild\t2\tAcetylsalicylic acid\t+\t+\t–\t+\t–\tN/A\tN/A\tN/A\tN/A\tN/A\t\n4\tModerate\t30\tAcetylsalicylic acid\t+\t+\t–\t+\t+\t\tMild VF deficient\tFatigue\tCMV reactivation\tAspirin, IVIG (1 g/kg), Rituximab\t\n5\tSevere\t30\tAcetylsalicylic acid\t+\t+\t+\tAzathioprine\t+\tSNHL\tbilateral VF deficient\tNo evidence for neurological residual\tPathological fracture\tPrednisone, Rituximab\t\n6\textremely severe\t21\tAcetylsalicylic acid(+Enoxaparin)\t+\t+\t+\t+\t\t\t\tHemiparesis,ataxia and severe cognitive decline\t\tAspirin, Prednisone, IVIG (1 g/kg),MMF\t\n7\tModerate\t20\tAcetylsalicylic acid\t+\t+\t+\t+\t–\t\t\tMild cognitive decline\t\tAspirin, prednisone and IVIG (1 g/kg)\t\nNote: N/A – not available; Abbreviations: CMV – cytomegalovirus, CPM – cyclophosphamid, IVMP – intravenous methylprednisolone, IVIG – intravenous immune globulin, MMF – mycophenolate mofetil, RTX - rituximab, SNHL - sensorineural hearing loss, VF – visual field\n\n\n\nPatients were clinically monitored with frequent clinical assessments in addition to routine brain MRI, FA and audiometry to evaluate treatment response and outcome. Treatment led to clinical and radiological stability in all patients. One patient who presented with severe encephalopathy and hemiparesis was stable under this regimen but suffered from a residual mild hemiparesis, ataxia, memory impairment, attention deficit and behavioral disinhibition. Another patient experienced a relapse after discontinuation of medication due to adherence problem. This patient has a residual mild cognitive decline. Three patients had no residual neurological deficits. Brain MRI lesions remained unchanged in five patients however, in one patient some lesions disappeared on follow-up MRI. Follow up MRI revealed global brain atrophy and corpus callosum atrophy in four patients.\n\nTwo patients had residual visual field defects. OCT at final visit was performed in patients and showed bilateral thinning of retinal layers in five patients. Three patients who presented with SNHL did not improve on follow up auditory testing. Major side effects of the treatment included pathological fracture in one patient and reactivation of CMV infection in two patients that caused GI symptoms and was diagnosed by testing CMV PCR in serum. Patient number 4 suffered from severe diarrhea and serum CMV PCR reached a maximum level of 70,635 IU/ml and return to negative after treatment with valcyclovir.\n\nThe maintenance treatment included aspirin, mycophenolate mofetil (MMF) 1000 mg BID, prednisone with very slowly tapering down, decreasing doses of IVIG and Rituximab every 6 months.\n\nDiscussion\nIn this case series, we describe seven patients diagnosed with SuS over a time period of thirteen months, representing at least a 5.4 - fold increase in the annual incidence of SuS expected in comparison to a published registry and a 7-fold increase in the annual incidence expected in our medical center. The clinical presentation and phenotype of our cohort was consistent with previously reported cases of SuS [4, 6, 7, 16–18]. We didn’t find any common environmental or toxic exposure preceding the disease onset.\n\nThe etiology of SuS remains unknown. An autoimmune process leading to occlusion of micro vessels have been postulated [2]. Elevated serum levels of anti-endothelial cells antibodies are found in approximately 25% of the patients, suggestive of an antibody-mediated immunity process [28, 29]. Recently a CD8+ T-cell-mediated endotheliopathy has been shown to play a key role in SuS [5]. What triggers this immune response is currently unknown.\n\nBased on review of the literature, an infectious trigger does not seem to play a major role since it was detected only in 19 out of 304, of published cases [6]. Given a predisposition of the disease onset to the summer-autumn months and the absence of a clear disease trigger in our cohort, we searched for a possible infectious trigger. Interestingly, at presentation three quarters of our patients, who were tested for CMV, had positive IgM antibodies in the sera, while PCR for CMV in CSF was negative. Two of these patients suffered from CMV reactivation that caused GI symptoms following immunosuppressive treatment. In another patient, there was evidence of a recent streptococcal infection with a high serum anti-streptolysin titer. The fact that despite strong immunosuppressive therapy there was marked improvement and no eruption of symptoms supports an inflammatory post or para-infectious pathophysiology. Accordantly, the use of anti-viral treatment does not seem to be indicated. One hypothesis regarding disease pathophysiology that supports a para-infectious mechanism is the presentation of viral antigen on the endothelium following viral infection [5].\n\nTwo conclusions might be derived from our observation: the importance of searching for an infectious trigger, which might shed some light on disease mechanism and risk factors. Additionally, we believe that it is highly recommended to screen for possible latent infections due to robust immune suppression used to effectively treat these patients.\n\nThere is a great variability in the clinical presentation of SuS and the complete triad is present in less than 20% of patients at presentation. As a result, misdiagnosis or delay in diagnosis and treatment are common [5–7]. Diagnostic procedures such as MRI, FA, OCT [19, 20] and audiometry are crucial to enable early and accurate diagnosis since, as mentioned above, subclinical pathology may occur without clinical manifestation [5, 7, 18]. Of note, only one patient in this cohort presented with the complete triad of neurological, auditory and visual symptoms. Using these diagnostic tools, we were able to establish the diagnosis of definite SuS at presentation in five patients and to reduce time to diagnosis from twenty-one weeks to three weeks [6]. Moreover, close monitoring using these tools may allow the detection of silent disease activity. Anti-endothelial cell antibodies were not checked. Although high levels of anti-endothelial cell antibodies have been reported, titers > 1:100 were found in only 25% of patients with SuS and therefore, are not included in the diagnosis criteria of SuS [12].\n\nGI symptoms reported by three of our patients may reflect the systemic nature of the disease as had already been proposed [30]. This could also be a result of preceding infection with CMV as two of these patients were CMV IgM positive.\n\nTreatment of SuS is particularly challenging [10, 11, 22]. Importantly, Multiple sclerosis treatments may cause exacerbation of SuS [31]. Due to the rarity of the disease, no randomized controlled trials have been done. Rennebohm et al. published treatment guidelines based on large cohort of patients [10]. Treatment regimen is based on disease manifestation and severity. This is the first case series published using these treatment guidelines and it demonstrates that in order to achieve optimal outcomes, rapid and sometimes aggressive immunosuppressive combination therapy is required.\n\nThis study has several limitations. This is a retrospective case series that relies on medical records. There was some missing data, such as CMV status in three patients, serology follow-up of CMV levels, CMV serology in the CSF and antibody detection rate of IgM CMV antibodies in a control group. The small sample size makes it difficult to establish causal interference between infections and SuS, so that we cannot rule out the possibility of co-incidence or false positivity. It is important to recognize that potentially rise in awareness due recently published diagnostic criteria and suggested therapeutic guidelines [10, 18] led to earlier and more frequent detection of the syndrome. However, this publications did not cause a shift in diagnosis as criteria have not been revised.\n\nMoreover, the mean follow-up time was less than two years, so that long-term outcomes cannot be drawn from this study. As this is a tertiary referral center, our case series probably includes more severe forms of SuS.\n\nConclusion\nOur case series adds to the present knowledge regarding this rare disorder. It emphasizes the variability in clinical presentation and highlights the importance of diagnostic procedures such as FA, audiometry and MRI in order to establish early diagnosis and avoid irreversible neurological damage. Further research on the pathophysiology of SuS and randomized controlled clinical trials are warranted to enable the development of evidence-based management strategies for these patients.\n\nSupplementary information\n\nAdditional file 1 Supplementary figure 1. PPT. Incidence of Susac syndrome between the years 2013-2018 in Tel-Aviv Medical Center. Each line represents a new diagnosis of Susac syndrome.\n\n Additional file 2 Supplementary Table 1. DOC. Diagnostic criteria for Susac syndrome. Adopted from Kleffner et al. J Neurol Neurosurg Psychiatry 2016. Abbreviations: AWH = arterial wall hyperfluorescence; BRAO = branch retinal artery occlusion; FLAIR = fluid-attenuated inversion recovery; SD-OCT = spectral domain optical coherence tomography; SuS = Susac syndrome; SNHL = sensorineural hearing loss.\n\n Additional file 3 Supplementary Table 2. DOC. Treatment guidelines according to severity of CNS involvement. Adopted from Rennebohm et al. International journal of stroke 2017. Abbreviations: BID twice a day; CPM-cyclophosphamid; IVIG – intravenous immune globulin; IVMP – intravenous methylprednisolone; MMF – mycophenolate mofetil; TAC-tacrolimus.\n\n \n\nAbbreviations\nAWHArterial wall hyperfluorescence\n\nBRAOBranch retinal artery occlusion\n\nCSFCerebrospinal fluid\n\nCMVCytomegalovirus\n\nCPMCyclophosphamide\n\nCCCorpus Callosum\n\nFAFluorescein angiography\n\nGIGastrointestinal\n\nIVIGIntravenous immune globulin\n\nIVMPIV Methyprednisolone\n\nMMFMycophenolate mofetil\n\nOBCOligoclonal bands\n\nOCTOptical coherence tomography\n\nSuSSusac syndrome\n\nSNHLSensorineural hearing loss\n\nRTXRituximab\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s12883-020-01892-0.\n\nAcknowledgements\nNo acknowledgements.\n\nAuthors’ contributions\nAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by AWY, OE, OA, YO, VF, DZ, MG, DB, HH, AK, ZHW, KR. The first draft of the manuscript was written by AWY and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or nonprofit sectors.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThe study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. The study was approved by the Tel Aviv Sourasky Medical Center Institutional Review Board (Helsinki Committee). (0435-15-TLV). The need for consent was waived by the IRB due to the retrospective nature of the study.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interest. None of the authors reports conflicts of interest related to this work. Dr. Karni Arnon received research support from Stem Cell Medicine Ltd., Medison Pharma Ltd. and from Novartis Pharmaceutical Ltd.\n==== Refs\nReferences\n1. Kleffner I A brief review of Susac syndrome J Neurol Sci 2012 322 1-2 35 40 10.1016/j.jns.2012.05.021 22640902 \n2. Susac JO Susac's syndrome: 1975-2005 microangiopathy/autoimmune endotheliopathy J Neurol Sci 2007 257 1-2 270 272 10.1016/j.jns.2007.01.036 17331544 \n3. Susac JO Hardman JM Selhorst JB Microangiopathy of the brain and retina Neurology 1979 29 3 313 316 10.1212/WNL.29.3.313 571975 \n4. 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Lubow M Fluorescein and indocyanine green angiographies in Susac syndrome Retina 2008 28 8 1174 10.1097/IAE.0b013e31817bf052 18779724 \n23. Susac JO MRI findings in Susac's syndrome Neurology 2003 61 12 1783 1787 10.1212/01.WNL.0000103880.29693.48 14694047 \n24. Wuerfel J Lesion morphology at 7 tesla MRI differentiates Susac syndrome from multiple sclerosis Mult Scler 2012 18 11 1592 1599 10.1177/1352458512441270 22711711 \n25. Egan RA Hills WL Susac JO Gass plaques and fluorescein leakage in Susac syndrome J Neurol Sci 2010 299 1-2 97 100 10.1016/j.jns.2010.08.043 20880549 \n26. Egan RA Diagnostic criteria and treatment algorithm for Susac syndrome J Neuroophthalmol 2019 39 1 60 67 10.1097/WNO.0000000000000677 29933288 \n27. Gordon DL Hayreh SS Adams HP Jr Microangiopathy of the brain, retina, and ear: improvement without immunosuppressive therapy Stroke 1991 22 7 933 7 10.1161/01.STR.22.7.933 1853414 \n28. Jarius S Anti-endothelial serum antibodies in a patient with Susac's syndrome J Neurol Sci 2009 285 1-2 259 261 10.1016/j.jns.2009.07.002 19643446 \n29. Magro CM Susac syndrome: an organ-specific autoimmune endotheliopathy syndrome associated with anti-endothelial cell antibodies Am J Clin Pathol 2011 136 6 903 912 10.1309/AJCPERI7LC4VNFYK 22095376 \n30. Marrodan M Gastrointestinal compromise in Susac syndrome J Neurol Sci 2017 379 318 320 10.1016/j.jns.2017.06.040 28716271 \n31. Zhovtis Ryerson L Incomplete Susac syndrome exacerbated after natalizumab Neurol Neuroimmunol Neuroinflamm 2015 2 5 e151 10.1212/NXI.0000000000000151 26445727\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2377", "issue": "20(1)", "journal": "BMC neurology", "keywords": "Branch retinal artery occlusion; Susac syndrome; Treatment; cmv post infectious", "medline_ta": "BMC Neurol", "mesh_terms": "D000328:Adult; D001927:Brain Diseases; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D015994:Incidence; D008279:Magnetic Resonance Imaging; D008297:Male; D011859:Radiography; D012189:Retrospective Studies; D055955:Susac Syndrome; D055815:Young Adult", "nlm_unique_id": "100968555", "other_id": null, "pages": "332", "pmc": null, "pmid": "32878610", "pubdate": "2020-09-02", "publication_types": "D016428:Journal Article", "references": "19643446;24424186;8164809;22640902;29933288;1853414;26200513;22095376;21515413;14694047;27787385;22221557;27788613;23628737;24606999;20880549;31176296;28103199;17331544;26445727;29971525;26203089;18779724;571975;24662104;31852955;11097286;22711711;26715396;28716271", "title": "Increased incidence of Susac syndrome: a case series study.", "title_normalized": "increased incidence of susac syndrome a case series study" }

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null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "125201", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE TREATMENT IN DECREASING DOSES", "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": "HUMAN IMMUNOGLOBULIN (GENERIC)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUSAC^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": "ACETYLSALICYLIC ACID" } ], "patientagegroup": "5", "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection reactivation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { 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SYNDROME: A CASE SERIES STUDY? WILF-YARKONI? 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE TREATMENT EVERY 6 MONTHS", "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": "RITUXIMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "NOT REPORTED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "VERY SLOW TAPERING", 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"literaturereference": "WILF-YARKONI A., ELKAYAM O., AIZENSTEIN O., ORON Y., FURER V., ZUR D. ET AL. INCREASED INCIDENCE OF SUSAC SYNDROME: A CASE SERIES STUDY. BMC NEUROLOGY. 2020?20:332", "literaturereference_normalized": "increased incidence of susac syndrome a case series study", "qualification": "3", "reportercountry": "IL" }, "primarysourcecountry": "IL", "receiptdate": "20201011", "receivedate": "20201011", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18369230, "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": "IL-BIO PRODUCTS LABORATORY LTD-2091070", "fulfillexpeditecriteria": "1", "occurcountry": "IL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, 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"drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUSAC^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": "HUMAN NORMAL IMMUNOGLOBULIN" } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection reactivation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "INCREASED INCIDENCE OF SUSAC SYNDROME: A CASE SERIES STUDY? WILF-YARKONI, A ET AL? BMC NEUROLOGY (2020) 20:332 HTTPS://DOI.ORG/10.1186/S12883-020- 01892-0", "literaturereference_normalized": "increased incidence of susac syndrome a case series study", "qualification": null, "reportercountry": "IL" }, "primarysourcecountry": "IL", "receiptdate": "20201001", "receivedate": "20200923", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18302551, "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": "Current management of osteosarcoma at the authors' institution involves intraarterial induction chemotherapy using intermittent cycles of cisplatin and doxorubicin (Adriamycin), surgical resection with limb-sparing wherever possible, and adjuvant systemic chemotherapy (high-dose methotrexate with retrieval and doxorubicin). Twenty cases treated in this way between May 1983 and May 1989 are reviewed. There were 18 Stage IIB osteosarcomas and two Stage IIB malignant fibrous histiocytomas. Chemotherapeutic effect was evaluated in the resected tumors. There was little correlation between the clinical response to the induction chemotherapy and cell necrosis present in the resected tumor mass. Wide resection margins were achieved in 17 cases, a minimal margin in two, and a contaminated margin in one. Radiotherapy was used in these three cases where resection margin was in doubt. There were two local recurrences in these three cases. Four patients have died of their disease, and there was one treatment-related death. Overall probability of survival in this group of 20 patients has been expressed by the Kaplan-Meier method as 58%.", "affiliations": "Department of Orthopaedics, Royal Prince Alfred Hospital, Sydney, Australia.", "authors": "Marsden|F W|FW|;Stephens|F O|FO|;McCarthy|S W|SW|;Ferrari|A M|AM|", "chemical_list": "D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0009-921X", "issue": null, "journal": "Clinical orthopaedics and related research", "keywords": null, "medline_ta": "Clin Orthop Relat Res", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000671:Amputation; D000971:Antineoplastic Combined Chemotherapy Protocols; D001315:Australia; D001859:Bone Neoplasms; D002648:Child; D002945:Cisplatin; D003131:Combined Modality Therapy; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007269:Injections, Intra-Arterial; D015993:Life Tables; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009336:Necrosis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D012516:Osteosarcoma; D010027:Osteotomy; D011183:Postoperative Complications; D011878:Radiotherapy; D012074:Remission Induction; D015996:Survival Rate", "nlm_unique_id": "0075674", "other_id": null, "pages": "113-9", "pmc": null, "pmid": "1884529", "pubdate": "1991-09", "publication_types": "D016428:Journal Article", "references": null, "title": "IIB osteosarcoma. Current management, local control, and survival statistics--the Australian experience.", "title_normalized": "iib osteosarcoma current management local control and survival statistics the australian experience" }

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{ "abstract": "Aromatase inhibitors are sometimes chosen for adjuvant therapy in post-menopausal breast cancer patients with a history of venous thromboembolism over an antiestrogen due to the lower risk of venous thromboembolism associated with aromatase inhibitors compared to antiestrogens. We report two cases where patients on warfarin therapy had an increase in their international normalized ratio with the initiation of exemestane therapy. Initially, the patients also showed international normalized ratio variability possibly due to variable absorption of exemestane. We suggest patients being treated with warfarin and exemestane concomitantly need close monitoring and education in order to decrease the risk of adverse events that could be associated with this possible interaction. To our knowledge, there are no similar reported cases in the literature.", "affiliations": "Department of Pharmacy, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, USA [email protected].;Department of Pharmacy, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, USA.;Department of Pharmacy, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, USA.;School of Pharmacy, The Ohio State University, Columbus, USA.", "authors": "Dush|Aaron|A|;Williams|Abby|A|;Mangini|Neha|N|;Klaczak|Kendra|K|", "chemical_list": "D000730:Androstadienes; D000925:Anticoagulants; D047072:Aromatase Inhibitors; D014859:Warfarin; C056516:exemestane", "country": "England", "delete": false, "doi": "10.1177/1078155214568583", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "22(2)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "INR; Warfarin; exemestane; interaction", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000730:Androstadienes; D000925:Anticoagulants; D047072:Aromatase Inhibitors; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008875:Middle Aged; D014859:Warfarin", "nlm_unique_id": "9511372", "other_id": null, "pages": "371-3", "pmc": null, "pmid": "25596194", "pubdate": "2016-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Initiation of exemestane in two warfarin-treated patients leading to elevation and variability of INR.", "title_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr" }

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} ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. J ONCOL PHARM PRACT. 2016;22(2):371-3.", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160407", "receivedate": "20160324", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12207194, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "PHHY2016US053988", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40196", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "23 MG, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "23", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40196", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37 MG, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. JOURNAL OF ONCOLOGY PHARMACY PRACTICE (USA). 2016;22(2):371-73", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160426", "receivedate": "20160426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12308387, "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": "US-MYLANLABS-2016M1016973", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED TO 12 MG/WEEK AFTER EXEMESTANE INITIATION", "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": "WARFARIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "21 MG/WEEK AND THEN DECREASED TO 12 MG/WEEK AFTER EXEMESTANE INITIATION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRADUCTAL PROLIFERATIVE BREAST LESION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "International normalised ratio fluctuation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. J-ONCOL-PHARM-PRACT 2016;22(2):371-373.", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160623", "receivedate": "20160623", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12493607, "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": "US-TEVA-646805USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TAMOXIFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74858", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMOXIFEN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AVERAGE TOTAL WEEKLY DOSE : 23 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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"drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOUR CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ENOXAPARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOUR CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOUR CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. JOURNAL OF ONCOLOGY PHARMACY PRACTICE. 2016; 22(2): 371-373", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160429", "receivedate": "20160325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12211612, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "PHHY2016US055947", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40196", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "21 MG, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "21", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40196", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 MG, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. JOURNAL OF ONCOLOGY PHARMACY PRACTICE (USA). 2016;22(2):371-73", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160426", "receivedate": "20160426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12308392, "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": "US-MYLANLABS-2016M1017038", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37 MG/WEEK AND THEN DECREASED TO 23 MG/WEEK AFTER EXEMESTANE INITIATION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED TO 23 MG/WEEK AFTER EXEMESTANE INITIATION", "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": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "International normalised ratio fluctuation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. 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INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. JOURNAL OF ONCOLOGY PHARMACY PRACTICE 2016;22(2):371-373.", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160726", "receivedate": "20160726", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12594191, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "US-TEVA-646806USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AVERAGE TOTAL WEEKLY DOSE OF WARFARIN WAS 12 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AVERAGE TOTAL WEEKLY DOSE 21 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRADUCTAL PROLIFERATIVE BREAST LESION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "International normalised ratio fluctuation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUSH A, WILLIAMS A, MANGINI N, KLACZAK K. INITIATION OF EXEMESTANE IN TWO WARFARIN-TREATED PATIENTS LEADING TO ELEVATION AND VARIABILITY OF INR. JOURNAL OF ONCOLOGY PHARMACY PRACTICE. 2016; 22(2): 371-373", "literaturereference_normalized": "initiation of exemestane in two warfarin treated patients leading to elevation and variability of inr", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160621", "receivedate": "20160325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12211453, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "Implantable cardioverter-defibrillator (ICD) is the gold standard therapy for the prevention of sudden cardiac death. Nevertheless, ICD placement in the paediatric population is still limited because of several technical difficulties. Several implantation techniques have been proposed but experience in infants with very low weight and less than 6 months is very limited. We herein describe a case of a minimally invasive ICD epicardial implantation in a 4-month-old infant weighing 5 kg. A diagnosis of arrhythmic cardiomyopathy with left ventricular non-compaction disease with ventricular tachycardia storms, QT prolongation and Wolff-Parkinson-White pattern was made. Antiarrhythmic drugs, radiofrequency ablation and sympathetic denervation were not effective. ICD implantation was successful allowing the infant to survive and bridging to heart transplantation.", "affiliations": "Pediatric Cardiology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Pediatric Cardiology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Pediatric Cardiology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Pediatric Cardiology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.", "authors": "Carro|Cristina|C|;Cereda|Alberto Francesco|AF|;Annoni|Giuseppe|G|;Marianeschi|Stefano Maria|SM|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/icvts/ivx129", "fulltext": null, "fulltext_license": null, "issn_linking": "1569-9285", "issue": "25(5)", "journal": "Interactive cardiovascular and thoracic surgery", "keywords": "Congenital heart disease; Electrical storms; Heart transplantation; Implantable cardioverter–defibrillator (ICD); Paediatric cardiomyopathy", "medline_ta": "Interact Cardiovasc Thorac Surg", "mesh_terms": "D016757:Death, Sudden, Cardiac; D017147:Defibrillators, Implantable; D006330:Heart Defects, Congenital; D016027:Heart Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D017180:Tachycardia, Ventricular", "nlm_unique_id": "101158399", "other_id": null, "pages": "832-833", "pmc": null, "pmid": "28510647", "pubdate": "2017-11-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Epicardial cardioverter-defibrillator implantation in a 4-month-old infant bridged to heart transplantation.", "title_normalized": "epicardial cardioverter defibrillator implantation in a 4 month old infant bridged to heart transplantation" }

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{ "abstract": "To determine the risk and pertinent features of non-Hodgkin's lymphoma (NHL) as a second malignancy, medical records were searched of 5484 consecutive children treated for various malignancies at a single institution during a 27 year period. Of these, three have developed secondary NHL. The probability of secondary NHL in this cohort at 5 and 10 years after the diagnosis of the first malignancy was 0.05% (95% confidence interval, 0.01%, 0.2%) and at 15 years 0.16% (0.04%, 0.63%). With 30710 person-years observed, the risk in this cohort was 9.8 per 100,000 person-years. A literature search disclosed variously detailed descriptions of 21 cases of secondary NHL in patients whose primary malignancy had been diagnosed when they were less than 20 years old. Of 18 cases with documented secondary NHL histology, the most common subtypes were large cell (n = 7) and small non-cleaved cell (n = 6); mixed histology was found in three and lymphoblastic in two cases. Twenty-three of 24 children with secondary NHL had initial lymphohematopoietic neoplasms: Hodgkin's disease (n = 18), acute lymphoblastic leukemia (n = 4) and acute myelogenous leukemia (n = 1); the remaining child had astrocytoma. Of 18 patients (including three cases from this institution) with known outcome, only four were reported to be alive at 5+, 6+, 12+ and 96+ months, respectively. Secondary NHL occurs most often after therapy for Hodgkin's disease and confers a dismal prognosis.", "affiliations": "Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38101.", "authors": "Eguiguren|J M|JM|;Ribeiro|R C|RC|;Pui|C H|CH|;Hancock|M L|ML|;Pratt|C B|CB|;Head|D R|DR|;Crist|W M|WM|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0887-6924", "issue": "5(10)", "journal": "Leukemia", "keywords": null, "medline_ta": "Leukemia", "mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D016609:Neoplasms, Second Primary; D012307:Risk Factors", "nlm_unique_id": "8704895", "other_id": null, "pages": "908-11", "pmc": null, "pmid": "1961025", "pubdate": "1991-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.; D016454:Review", "references": null, "title": "Secondary non-Hodgkin's lymphoma after treatment for childhood cancer.", "title_normalized": "secondary non hodgkin s lymphoma after treatment for childhood cancer" }

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{ "abstract": "BACKGROUND\nIsolated splenic metastasis from colorectal cancer is very rare, as metastatic colorectal cancer involving the spleen is usually a manifestation of widely disseminated disease. Splenectomy is the best therapeutic option for this entity and probably the only chance for radical cure.\nA 73-year-old male presented with abdominal distension and dark red bloody stool of 6-month duration.\nSynchronous isolated splenic metastasis from colorectal cancer.\n\n\nMETHODS\nBased on multidisciplinary team (MDT) mode, the patient underwent the primary hepatic flexure tumor resection due to his poor general condition. One month after surgery the patient began treatment with Xelox (capecitabine 1000 mg/m, oxaliplatin 130 mg/m) every 3 weeks. The patient underwent isolated splenic metastasis resection successfully by laparoscopic after four courses of chemotherapy.\n\n\nRESULTS\nThe patient's postoperative course was uneventful and he completed four courses of postoperative chemotherapy using the original chemotherapy regimen Xelox (capecitabine 1000 mg/m, oxaliplatin 130 mg/m). The patient was subsequently followed up every 3 months and no signs of recurrence were noted in a recent examination.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first case report of isolated splenic metastasis from colorectal cancer in China. It is also the first case in which treatment was overseen by an MDT. The possibility of splenic metastasis should be considered in cases in which colorectal cancer is associated with a splenic lesion, despite its rarity. Splenectomy and adjuvant chemotherapy are the optimal therapeutic approaches, as such an approach prolongs survival and palliates the disease.", "affiliations": "Department of Colorectal Surgery.;Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.;Department of Colorectal Surgery.;Department of Colorectal Surgery.", "authors": "Zhao|Huiying|H|;Zhong|Weixiang|W|;Chen|Dong|D|;Cheng|Xiaofei|X|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000015016", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30946331MD-D-18-0801710.1097/MD.0000000000015016150164500Research ArticleClinical Case ReportSynchronous isolated splenic metastasis from cancer of hepatic flexure of colon A case reportZhao Huiying MDaZhong Weixiang MDbChen Dong MDaCheng Xiaofei MDa∗NA. a Department of Colorectal Surgeryb Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.∗ Correspondence: Xiaofei Cheng, Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou 310003, Zhejiang Province, China (e-mail: [email protected]).6 2019 05 4 2019 98 14 e1501630 10 2018 20 2 2019 6 3 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nIsolated splenic metastasis from colorectal cancer is very rare, as metastatic colorectal cancer involving the spleen is usually a manifestation of widely disseminated disease. Splenectomy is the best therapeutic option for this entity and probably the only chance for radical cure.\n\nPatient Concerns:\nA 73-year-old male presented with abdominal distension and dark red bloody stool of 6-month duration.\n\nDiagnoses:\nSynchronous isolated splenic metastasis from colorectal cancer.\n\nInterventions:\nBased on multidisciplinary team (MDT) mode, the patient underwent the primary hepatic flexure tumor resection due to his poor general condition. One month after surgery the patient began treatment with Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2) every 3 weeks. The patient underwent isolated splenic metastasis resection successfully by laparoscopic after four courses of chemotherapy.\n\nOutcomes:\nThe patient's postoperative course was uneventful and he completed four courses of postoperative chemotherapy using the original chemotherapy regimen Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2). The patient was subsequently followed up every 3 months and no signs of recurrence were noted in a recent examination.\n\nLessons:\nTo the best of our knowledge, this is the first case report of isolated splenic metastasis from colorectal cancer in China. It is also the first case in which treatment was overseen by an MDT. The possibility of splenic metastasis should be considered in cases in which colorectal cancer is associated with a splenic lesion, despite its rarity. Splenectomy and adjuvant chemotherapy are the optimal therapeutic approaches, as such an approach prolongs survival and palliates the disease.\n\nKeywords\ncolorectal cancerisolated splenic metastasesmultidisciplinary teamsplenectomyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nIsolated splenic metastasis from colorectal cancer is very rare, as metastatic colorectal cancer involving the spleen is usually a manifestation of widely disseminated disease.[1] In a cadaver study, the incidence of splenic metastases from colorectal cancer was 2% of 1019 cases, but the incidence of isolated splenic metastasis was not reported.[2] To the best of our knowledge, only 32 cases (5 synchronous and 27 metachronous cases) of isolated splenic metastasis from colorectal cancer have been reported in the English-language literature.[3] Because synchronous splenic metastasis is very rare, preoperative diagnosis is difficult. Splenectomy is the best therapeutic option for isolated splenic metastasis and probably the only chance for radical cure. Some authors suggest that splenectomy may lead to long-term survival in patients with isolated splenic metastasis.[4,5] Herein, we report the first case of isolated splenic metastasis from colorectal cancer in China. We diagnosed this rare clinical entity and resected the primary tumor and isolated splenic metastasis using a multidisciplinary team (MDT) approach. MDT approach is important for advanced colorectal cancer, especially for patients with synchronous metastasis.[6,7]\n\n2 Case report\nIn October 2017, a 73-year-old male presented with abdominal distension and dark-red bloody stool of 6-month duration. He also complained of general fatigue and weight loss of 15 kg. He had no familial history of cancer, no prior pathological conditions, and no concomitant medication use. The patient's carcinoembryonic antigen (CEA) and hemoglobin levels were 6.9 ng/mL (0–5 ng/mL) and 101 g/L (131–175 g/L), respectively. The results of all other laboratory tests were normal, including cancer antigen 19 to 9 (CA 19–9), biochemical, and hematologic tests. Endoscopic examination revealed an obstructing neoplasm in the hepatic flexure, about 4.5 cm in diameter, with surface depression, erosion, and a propensity for bleeding. A biopsy of the lesion established a diagnosis of moderately differentiated adenocarcinoma. Whole-abdomen computed tomography (CT) revealed wall thickening of the hepatic flexure with proximal incomplete intestinal obstruction (Fig. 1A). The CT scan also revealed a single low-density lesion of about 5.7 cm diameter in the spleen (Fig. 1B). Genetic testing of the biopsy material indicated non-mutated KRAS, NRAS, and BRAF genes. After the first MDT discussion, due to the poor general condition of the patient, we decided to remove the primary lesion and biopsy the splenic mass during the operation. The biopsy indicated the presence of splenic metastasis from adenocarcinoma. The patient underwent a laparoscopic right hemicolectomy due to the histopathological finding of a moderately and poorly differentiated adenocarcinoma invading the serosa. Twenty-two lymph nodes were removed and 7 showed metastases (pT3N2M1, stage IV). One month later, the patient's CEA level had decreased to 3 ng/mL. The patient's postoperative recovery was uneventful, and 1 month after surgery he began treatment with Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2) every 3 weeks for 3 months. After 4 courses of Xelox therapy, the patient's clinical response was excellent, with II degree vomiting and no obvious bone marrow suppression or neurotoxicity. The diameter of the splenic lesion had decreased from 5.7 to 2.5 cm (Fig. 1C), and a partial response had been achieved after 4 courses of chemotherapy. In April 2018, based on a second MDT discussion, the patient underwent laparoscopic splenectomy. The histological findings showed that the splenic tumor was a moderately and poorly differentiated adenocarcinoma, similar to the tumor of the hepatic flexure (Fig. 2A). Negative staining for cytokeratin 7 and positive staining for cytokeratin 20 was consistent with splenic metastasis of an adenocarcinoma of the hepatic flexure (Fig. 2B and C). The patient's postoperative course was uneventful and he completed 4 courses of postoperative chemotherapy using the original chemotherapy regimen Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2). The patient's clinical response was good, with II degree vomiting, II degree bone marrow suppression, and II degree neurotoxicity. The patient was subsequently followed up every 3 months and no signs of recurrence were noted in a recent examination on January, 2019.\n\nFigure 1 Whole abdominal computed tomography (CT). (A) a heterogeneous enhanced tumor in hepatic flexure; (B) a single low-density lesion of the spleen about 5.7 cm in diameter before primary treatment; (C) the spleen mass about 2.5 cm in diameter after 4 courses chemotherapy with Xelox (capecitabine, oxaliplatin).\n\nFigure 2 Histological findings of the tumor of the spleen. (A) Moderately-poorly differentiated adenocarcinoma (HE, ×100); (B) immunostaining for cytokeratin 7 showing a negative reaction (×100); (C) immunostaining for cytokeratin 20 showing a positive reaction (×100).\n\n3 Discussion\nApproximately 1 in 4 patients with colorectal cancer have metastases at the time of initial diagnosis.[8] Metastases to the spleen from colorectal cancer in the absence of liver or lung involvement are extremely rare,[9,10] possibly due to the anatomical and immunological characteristics of the tumor. The anatomical factors that restrict metastasis include the rhythmic contraction of the sinusoidal splenic architecture and the sharp angle of the splenic artery with the celiac axis.[11] Moreover, immune surveillance in the spleen inhibits tumor cell proliferation.[12] A PubMed search yielded only 32 cases of isolated solitary splenic metastasis from colorectal cancer (synchronous, 5 cases summarized in Table 1;[13–16] metachronous, 27 cases) in the English language literature. We report here the sixth case in which an isolated splenic lesion was synchronous with colorectal cancer. A particularly interesting aspect of this case is its diagnosis and treatment by an MDT. The MDT is defined as “a group of people of different health-care disciplines, which meets together at a given time to discuss a given patient and who are each able to contribute independently to the diagnostic and treatment decisions about the patients.” The colorectal cancer MDT in our hospital includes colorectal surgeons, hepatobiliary surgeons, urological surgeons, thoracic surgeons, gynecologists, radiologists, radiation therapist, histopathologists, medical oncologists, and nurse specialist. An MDT approach may not only reduce the risk for perioperative morbidity and mortality but also improves long-term survival.[17,18] Because of the poor general condition of the patient, the staging and resection of the primary and metastatic lesions were overseen by an MDT.\n\nTable 1 Summary of reported cases of synchronous isolated splenic metastasis from colorectal cancer.\n\nBecause the majority of patients with isolated splenic metastasis from colorectal cancer are asymptomatic, the condition is typically diagnosed through imaging tests and evaluation of CEA levels. CEA levels are elevated in more than 80% of such cases, to 4.6 to 223 ng/mL3; the level in our patient was 6.0 ng/mL. In addition, careful examination of an abdominal CT scan can facilitate early diagnosis of synchronous and metachronous splenic metastasis; therefore, this should be a priority.[19] None of the cases reported to date were misdiagnosed. Overall, isolated splenic metastasis is relatively easy to diagnose.\n\nSplenectomy is necessary in the presence of isolated metastases from colorectal cancer.[16] Splenectomy was performed in all reported cases of isolated splenic metastasis from colorectal cancer, but only two cases were treated using a laparoscopic approach, as in our patient. Due to the risk for peritoneal dissemination, use of laparoscopy for splenic malignancies is controversial. However, laparoscopic splenectomy for splenic metastasis reportedly does not increase the rate of surgical complications, and survival ranges from 2 months to 11 years.[5] Moreover, laparoscopic surgery for other abdominal tumors is not associated with a greater risk of surgical complications compared to conventional techniques.[20,21] Thus, laparoscopic splenectomy for splenic metastasis is safe and reproducible, and yields outcomes superior to those of open surgery. The survival duration after splenectomy ranges from 3 to 84 months (mean, 22.5 months).[3] Only 2 of 27 reported cases of metachronous splenic metastasis relapsed between 9 and 11 months, compared to 3 of 5 cases of synchronous splenic metastases.[3,22] Chemotherapy is the appropriate treatment for isolated splenic metastases from colorectal cancer, particularly synchronous splenic metastases.[23] Chemotherapy regimens for metastatic colorectal cancer include CapeOX/Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2), mFOLFOX6 (5-fluorouracil 2400 mg/m2, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2), and FOLFIRI (5-fluorouracil 2400 mg/m2, leucovorin 400 mg/m2, and irinotecan 180 mg/m2).[18,24,25] Our patient underwent the primary hepatic flexure tumor and isolated splenic metastasis resection in stages due to his poor general condition. The interval between the 2 operations is about 3 to 4 months. Since this entity was advanced colorectal cancer (pT3N2M1, stage IV), our MDT team recommended that the patient underwent adjuvant chemotherapy first during the waiting period. Our patient completed perioperative chemotherapy using the regimen Xelox (capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2).\n\nIn conclusion, we report the first case of isolated splenic metastasis from colorectal cancer in China; it is also the first case in which treatment was overseen by an MDT. Despite its rarity, the possibility of splenic metastasis should be considered in cases in which colorectal cancer is associated with a splenic lesion. Splenectomy and adjuvant chemotherapy is the optimal therapeutic approach; such an approach prolongs survival and palliates the disease. We report this rare clinical entity for the purpose of improving the management and survival of patients with isolated splenic metastases from colorectal cancer.\n\nAcknowledgments\nWe gratefully acknowledge the contributions made by the clinical nurse specialists, surgeons, radiologists, pathologists, and oncologists to the Colorectal MDT. In particular, we would like to thank: Jianjiang Lin, Wenbin Chen, and Yingsheng Wu.\n\nAuthor contributions\nData curation: Huiying Zhao, Weixiang Zhong.\n\nInvestigation: Dong Chen.\n\nVisualization: Weixiang Zhong.\n\nWriting – Original Draft: Huiying Zhao.\n\nWriting – Review & Editing: Xiaofei Cheng.\n\nAbbreviations: CA 19–9 = cancer antigen 19–9, CEA = carcinoembryonic antigen, CT = computed tomography, MDT = multidisciplinary team.\n\nThis study was supported by the Zhejiang Province Natural Science Foundation of China (LGF18H030001; LY19H160040), Chinese traditional medicine Foundation of Zhejiang Province (2017ZA077), and Zhejiang education department scientific research project (Y201636334).\n\nAll data generated or analyzed during this study are included in this published article.\n\nWritten informed consent was obtained from the patient and the present study (Ethics approval number; 2018-604) was approved by the Ethics Board of the First Affiliated Hospital Zhejiang University School of Medicine.\n\nWritten informed consent was obtained from the patient for the publication of their data.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Abi Saad GS Hussein M El-Saghir NS \nIsolated splenic metastasis from colorectal cancer . Int J Clin Oncol \n2011 ;16 :306–13 .21258837 \n[2] Berge T \nSplenic metastases. Frequencies and patterns . Acta Pathol Microbiol Scand A \n1974 ;82 :499–506 .4854372 \n[3] Abdou J Omor Y Boutayeb S \nIsolated splenic metastasis from colon cancer: case report . World J Gastroenterol \n2016 ;22 :4610–4 .27182171 \n[4] Takada T Takami H \nSolitary splenic metastasis of a carcinoid tumor of the lung eight years postoperatively . J Surg Oncol \n1998 ;67 :47–8 .9457257 \n[5] Lopez Monclova J Targarona Soler E Peraza Solis Y \nLaparoscopic approach for isolated splenic metastasis: comprehensive literature review and report of 6 cases . Surg Laparosc Endosc Percutan Tech \n2013 ;23 :21–4 .23386144 \n[6] Lamb BW Sevdalis N Taylor C \nMultidisciplinary team working across different tumour types: analysis of a national survey . Ann Oncology \n2012 ;23 :1293–300 .\n[7] Lowes M Kleiss M Lueck R \nThe utilization of multidisciplinary tumor boards (MDT) in clinical routine: results of a health care research study focusing on patients with metastasized colorectal cancer . Int J Colorectal Dis \n2017 ;32 :1463–9 .28779354 \n[8] Simmonds PC Primrose JN Colquitt JL \nSurgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies . Br J Cancer \n2006 ;94 :982–99 .16538219 \n[9] Klein B Stein M Kuten A \nSplenomegaly and solitary spleen metastasis in solid tumors . Cancer \n1987 ;60 :100–2 .3581023 \n[10] Place RJ \nIsolated colon cancer metastasis to the spleen . Am Surg \n2001 ;67 :454–7 .11379648 \n[11] Kim JC Jeong CS Kim HC \nIsolated splenic metastasis from colorectal carcinoma: a case report . J Korean Med Sci \n2000 ;15 :355–8 .10895982 \n[12] Gabizon A Small M Trainin N \nKinetics of the response of spleen cells from tumor-bearing animals in an in vivo tumor neutralization assay . Int J Cancer \n1976 ;18 :813–9 .992909 \n[13] Ishida H Konno K Ishida J \nIsolated splenic metastases . J Ultrasound Med \n1997 ;16 :743–9 .9360238 \n[14] Avesani EC Cioffi U De Simone M \nSynchronous isolated splenic metastasis from colon carcinoma . Am J Clin Oncol \n2001 ;24 :311–2 .11404507 \n[15] Hiraiwa K Morozumi K Miyazaki H \nIsolated splenic vein thrombosis secondary to splenic metastasis: a case report . World J Gastroenterol \n2006 ;12 :6561–3 .17072993 \n[16] Pisanu A Ravarino A Nieddu R \nSynchronous isolated splenic metastasis from colon carcinoma and concomitant splenic abscess: a case report and review of the literature . World J Gastroenterol \n2007 ;13 :5516–20 .17907299 \n[17] Lordan JT Karanjia ND Quiney N \nA 10-year study of outcome following hepatic resection for colorectal liver metastases: the effect of evaluation in a multidisciplinary team setting . Eur J Surg Oncol \n2009 ;35 :302–6 .18328668 \n[18] Van Cutsem E Cervantes A Adam R \nESMO consensus guidelines for the management of patients with metastatic colorectal cancer . Ann Oncol \n2016 ;27 :1386–422 .27380959 \n[19] Gilardi L Vadrucci M \nIsolated metachronous splenic metastasis from colon cancer found by 18F-FDG PET/CT . Clin Nucl Med \n2017 ;42 :79–80 .27775944 \n[20] Jingli C Rong C Rubai X \nInfluence of colorectal laparoscopic surgery on dissemination and seeding of tumor cells . Surg Endosc \n2006 ;20 :1759–61 .17024537 \n[21] Zanghi A Cavallaro A Piccolo G \nDissemination metastasis after laparoscopic colorectal surgery versus conventional open surgery for colorectal cancer: a metanalysis . Eur Rev Med Pharmacol Sci \n2013 ;17 :1174–84 .23690186 \n[22] Pavlovic M Separovic R Vukelic-Markovic M \nIsolated splenic metastasis from colorectal carcinoma in a high risk patient: a case report . Coll Antropol \n2011 ;35 :1307–10 .22397278 \n[23] Cavallaro A Modugno P Specchia M \nIsolated splenic metastasis from colon cancer . J Exp Clin Cancer Res \n2004 ;23 :143–6 .15149163 \n[24] Glynne-Jones R Wyrwicz L Tiret E \nRectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol \n2017 ;28 suppl_4 :iv22–40 .28881920 \n[25] Messersmith WA \nSystemic management of colorectal cancer . J Natl Compr Canc Netw \n2017 ;15 (5S) :699–702 .28515248\n\n", "fulltext_license": "CC BY", "issn_linking": "0025-7974", "issue": "98(14)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000368:Aged; D044682:Colon, Ascending; D003110:Colonic Neoplasms; D006801:Humans; D008297:Male; D013154:Spleen; D013160:Splenic Neoplasms", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e15016", "pmc": null, "pmid": "30946331", "pubdate": "2019-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Synchronous isolated splenic metastasis from cancer of hepatic flexure of colon: A case report.", "title_normalized": "synchronous isolated splenic metastasis from cancer of hepatic flexure of colon a case report" }

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{ "abstract": "OBJECTIVE\nTo report a case of aplastic anemia in a patient treated with cyanamide, an alcohol-aversive drug. A 67-year-old man was admitted to hospital because of fever and pancytopenia. He had taken cyanamide for 6 months as an alcohol deterrent. No other risk factors for aplastic anemia were identified by interviewing the patient using a structured validated questionnaire. The results of bone-marrow biopsy showed severe aplastic anemia. Cyanamide was discontinued and the patient was treated according to a prespecified treatment protocol. One year after hospital admission, the patient was completely recovered with no need of immunosuppressive therapy. An objective causality assessment revealed that an adverse drug reaction was probable.\n\n\nCONCLUSIONS\nAs the efficacy of cyanamide has been questioned, due to the failure of various trials to show any benefit over placebo, its overall benefit/risk ratio should be reconsidered. The complete and rapid hematological recovery after discontinuation of the drug, and the absence of other factors that could explain the condition support the association of the present case of aplastic anemia with cyanamide. The mechanism remains unknown. Aplastic anemia is a rare but potentially serious adverse drug effect of cyanamide treatment.\n\n\nCONCLUSIONS\nGiven the poor evidence on the efficacy of cyanamide and the associated risk of aplastic anemia, its use in reducing alcohol consumption should be reconsidered.", "affiliations": "Fundació Institut Català de Farmacologia Servei de Farmacologia Clínica, Hospital Universitari Vall d'Hebron Universitat Autònoma de Barcelona, P Vall d'Hebron 129-139, 08035, Barcelona, Spain. [email protected]", "authors": "Ballarín|Elena|E|;Ibáñez|Luisa|L|;Hernández|José-Angel|JA|;Force|Lluís|L|;Laporte|Joan-Ramon|JR|", "chemical_list": "D003484:Cyanamide", "country": "Germany", "delete": false, "doi": "10.1007/s00228-005-0954-1", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-6970", "issue": "61(5-6)", "journal": "European journal of clinical pharmacology", "keywords": null, "medline_ta": "Eur J Clin Pharmacol", "mesh_terms": "D000368:Aged; D000437:Alcoholism; D000741:Anemia, Aplastic; D003484:Cyanamide; D006801:Humans; D008297:Male; D013997:Time Factors", "nlm_unique_id": "1256165", "other_id": null, "pages": "467-9", "pmc": null, "pmid": "15991038", "pubdate": "2005-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "2291154;6112345;10320388;11168499;12554608;5334883;8044121;58177;1543940;1559576;9746025;2673441;7249508;10803790;9313109;6101808;6346921", "title": "Cyanamide-induced aplastic anemia.", "title_normalized": "cyanamide induced aplastic anemia" }

[ { "companynumb": "JP-DSJP-DSJ-2018-152837", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLMESARTAN MEDOXOMIL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021286", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORODISPERSIBLE TABLET", "drugdosagetext": "40MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLMETEC OD" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYANAMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ABSTAINS FROM ALCOHOL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYANAMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MIGLITOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50MG/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": "MIGLITOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EPALRESTAT" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50MG/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": "EPALRESTAT" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750MG/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": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TENELIGLIPTIN HYDROBROMIDE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20MG/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": "TENELIGLIPTIN HYDROBROMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aplastic anaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YOHEI OSAKI, YUKIE TERASAKI, SHUHEI KANAYA, KENICHI TAHARA, HIROAKI SHIMIZU, KUNIO YANAGISAWA, ET AL.. CYANAMIDE INDUCED APLASTIC ANEMIA. THE KITAKANTO MEDICAL JOURNAL. 2018?68 (4):261-265", "literaturereference_normalized": "cyanamide induced aplastic anemia", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181220", "receivedate": "20181220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15747295, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "BACKGROUND\nVerrucous carcinoma is an uncommon variant of low-grade squamous cell malignancy with a low malignant potential but a high risk of recurrence.\n\n\nMETHODS\nWe report a case of a Human Papilloma Virus negative local verrucous carcinoma in the perianal area of a 45-year old otherwise healthy female. The tumor presented clinically as a persistent genital wart not responding to usual dermatologic local therapy. The patient was referred to the Department of Plastic Surgery and Breast Surgery after primary excision in a private practice setting of a general surgeon. Three months later, further excision revealed local lichen sclerosus inflammatory changes in close proximity to the excision scar.\n\n\nCONCLUSIONS\nDue to the low occurrence of verrucous carcinoma in the perianal area, no guidelines are available for the management of this disease. Conflicting reports on the ethiology and the nomenclature and classifications of verrucous carcinomas exist.\n\n\nCONCLUSIONS\nAvoid pitfalls in the diagnosis of a rare variant of squamous cell cancer with a high recurrence ratio: Common genital warts not responding to ordinary local antimitotic Podophyllotoxin treatment require biopsy to exclude verrucous carcinoma. Follow-up is recommended at a 3-6 months interval due to the relative high risk of relapse.", "affiliations": "Department of Plastic Surgery and Breast Surgery, Zealand University Hospital, Roskilde, Denmark. Electronic address: [email protected].;Department of Plastic Surgery and Breast Surgery, Zealand University Hospital, Roskilde, Denmark.", "authors": "Trøstrup|Hannah|H|;Matzen|Steen H|SH|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.ijscr.2018.11.017", "fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(18)30524-810.1016/j.ijscr.2018.11.017ArticleAnogenital Verrucous Carcinoma—A case report Trøstrup Hannah [email protected]@regionsjaelland.dk⁎Matzen Steen H. Department of Plastic Surgery and Breast Surgery, Zealand University Hospital, Roskilde, Denmark⁎ Corresponding author at: Department of Plastic Surgery and Breast Surgery, Zealand University Hospital, 4000, Roskilde, Denmark. [email protected]@regionsjaelland.dk27 11 2018 2019 27 11 2018 54 7 9 27 9 2018 23 10 2018 10 11 2018 © 2018 The Authors2018This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Verrucous carcinoma (VC) is a variant of squamous cell carcinoma.\n\n• Anogenital VC is a rare condition, which clinically presents as common genital warts.\n\n• Early recognition of VC and radical excision is crucial due to local destruction of tissue.\n\n• Recurrence of VC is not uncommon.\n\n\n\nIntroduction\nVerrucous carcinoma is an uncommon variant of low-grade squamous cell malignancy with a low malignant potential but a high risk of recurrence.\n\nPresentation of case\nWe report a case of a Human Papilloma Virus negative local verrucous carcinoma in the perianal area of a 45-year old otherwise healthy female. The tumor presented clinically as a persistent genital wart not responding to usual dermatologic local therapy. The patient was referred to the Department of Plastic Surgery and Breast Surgery after primary excision in a private practice setting of a general surgeon. Three months later, further excision revealed local lichen sclerosus inflammatory changes in close proximity to the excision scar.\n\nDiscussion\nDue to the low occurrence of verrucous carcinoma in the perianal area, no guidelines are available for the management of this disease. Conflicting reports on the ethiology and the nomenclature and classifications of verrucous carcinomas exist.\n\nConclusion\nAvoid pitfalls in the diagnosis of a rare variant of squamous cell cancer with a high recurrence ratio: Common genital warts not responding to ordinary local antimitotic Podophyllotoxin treatment require biopsy to exclude verrucous carcinoma. Follow-up is recommended at a 3–6 months interval due to the relative high risk of relapse.\n\nKeywords\nAnogenital verrucous carcinomaSquamous cell cancer variantCase report\n==== Body\n1 Introduction\nVerrucous carcinomas are rare, low-grade warty exophytic squamous cell carcinomas (SCC). Verrucous carcinomas were first described by Ackermann in 1948 in the oral pharynx. However, the lesions can also be located to the larynx or plantar surface of the foot (epithelioma cuniculatum or carcinoma cuniculatum). In the anogenital region, the tumor may present as condyloma accuminatum, common genital warts. Dawson et al. described for the first time anorectal giant condyloma accuminatum in 1965 [1]. A morfologically alike tumour in the anogenital area is the rare sexually transmitted disease Giant Condylomata of Buschke and Lowenstein tumour (BLT), which was first described in 1925 [2]. It is believed to account for 5–16% of all penile carcinomas [3]. It is not clear whether VC and BLT belong to the same entity of tumours or not.\n\nDue to the low incidence, no estimates of cutaneous presentations of verrucous carcinomas of the anogenital area exists. It is more common in middle-aged white individuals, predominantly males [4] or in immunocompromised patients. In females, it is more often localised to the vulva, whereas perianal verrucous tumours are more seldom. Lichen sclerosis (LS) may predispose to verrucous carcinomas [5,6].\n\nHistopathologically, the tumor grows locally in a papillary manner, destructing surrounding tissue, but distant metastases are uncommon. Pushing tumour margins as opposed to infiltrating margins as seen in SCC is described histopathologically. Early, radical excision is crucial.\n\n2 Case\nA 45- year old unmarried heterosexual, otherwise healthy and non-smoking female with no previous history of cancer, diabetes or lichen sclerosus was referred to the Department of Breast and Plastic Surgery for reexcision of a histopathologically verified 20 mm x 10 mm perianal verrucous carcinoma. The resection base margin was not free, so the patient was referred to Dep. of Plastic Surgery for further surgical intervention and follow-up. Histopathologically, there was some discussion whether the tumor excised prior to admission should be described as a verrucous carcinoma or a Buschke Loewenstein tumour. However, since no Human Papilloma Virus (HPV) could be found in the tissue by immunohistochemical staining, the final conclusion was verrucous carcinoma of the anogenital area (Fig. 1).Fig. 1 The postoperative appearance of the excised verrucous carcinoma: A mobile 20 × 18 mm scar, located at 7–9 o-clock in the perianal area is observed.\n\nFig. 1\n\nThe tumour had been present and growing for 3 months. As local treatment by Podophyllotoxin failed to treat the lesion, the patient was referred to a general surgeon in a private clinic, who had excised the tumor. Resection borders were not reported.\n\nNo bleeding, itching, painful sensations or previous history of lichen sclerosus were reported. The patient had no risk factors for HIV or symptoms from the gastrointestinal tract. The only medicine prescribed was peroral Imigrane for intermittent migraine. No lymphadenopathy was found.\n\nThe clinical presentation was a scar (a) of 20 × 18 mm located in close proximity to the anus remained from the primary excision (Fig. 1). A stalked, soft mobile tumor of 5 × 4 mm (b) was also observed in the perianal region at 4 o’clock (Fig. 2). Histopathologic evaluation of a 4 mm punch biopsy from lesion b determined that is was a benign fibroepithelial tumor. The patient was referred to the department of surgical gastroenterology, Herlev, Denmark, for endoscopy and further surgical intervention on the suspicion of involvement of the anal canal. PET-CT scan determined no signs of dissemination. A transrectal ultrasound examination revealed a tumour observed at 4 o’clock. This tumour involved the internal muscular sphincter of the anus and it was excised in toto. Histologic diagnosis was lichenoid inflammation.Fig. 2 a) H&E stained slide (magnification ×2.5) of the verrucous carcinoma (primary excision). Epidermis is seen to the upper left. Explicit dyskeratotic changes are observed. b) H&E stained slide (magnification ×25) of the verrucous carcinoma (primary excision). Note the several mitosis in proximity to the basal membrane.\n\nFig. 2\n\nFollow-up was set for 6 months in which the patient did not display any signs of relapse (Table 1).Table 1 Clinical conclusions.\n\nTable 1Management of verrucous carcinomas in the anogenital area:\t\nVerrucous carcinomas of the anogenital area are rare, low-grade squamous cell cancers clinically resembling common genital warts\nMeticulous surgery including subcutaneous tissue should ensure free surgical margins\nLong term follow-up due to the propensity for recurrence\nLong term prognosis is good\nClinicians should consider verrucous carcinoma in case of failure of local antimitotic Podophyllotoxin treatment of genital warts\t\n\n\n3 Discussion\nVerrucous carcinomas of the anogenital area are rare. They are low-grade variants of squamous cell cancer presenting as common genital warts [7]. Pathophysiological ethiologies for anogenital verrucous carcinomas suspected are Human Papilloma Virus (HPV) type 6 and 11 [4]. Immunohistochemical staining showed no HPV in the excised tissue. The final histopathological diagnosis was VC. Tumour staging was …\n\nDifferentiation between VC and BLT is clinically and histopathologically challenging. Zidar and collegues recently suggested that anal verrucous carcinoma should be distinguished from BLT due to the lack of HPV [8]. This might also explain the lack of effect of local treatment by Podyphyllotoxin to treat VC/BLT [8]. Some pathologists equate BLT to verrucous carcinoma of the anogenital region [9], however, other authors classify VC as an intermediary lesion between condyloma acuminata and squamous cell carcinoma [10,11].\n\nIn this case, excision was done before admission to our department, which also sets limitations to the study. However, it is our belief that early recognition of VC is crucial in order to prevent late effects of such tumours. In larger VCs, endoscopy, Computed Tomography (CT) or Magnetic Resonance\n\nImaging (MRI) may locate extent of the lesion prior to surgical intervention. Rigorous excision with standard surgical margins and excision of subcutaneous fat is required as recurrence of verrucous carcinomas has a poor prognosis. Recurrence is not uncommon. Long term follow is thus suggested at 3–6 months interval due to the frequent transformation to usual type squamous carcinoma.\n\n4 Conclusions\nClinicians should be aware of genital warts not responding to ordinary gold standard treatment and should consider tissue biopsies in these cases.\n\nThis work is reported in line with the SCARE criteria [12] and as well the PROCESS criteria [13].\n\nConflicts of interest\nNone declared.\n\nFunding\nNo funding was received.\n\nEthical approval\nThe institution (Zealand University Hospital) exempts the case report from ethical approval.\n\nConsent\nWritten consent from the patient was given prior to the data collection.\n\nAuthor contribution\nHannah Trøstrup: study consent, design, data collection, interpretation, writing of the paper.\n\nSteen H. Matzen: design, interpretation, writing of the paper.\n\nRegistration of research studies\nNot applicable.\n\nGuarantor\nSteen H. Matzen.\n\nProvenance and peer review\nNot commissioned, externally peer reviewed.\n\nAcknowledgement\nThe Department of Pathology, Zealand University Hospital, Roskilde, Denmark, who provided the H&E slides.\n==== Refs\nReferences\n1 Dawson D.F. Duckworth J.K. Bernhard H. Giant condyloma and verrucous carcinoma of the genital area Arch. Pathol. 79 1965 225 231 14246201 \n2 Lowenstein L.W. Carcinoma-like condylomata acuminata of the penis Med. Clin. North Am. 23 1939 789 795 \n3 Nomikos M. Barmpoutis P. Papakonstantinou E. Chousiantis Z. Ouzounoglou P. Efstathiadou P. Katsifotis C. A giant verrucous carcinoma of the penis presenting with a urinary sepsis and angina Case Rep. Med. 2014 2014 207026 25477967 \n4 Schwartz R.A. Verrucous carcinoma of the skin and mucosa J. Am. Acad. Dermatol. 32 January (1) 1995 1 21 7822496 \n5 Nasca M.R. Innocenzi D. Micali G. Penile cancer among patients with genital lichen sclerosus J. Am. Acad. Dermatol. 41 December (6) 1999 911 914 10570372 \n6 Wang S.H. Chi C.C. Wong Y.W. Salim A. Manek S. Wojnarowska F. J. Eur. Acad. Dermatol. Venereol. 24 July (7) 2010 815 819 20015174 \n7 Vandeweyer E. Sales F. Deraemacker R. Cutaneous verrucous carcinoma Br. J. Plast. Surg. 54 March (2) 2001 168 170 11207133 \n8 Zidar N. Langner C. Odar K. Hosniak L. Kamaradova K. Daum O. Pollheimer M.J. Koserok P. Poljak M. Anal verrucous carcinoma is not related to infection with human papillomaviruses and should be distinguished from giant condyloma (Buschke-Löwenstein tumour) Histopathology 70 May (6) 2017 938 945 28012208 \n9 Lévy Lebbe C. Buschke-Löwenstein tumour: diagnosis and treatment Ann. Urol. 40 3 2006 175 178 \n10 Creasman Malignant transformation of anorectal giant condyloma acuminatum (Buschke-Loewenstein tumor) Diseases of the Colon & Rectum 1989 \n11 Bogomoletz W.V. Potet F. Molas G. Condylomata acuminata, giant condyloma acuminatum (Buschke‐Loewenstein tumour) and verrucous squamous carcinoma of the perianal and anorectal region: a continuous precancerous spectrum? Histopathology 9 November (11) 1985 1155 1169 4085991 \n12 Agha R.A. Fowler A.J. Saetta A. Barai I. Rajmohan S. Orgill D.P. for the SCARE Group The SCARE statement: consensus-based surgical case report guidelines Int. J. Surg. 34 2016 180 186 27613565 \n13 Agha Riaz A. Fowler Alexander J. Rajmohan Shivanchan Barai Ishani Orgill Dennis P. for the PROCESS Group Preferred reporting of case series in surgery; the PROCESS guidelines Int. J. Surg. 36 Pt A 2016 319 323 27770639\n\n", "fulltext_license": "CC BY", "issn_linking": "2210-2612", "issue": "54()", "journal": "International journal of surgery case reports", "keywords": "Anogenital verrucous carcinoma; Case report; Squamous cell cancer variant", "medline_ta": "Int J Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101529872", "other_id": null, "pages": "7-9", "pmc": null, "pmid": "30508696", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": "16869538;28012208;27770639;25477967;14246201;27613565;7822496;4085991;11207133;2791784;10570372;20015174", "title": "Anogenital Verrucous Carcinoma-A case report.", "title_normalized": "anogenital verrucous carcinoma a case report" }

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{ "abstract": "Presently described is a case of disseminated adenovirus infection in a heart-kidney transplant recipient that was successfully treated with cidofovir. There are several reports of adenovirus infections in adult solid organ transplant recipients and the prognosis is usually poor, with mortality rates of 40% to 60%. Severe disseminated adenovirus infections have been associated with increased risk of adverse transplant events, such as rejection, ventricular dysfunction, allograft vasculopathy, graft loss, and the need for re-transplantation. The patient's lack of clinical improvement, the onset of hemorrhagic cystitis and acute kidney injury were factors in our decision to temporarily discontinue administration of immunosuppressive agents and start an antiviral agent. It is important to suspect adenovirus in transplant patients when they do not respond to antibiotics and cultures are negative. Early diagnosis and treatment are critical to improving outcomes in immunocompromised patients.", "affiliations": "Department of Internal Medicine, Rutgers Robert Wood Johnson University Hospital, New Brunswick, NJ, USA. [email protected].", "authors": "Xu|Jack|J|;Patel|Keval V|KV|;Dsouza|Melroy|M|;Almendral|Jesus|J|;Mody|Kanika|K|;Iyer|Deepa|D|", "chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D007166:Immunosuppressive Agents", "country": "Turkey", "delete": false, "doi": "10.5543/tkda.2017.74957", "fulltext": null, "fulltext_license": null, "issn_linking": "1016-5169", "issue": "46(3)", "journal": "Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir", "keywords": null, "medline_ta": "Turk Kardiyol Dern Ars", "mesh_terms": "D000256:Adenoviridae; D000257:Adenoviridae Infections; D000368:Aged; D000998:Antiviral Agents; D004279:DNA, Viral; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D019562:Viral Load", "nlm_unique_id": "9426239", "other_id": null, "pages": "231-233", "pmc": null, "pmid": "29664432", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Disseminated adenovirus infection in heart and kidney transplant.", "title_normalized": "disseminated adenovirus infection in heart and kidney transplant" }

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"reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adenovirus infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary incontinence", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "XU J, PATEL KV, DSOUZA M, ALMENDRAL J, MODY K, IYER D. DISSEMINATED ADENOVIRUS INFECTION IN HEART AND KIDNEY TRANSPLANT. TURK KARDIYOLOJI DERNEGI ARSIVI. 2018?46(3):231-3", "literaturereference_normalized": "disseminated adenovirus infection in heart and kidney transplant", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180502", "receivedate": "20180502", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14839578, "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": "Full- or lower-dose anticoagulant therapy or aspirin can be used for extended therapy in patients with venous thromboembolism (VTE), but information on their relative benefit-risk profiles is limited.\n\n\n\nData from the EINSTEIN-CHOICE trial were used to compare the benefit-risk profiles of extended treatment with rivaroxaban (20 or 10 mg once daily) and aspirin (100 mg once daily) in VTE patients who had completed 6 to 12 months of anticoagulation therapy. One-year cumulative incidences of recurrent VTE and major bleeding were estimated and benefits and risks were calculated by determining the between group differences in a hypothetical population of 10,000 VTE patients treated for 1 year.\n\n\n\nA total of 1107 patients were treated with 20 mg of rivaroxaban, 1127 with 10 mg of rivaroxaban, and 1131 with aspirin. The cumulative incidences of recurrent VTE in the rivaroxaban 20-mg, rivaroxaban 10-mg and aspirin groups were 1.9%, 1.6%, and 5.0%, respectively, whereas the cumulative incidences of major bleeding were 0.7%, 0.4% and 0.5%, respectively. The incidences of the combined outcome of recurrent VTE and major bleeding were 2.8% and 3.4% lower in the rivaroxaban 20-mg and 10-mg groups than in the aspirin group. For 10,000 patients treated for 1 year, there would be 284 (95% confidence interval [CI] 106 to 462) and 339 (95% CI 165 to 512) fewer events with rivaroxaban 20 mg or 10 mg than with aspirin.\n\n\n\nCompared with aspirin, extended anticoagulation with once daily rivaroxaban reduces recurrent VTE with a favourable benefit-risk profile.\n\n\n\nBayer AG.", "affiliations": "Department of Cardiothoracic & Vascular Sciences, Vascular Medicine Unit, University of Padua, Italy.;Bayer AG, Leverkusen, Germany.;Department of Epidemiology and Technology Assessment, University of Maastricht, Maastricht, The Netherlands.;Bayer AG, Leverkusen, Germany.;Bayer AG, Leverkusen, Germany.;Bayer AG, Leverkusen, Germany.;Department of Vascular Medicine, Klinikum Darmstadt GmbH, Germany.;Department of Hematology, Medical Clinic I, University Hospital \"Carl Gustav Carus\" Dresden, Germany; Department of Haematology, Oncology Kings College London, UK.;Division of Angiology and Hemostasis, University Hospitals of Geneva, Faculty of Medicine, Geneva, Switzerland.;Department of Haematological Medicine, Guys and St Thomas' Hospitals, King's College Hospital, London, UK.;University of Washington School of Medicine, Seattle, WA, USA.;Hospital Beneficência Portuguesa, São Paulo, Brazil.;Vascular Medicine and Hemostasis, University of Leuven, Belgium.;Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ontario, Canada.;Janssen Research & Development, Raritan, NJ, USA.;Janssen Research & Development, Raritan, NJ, USA.;Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada. Electronic address: [email protected].", "authors": "Prandoni|Paolo|P|;Lensing|Anthonie W A|AWA|;Prins|Martin H|MH|;Gebel|Martin|M|;Pap|Akos F|AF|;Homering|Martin|M|;Bauersachs|Rupert|R|;Beyer-Westendorf|Jan|J|;Bounameaux|Henri|H|;Cohen|Alexander T|AT|;Davidson|Bruce L|BL|;van Bellen|Bonno|B|;Verhamme|Peter|P|;Wells|Philip S|PS|;Yuan|Zhong|Z|;Levitan|Bennett|B|;Weitz|Jeffrey I|JI|", "chemical_list": "D065427:Factor Xa Inhibitors; D010975:Platelet Aggregation Inhibitors; D000069552:Rivaroxaban; D001241:Aspirin", "country": "United States", "delete": false, "doi": "10.1016/j.thromres.2018.06.009", "fulltext": null, "fulltext_license": null, "issn_linking": "0049-3848", "issue": "168()", "journal": "Thrombosis research", "keywords": null, "medline_ta": "Thromb Res", "mesh_terms": "D001241:Aspirin; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D012307:Risk Factors; D000069552:Rivaroxaban; D054556:Venous Thromboembolism", "nlm_unique_id": "0326377", "other_id": null, "pages": "121-129", "pmc": null, "pmid": "30064683", "pubdate": "2018-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin.", "title_normalized": "benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin" }

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{ "abstract": "Drug induced myocardial infarction is a known entity with different forms of steroids linked to coronary artery disease (CAD) either through promoting its traditional risk factors, inducing coronary spasm, or by other unidentified mechanisms. Dexamethasone is known to promote an atherogenic and hypercoagulable state. We report a case of a 75-year-old woman who had ST elevation myocardial infarction (STEMI) associated with dexamethasone use just 4 days following an angiogram showing minor luminal irregularities.", "affiliations": "Internal Medicine Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA.;Cardiology Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA.;Cardiology Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA.;Cardiology Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA.", "authors": "Shokr|Mohamed|M|0000-0002-8227-0463;Rashed|Ahmed|A|;Lata|Kusum|K|;Kondur|Ashok|A|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2016/4970858", "fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2016/4970858Case ReportDexamethasone Associated ST Elevation Myocardial Infarction Four Days after an Unremarkable Coronary Angiogram—Another Reason for Cautious Use of Steroids: A Case Report and Review of the Literature http://orcid.org/0000-0002-8227-0463Shokr Mohamed \n1\n\n*\nRashed Ahmed \n2\nLata Kusum \n2\nKondur Ashok \n2\n1Internal Medicine Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA2Cardiology Department, Detroit Medical Center/Wayne State University, Detroit, MI 48201, USA*Mohamed Shokr: [email protected] Editor: Antonio de Padua Mansur\n\n2016 18 7 2016 2016 49708583 5 2016 20 6 2016 Copyright © 2016 Mohamed Shokr et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug induced myocardial infarction is a known entity with different forms of steroids linked to coronary artery disease (CAD) either through promoting its traditional risk factors, inducing coronary spasm, or by other unidentified mechanisms. Dexamethasone is known to promote an atherogenic and hypercoagulable state. We report a case of a 75-year-old woman who had ST elevation myocardial infarction (STEMI) associated with dexamethasone use just 4 days following an angiogram showing minor luminal irregularities.\n==== Body\n1. Introduction\nST elevation myocardial infarction is a substantial health problem with estimated 30-day mortality between 2.5 and 10% [1]. Nontraditional risk factors play a significant role in more than 50% of CAD cases [2]. More than 150 drugs were reported as possible causes of acute MI. Betamethasone, methylprednisolone, and dexamethasone were among 39 drugs highlighted as prime suspects that can cause acute MI [3]. We report a case of STEMI associated with dexamethasone use 4 days following a coronary angiogram with only minor luminal irregularities.\n\n2. Case Presentation\nOur patient is a 75-year-old African-American woman with a history of diabetes mellitus, hypertension, hyperlipidemia, and four prior cerebrovascular accidents with mild right sided residual weakness and ventral hernia status after surgical repair. She has no prior history of smoking, alcohol use, illicit drug use, or family history of premature coronary artery disease. She initially presented with shortness of breath, rhinorrhea, and cough productive of yellowish sputum and tested positive for influenza A for which she was started on oseltamivir. On her second day of hospitalization she reported mild retrosternal chest pain accompanied with a Troponin I elevation up to 0.3 ng/mL with an unchanged EKG showing right bundle branch block (RBBB) (Figure 1(a)). She received Aspirin, Clopidogrel, and Heparin drip in addition to Diltiazem and Atorvastatin as treatment for a NSTEMI.\n\nOn the following day, she underwent a coronary angiogram revealing only minor luminal irregularities and no significant CAD (Figure 2(a)). Two days later, she underwent nasopharyngolaryngoscopy for progressive dysphonia that showed inflammatory changes of true and false vocal folds, mild granulation changes of the subglottis, and pachydermia. This was deemed secondary to her upper respiratory tract infection and the resulting acute tracheobronchitis. Subsequently, she was started on intramuscular dexamethasone 10 mg Q8 hours.\n\nOne day later, she complained of severe retrosternal chest pain with a blood pressure of 90/65 mmHg, heart rate of 95 bpm, and oxygen saturation of 95% on room air. Cardiovascular exam was unremarkable revealing regular heart rate and normal S1 and S2 with no appreciated murmurs, rubs, or gallop. She had no JVD and clear lungs on auscultation. Distal pulses were well felt without appreciated lower extremity edema. The EKG however showed ST elevation in the anterior leads, V2 to V5 (Figure 1(b)). Bedside echocardiogram revealed a left ventricular ejection fraction (EF) of 30–35% and regional wall motion in the form of apical dyskinesis and severe hypokinesis in the mid to apical anteroseptal, anterior, apical inferior, inferoseptal, and lateral segments. Of note, the pre-MI echocardiogram showed a normal EF with no appreciated regional wall motion abnormalities. The Troponin I level was 0.1 ng/mL (cutoff value of 0.2 ng/mL). She was immediately transferred to the catheterization lab where the angiogram surprisingly revealed a filling defect, likely a thrombus, occluding the midsegment of the LAD (Figure 2(b)). Subsequently, a 2.5 × 18 mm drug eluting stent was deployed with pre- and postballoon dilation resulting in TIMI III flow (Figure 2(c)). Eptifibatide was started in addition to Ticagrelor, Aspirin, Deltiazem, and Atorvastatin. The chest pain resolved shortly after the intervention and the EKG returned to baseline (Figure 1(c)).\n\nBlood work revealed a platelet count of 461 k/cumm, hemoglobin of 10.5 mg/dL, and white blood cell count of 9 k/cumm. Homocysteine level was mildly elevated (15.5 micromoles/L, normal range 3.2–10.7). High sensitivity CRP was elevated at 40.9 mg/L. Factor VIII activity (325%, normal range: 63–150), factor XI activity (211%, normal range: 71–124), and thrombin antithrombin complex (13.7 ng/mL, normal range: 0.7–3.2) were all increased while factor VII activity was normal. Fibrinogen level and protein C and S activity were normal. Cardiolipin antibody, JAK2 V617F mutation, and Factor V Leiden were all negative.\n\n3. Discussion\nBesides impacting traditional risk factors for CAD such as hypertension (HTN), glucose intolerance, obesity, and hyperlipidemia (HLD), glucocorticoids influence vascular functions, atherogenesis, and remodeling following ischemia or intravascular injury. This influence is mediated by both glucocorticoids and mineralocorticoid receptors and is modified by 11b-hydroxysteroid dehydrogenase enzyme local metabolism of glucocorticoids [4].\n\nDexamethasone was shown to promote an atherogenic and hypercoagulable state through different mechanisms. In high doses, it increases Von Willebrand Factor (VWF) which is a prothrombotic marker and increases the platelet activator P-selectin. Moreover, short term use of dexamethasone is associated with increased levels of Fibrinogen, VII, VIII, and XI [5, 6].\n\nIn 2014 Okumura et al. reported 3 cases of steroid induced coronary spasm [7]. This might be explained by the fact that, in a dose dependent manner, cortisol treatment decreases ATP-induced intracellular calcium mobilization, which in turn decreases nitrate, nitrite, and nitric oxide release [8]. Similarly, glucocorticoids downregulate cyclooxygenase-1 gene expression and subsequently suppress the production of the vasodilator prostacyclin; meanwhile they increase the synthesis of thromboxane which is a vasoconstrictor [9]. There is also evidence that elevated serum cortisol levels might sensitize the coronary vasoconstricting responses through Rho-kinase activation [10]. Additionally, it reduces endothelial nitric oxide synthase mRNA stability and inhibits the synthesis of tetrahydrobiopterin, which is an important cofactor of endothelial nitric oxide synthase [11].\n\nInterestingly, Okumura hypothesized that corticosteroid-induced vasospastic angina might be underestimated due to being mistakenly confused with its known side effect of epigastric discomfort. Wei et al. reported that, among patients using high dose glucocorticoids (>7.5 mg/day), the relative risk for cardiovascular events occurrence was 2.56 [12].\n\nIn 2007, Varas-Lorenzo et al. performed a cohort study with nested case-control analysis to estimate the risk of acute myocardial infarction (AMI) associated with the use of oral corticosteroids by dose and duration. The study included 4795 hospitalized cases of AMI or CAD deaths and randomly sampled 20,000 controls and frequency matched by sex, age, and calendar year.\n\nThe adjusted OR for AMI in current users of oral corticosteroids compared to nonusers was 1.42 (95% CI: 1.17–1.72). The risk during the first 30 days of use (OR = 2.24; 95% CI: 1.56–3.20) was greater than with longer duration (OR = 1.22; 95% CI 0.98–1.52). The risk was more pronounced (OR = 2.15; 95% CI 1.45–3.14) among users of prednisolone equivalent doses >10 mg/day. The study concluded that there is a small increased risk of AMI with oral corticosteroid use with a greater risk observed among users of high corticosteroid dose [13].\n\nIn 2013, Coloma et al. identified 163 drugs reported to cause acute MI in various case reports, out of which 39 had a more probable association with MI including betamethasone, prednisolone, and dexamethasone (RR (95% confidence interval) 3.2 (2.9, 3.5), OR 1.9 (1.7, 2.2), and IRR 5.4 (4.1, 7.2)). Of note, 285 excess cases representing patients on dexamethasone who had an AMI however with other more plausible causes were identified [3]. All the previous mechanisms might explain a possible “spasm-thrombosis” sequence that occurred in our patient in the setting of her long standing other risk factors including diabetes mellitus, hypertension, and hyperlipidemia as mentioned. Interestingly, two prior cases reported angiographically normal coronaries in androgen using athletes who ended up having a coronary occlusion [14]. We are including a comparison between six prior cases of AMI associated with steroid use shedding the light on their different clinical scenarios and other preexisting risk factors for coronary artery disease (Table 1).\n\n4. Conclusion\nDifferent forms of steroids have been linked to CAD either through promoting its traditional risk factors or by other unidentified mechanisms. In most reported cases of steroid-associated AMI, the temporal relation was the main factor suggesting causality. We believe that, with the wide use of corticosteroids for a variety of indications, physicians should be aware of this possible association. Cautious use should be considered particularly in patients with other risk factors for CAD until there is a larger and more convincing pool of evidence.\n\nCompeting Interests\nThe authors have no conflict of interests to disclose.\n\nFigure 1 (a) Baseline EKG with RBBB. (b) EKG showing ST elevation in leads V2–V5. (c) EKG showing resolution of the ST elevation following LAD intervention.\n\nFigure 2 (a) First left heart catheterization showing LAD with minor luminal irregularities. (b) Second left heart catheterization (4 days later) showing the mid-LAD lesion. (c) LAD after intervention.\n\nTable 1 Comparison between six other cases of MI associated with steroid use.\n\nCase\tFerenchick and Adelman [14]\tYildirim et al. [15]\tArslan et al.\n[16]\tTakamatsu et al. [17]\tOwecki and Sowiński [18]\tPoorzand et al. [2]\t\nAge (years)\t37\t64\t20\t79\t66\t23\t\n\n\n\t\nRisk factors\tFamily history of CAD\tHLD\tSmoking\n(7 years)\tBortezomib use\tSmoking\nHLD\t \t\n\n\n\t\nGender\tMale\tMale\tMale\tFemale\tFemale\tMale\t\n\n\n\t\nSteroid type\tNandrolone-decanoate,\nBoldenone,\ntestosterone-cypionate,\nStanozolol,\nand veterinary\noxandrolone\tPrednisolone\tMethylprednisolone\tDexamethasone\tMethylprednisolone\tDexamethasone\t\n\n\n\t\nIndication\tAnabolic steroids (weightlifting)\tIdiopathic intracranial HTN\n(papilledema)\tAnaphylaxis\tMultiple\nmyeloma\tGraves\tAnabolic steroids\n(wrestling)\t\n\n\n\t\nRoute\tIntramuscular & oral\tOral\tIntravenous\tIntravenous\tIntravenous\tIntramuscular\t\n\n\n\t\nDose\t200 mg/week for 16 weeks\n1.5 cc q3 days/16 weeks\n1.5 cc q4 days/16 weeks\n1.5 cc q3 days/16 weeks\n50 mg daily for 16 weeks\t40 mg\ndaily\t40 mg\tNA\t1 gm daily\tNA\t\n\n\n\t\nDuration of use\tIntermittent for 7 years\nand then 16 weeks before the event\tOne month\t7 minutes\t5 days\t5 days\t6 months\t\n\n\n\t\nPossible confounders\t \t \tHypotension secondary to anaphylaxis\tBortezomib use\t \t \t\n\n\n\t\nAcute coronary syndrome type\tSTEMI\tNSTEMI and then STEMI few days later\tSTEMI\tSTEMI\tNSTEMI\tSTEMI\t\n\n\n\t\nEKG\tST elevation,\nII, III, and aVF\tST elevation, II, III, and aVF;\nST depression,\nI, aVL\tST elevation,\nI, aVL\tST elevation,\naVR;\nST depression,\nI, II, and aVF\nV2–6\tNA\tST elevation,\nI, aVL\t\n\n\n\t\nEcho\tNormal\tNormal\tEF 35% apical & posterolateral wall motion abnormality\tEF 68%\nposterior &\nanterolateral akinesia\tAnteroseptal akinesia\tEF 35%\napical, midanterior, anteroseptal\nakinesia\t\n\n\n\t\nLeft heart catheterization findings\tNormal coronaries\n(3 days following tissue plasminogen activator)\tRCA: slow flow\nand then PDA total occlusion\n& LAD slow flow\tNormal coronaries 10 days later\n(normal IVUS)\n(treated with Aspirin & Heparin)\tLM/LCX significant lesions LAD mod stenosis\tLAD total occlusion RCA critical stenosis\tNonobstructive CAD (4 days after streptokinase)\t\n\n\n\t\nComplications\t \t \t \t \t \tLV thrombus\n==== Refs\n1 Roe M. T. Messenger J. C. Weintraub W. S. Treatments, trends, and outcomes of acute myocardial infarction and percutaneous coronary intervention Journal of the American College of Cardiology 2010 56 4 254 263 10.1016/j.jacc.2010.05.008 2-s2.0-77955641943 20633817 \n2 Poorzand H. Jafarzadeh Esfehani R. Hosseinzadeh P. Vojdanparast M. Acute myocardial infarction in a young male wrestler: a case report ARYA Atheroscler 2015 11 6 366 369 26862345 \n3 Coloma P. M. Schuemie M. J. Trifirò G. Drug-induced acute myocardial infarction: identifying ‘prime suspects’ from electronic healthcare records-based surveillance system PLoS ONE 2013 8 8, article e72148 10.1371/journal.pone.0072148 2-s2.0-84883144641 \n4 Walker B. R. Glucocorticoids and cardiovascular disease European Journal of Endocrinology 2007 157 5 545 559 10.1530/eje-07-0455 2-s2.0-36549001222 17984234 \n5 Jilma B. Cvitko T. Winter-Fabry A. Petroczi K. Quehenberger P. Blann A. D. High dose dexamethasone increases circulating P-selectin and von Willebrand factor levels in healthy men Thrombosis and Haemostasis 2005 94 4 797 801 10.1160/T04-10-0652 2-s2.0-27144545040 16270633 \n6 Brotman D. J. Girod J. P. Posch A. Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers Thrombosis Research 2006 118 2 247 252 10.1016/j.thromres.2005.06.006 2-s2.0-33744809252 16005496 \n7 Okumura W. Nakajima M. Tateno R. Fukuda N. Kurabayashi M. Three cases of vasospastic angina that developed following the initiation of corticosteroid therapy Internal Medicine 2014 53 3 221 225 10.2169/internalmedicine.53.1008 2-s2.0-84893500177 24492690 \n8 Rogers K. M. Bonar C. A. Estrella J. L. Yang S. Inhibitory effect of glucocorticoid on coronary artery endothelial function American Journal of Physiology—Heart and Circulatory Physiology 2002 283 5 H1922 H1928 10.1152/ajpheart.00364.2002 2-s2.0-0036839107 12384470 \n9 Jun S. S. Chen Z. Pace M. C. Shaul P. W. Glucocorticoids downregulate cyclooxygenase-1 gene expression and prostacyclin synthesis in fetal pulmonary artery endothelium Circulation Research 1999 84 2 193 200 10.1161/01.res.84.2.193 2-s2.0-0033524664 9933251 \n10 Hizume T. Morikawa K. Takaki A. Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm Circulation Research 2006 99 7 767 775 10.1161/01.res.0000244093.69985.2f 2-s2.0-33749336971 16960099 \n11 Wallerath T. Witte K. Schäfer S. C. Down-regulation of the expression of endothelial NO synthase is likely to contribute to glucocorticoid-mediated hypertension Proceedings of the National Academy of Sciences of the United States of America 1999 96 23 13357 13362 10.1073/pnas.96.23.13357 2-s2.0-0033539502 10557325 \n12 Wei L. MacDonald T. M. Walker B. R. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease Annals of Internal Medicine 2004 141 10 764 770 10.7326/0003-4819-141-10-200411160-00007 2-s2.0-19644401171 15545676 \n13 Varas-Lorenzo C. Rodriguez L. A. G. Maguire A. Castellsague J. Perez-Gutthann S. Use of oral corticosteroids and the risk of acute myocardial infarction Atherosclerosis 2007 192 2 376 383 10.1016/j.atherosclerosis.2006.05.019 2-s2.0-34248578281 16787647 \n14 Ferenchick G. S. Adelman S. Myocardial infarction associated with anabolic steroid use in a previously healthy 37-year-old weight lifter American Heart Journal 1992 124 2 507 508 10.1016/0002-8703(92)90620-b 2-s2.0-0026777921 1636596 \n15 Yildirim U. Gulel O. Soylu K. Yuksel S. Sahin M. Steroid-induced recurrent myocardial ischemia Revista Portuguesa de Cardiologia (English Edition) 2014 33 7-8 473.e1 473.e4 10.1016/j.repc.2014.02.016 2-s2.0-84908291487 \n16 Arslan Z. Iyisoy A. Tavlasoglu M. Acute myocardial infarction after prednisolone administration for the treatment of anaphylaxis caused by a wasp sting Cardiovascular Journal of Africa 2013 24 4 e4 e6 10.5830/cvja-2013-013 2-s2.0-84880905597 24217126 \n17 Takamatsu H. Yamashita T. Kotani T. Sawazaki A. Okumura H. Nakao S. Ischemic heart disease associated with bortezomib treatment combined with dexamethasone in a patient with multiple myeloma International Journal of Hematology 2010 91 5 903 906 10.1007/s12185-010-0586-9 2-s2.0-77954539849 20458563 \n18 Owecki M. Sowiński J. Acute myocardial infarction during high-dose methylprednisolone therapy for Graves' ophthalmopathy Pharmacy World and Science 2006 28 2 73 75 10.1007/s11096-006-9013-y 2-s2.0-33749438522 16791713\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6404", "issue": "2016()", "journal": "Case reports in cardiology", "keywords": null, "medline_ta": "Case Rep Cardiol", "mesh_terms": null, "nlm_unique_id": "101576452", "other_id": null, "pages": "4970858", "pmc": null, "pmid": "27504205", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": "16787647;24492690;16270633;12384470;9933251;10557325;24217126;24015213;17984234;1636596;16791713;16960099;26862345;20458563;16005496;20633817;25155001;15545676", "title": "Dexamethasone Associated ST Elevation Myocardial Infarction Four Days after an Unremarkable Coronary Angiogram-Another Reason for Cautious Use of Steroids: A Case Report and Review of the Literature.", "title_normalized": "dexamethasone associated st elevation myocardial infarction four days after an unremarkable coronary angiogram another reason for cautious use of steroids a case report and review of the literature" }

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DEXAMETHASONE ASSOCIATED ST ELEVATION MYOCARDIAL INFARCTION FOUR DAYS AFTER AN UNREMARKABLE CORONARY ANGIOGRAM - ANOTHER REASON FOR CAUTIOUS USE OF STEROIDS: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DEXAMETHASONE ASSOCIATED ST ELEVATION MYOCARDIAL INFARCTION FOUR DAYS AFTER AN UNREMARKABLE CORONARY ANGIOGRAM - ANOTHER REASON FOR CAUTIOUS USE OF STEROIDS: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DEXAMETHASONE ASSOCIATED ST ELEVATION MYOCARDIAL INFARCTION FOUR DAYS AFTER AN UNREMARKABLE CORONARY ANGIOGRAM ANOTHER REASON FOR CAUTIOUS USE OF STEROIDS: A CASE REPORT AND REVIEW OF THE LITERATURE. 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"medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DRIP", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DILTIAZEM." } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20160321" } }, "primarysource": { "literaturereference": "SHOKR M,RASHED A,LATA K,KONDUR A. DEXAMETHASONE ASSOCIATED ST ELEVATION MYOCARDIAL INFARCTION FOUR DAYS AFTER AN UNREMARKABLE CORONARY ANGIOGRAM - ANOTHER REASON FOR CAUTIOUS USE OF STEROIDS: A CASE REPORT AND REVIEW OF THE LITERATURE. CASE REPORTS IN CARDIOLOGY 2016;4970858:.", "literaturereference_normalized": "dexamethasone associated st elevation myocardial infarction four days after an unremarkable coronary angiogram another reason for cautious use of steroids a case report and review of the literature", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160902", "receivedate": "20160902", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12710303, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "BACKGROUND\nA posterior subtenon injection of triamcinolone acetonide is an alternative to intravitreal injection in diabetic macular edema and is known to have fewer vision-threatening complications. Here, we report a case of periocular abscess following posterior subtenon injection of triamcinolone.\n\n\nMETHODS\nA 62-year-old woman who had diabetic macular edema and disc neovascularization underwent a posterior subtenon injection of triamcinolone acetonide and panretinal laser photocoagulation. One month later a periocular abscess was noted in the inferotemporal area adjacent to the scleral wall. Pus was removed by fine-needle aspiration, and microbiologic cultures identified Pseudallescheria boydii. The patient was given systemic and subconjunctival treatment with itraconazole. However, conjunctival infection and anterior chamber inflammation worsened, and another posterior subtenon abscess was found.\n\n\nRESULTS\nDespite long-term systemic and topical itraconazole therapy, retinal detachment and vitreous opacity were shown on B-scan, and atrophic bulbi resulted.\n\n\nCONCLUSIONS\nPseudallescheria boydii infection of the eye and orbit can result in a poor visual outcome. Prompt surgical debridement and drainage of the abscess, along with appropriate antifungal therapy based on susceptibility testing, must be mandatory.", "affiliations": "Department of Ophthalmology, Anam Hospital, Korea University College of Medicine, 26-1 Anam-dong 5-ga, Sungbuk-gu, Seoul, 136-705, South Korea.", "authors": "Oh|In Kyung|IK|;Baek|Sehyun|S|;Huh|Kuhl|K|;Oh|Jaeryung|J|", "chemical_list": "D000935:Antifungal Agents; D005938:Glucocorticoids; D017964:Itraconazole; D014222:Triamcinolone Acetonide", "country": "Germany", "delete": false, "doi": "10.1007/s00417-006-0325-3", "fulltext": null, "fulltext_license": null, "issn_linking": "0721-832X", "issue": "245(1)", "journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie", "keywords": null, "medline_ta": "Graefes Arch Clin Exp Ophthalmol", "mesh_terms": "D000038:Abscess; D000935:Antifungal Agents; D003238:Connective Tissue; D003930:Diabetic Retinopathy; D015821:Eye Infections, Fungal; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007267:Injections; D017964:Itraconazole; D008269:Macular Edema; D008875:Middle Aged; D008271:Mycetoma; D009916:Orbital Diseases; D011541:Pseudallescheria; D014057:Tomography, X-Ray Computed; D014222:Triamcinolone Acetonide", "nlm_unique_id": "8205248", "other_id": null, "pages": "164-6", "pmc": null, "pmid": "16612634", "pubdate": "2007-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "16207168;15078688;15733990;1841583;10364610;9261319;7574531;12352630", "title": "Periocular abscess caused by Pseudallescheria boydii after a posterior subtenon injection of triamcinolone acetonide.", "title_normalized": "periocular abscess caused by pseudallescheria boydii after a posterior subtenon injection of triamcinolone acetonide" }

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PERIOCULAR ABSCESS CAUSED BY PSEUDALLESCHERIA BOYDII AFTER A POSTERIOR SUBTENON INJECTION OF TRIAMCINOLONE ACETONIDE. GRAEFES ARCH CLIN EXP OPHTHALMOL.. 2007?245:164?6", "literaturereference_normalized": "periocular abscess caused by pseudallescheria boydii after a posterior subtenon injection of triamcinolone acetonide", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180306", "receivedate": "20180306", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14601962, "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" }, { "companynumb": "KR-G+W LABS-GW2016KR000128", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "089129", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LOTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MACULAR OEDEMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "089129", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LOTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL NEOVASCULARISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "EYE OINTMENT", "drugdosagetext": "UNK, QHS", "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": "OFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "EYE DROPS", "drugdosagetext": "UNK, QID", "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": "OFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eye abscess", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pseudallescheria infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "IK OH, S BAEK, K HUH. PERIOCULAR ABSCESS CAUSED BY PSEUDALLESCHERIA BOYDII AFTER A POSTERIOR SUBTENON INJECTION OF TRIAMCINOLONE ACETONIDE.. GRAEFE^S ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY. 2007;245(1):164-166", "literaturereference_normalized": "periocular abscess caused by pseudallescheria boydii after a posterior subtenon injection of triamcinolone acetonide", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160922", "receivedate": "20160922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12771893, "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": "OBJECTIVE\nIntra-arterial chemotherapy is a promising strategy for intra-ocular retinoblastoma. Neutropenia is the most commonly encountered systemic toxicity and in this study we aimed to determine the risk factors associated with the development of severe (≥ grade 3) neutropenia.\n\n\nMETHODS\nRetrospective review of 187 evaluable cycles of melphalan-containing intra-arterial chemotherapy from the first three cycles administered to 106 patients with intra-ocular retinoblastoma from May 2006 to June 2011. Cycles were considered to be evaluable if (1) blood count results were available in the 7 to 14 days post-treatment interval and (2) concurrent intravenous chemotherapy was not administered. Toxicity was assessed via the Common Terminology Criteria for Adverse Events version 4.0.\n\n\nRESULTS\n54 cycles (29%) were associated with grade 3 (n = 43) or grade 4 (n = 11) neutropenia. Multivariate stepwise logistic regression revealed that a higher melphalan dose (>0.40 mg/kg) was significantly associated with severe neutropenia during all 3 cycles (odds ratio during cycle one 4.11, 95% confidence interval 1.33-12.73, p = 0.01), but the addition of topotecan and/or carboplatin were not. Prior treatment with systemic chemotherapy was not associated with severe neutropenia risk in any analysis.\n\n\nCONCLUSIONS\nIntra-arterial melphalan-based chemotherapy can cause severe neutropenia, especially when a dose of greater than 0.40 mg/kg is administered. Further study with a larger sample may be warranted.", "affiliations": "Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America; Department of Pediatrics, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America.;Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America.;Department of Neurosurgery, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America.;Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America; Department of Ophthalmology, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America.;Department of Ophthalmology, Mount Sinai Medical Center, New York, NY, United States of America.;Department of Neurosurgery, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America.;Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America; Department of Ophthalmology, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America.", "authors": "Dunkel|Ira J|IJ|;Shi|Weiji|W|;Salvaggio|Kim|K|;Marr|Brian P|BP|;Brodie|Scott E|SE|;Gobin|Y Pierre|YP|;Abramson|David H|DH|", "chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0108692", "fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, USA 25303673PONE-D-14-0594910.1371/journal.pone.0108692Research ArticleMedicine and Health SciencesOncologyCancers and NeoplasmsBlastomasRetinoblastomaOphthalmologic TumorsCancer TreatmentOncology AgentsPediatric OncologyOphthalmologyOcular TumorsPediatric OphthalmologyPediatricsRadiology and ImagingInterventional RadiologyRisk Factors for Severe Neutropenia following Intra-Arterial Chemotherapy for Intra-Ocular Retinoblastoma Risk for Neutropenia Post-IA ChemotherapyDunkel Ira J. \n1\n\n2\n\n*\nShi Weiji \n3\nSalvaggio Kim \n4\nMarr Brian P. \n5\n\n6\nBrodie Scott E. \n7\nGobin Y. Pierre \n4\nAbramson David H. \n5\n\n6\n\n1 \nDepartment of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America\n\n2 \nDepartment of Pediatrics, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America\n\n3 \nDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America\n\n4 \nDepartment of Neurosurgery, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America\n\n5 \nDepartment of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America\n\n6 \nDepartment of Ophthalmology, New York Presbyterian Hospital Weill Cornell Medical College, New York, NY, United States of America\n\n7 \nDepartment of Ophthalmology, Mount Sinai Medical Center, New York, NY, United States of America\nGlod John W. Editor\nNational Cancer Institute, United States of America\n* E-mail: [email protected] Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: IJD BPM SEB YPG DHA. Analyzed the data: IJD WS. Contributed reagents/materials/analysis tools: IJD KS BPM SEB YPG DHA. Wrote the paper: IJD WS KS BPM SEB YPG DHA.\n\n2014 10 10 2014 9 10 e10869211 2 2014 2 9 2014 © 2014 Dunkel et al2014Dunkel et alThis 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 properly credited.Purpose\nIntra-arterial chemotherapy is a promising strategy for intra-ocular retinoblastoma. Neutropenia is the most commonly encountered systemic toxicity and in this study we aimed to determine the risk factors associated with the development of severe (≥grade 3) neutropenia.\n\nMethods\nRetrospective review of 187 evaluable cycles of melphalan-containing intra-arterial chemotherapy from the first three cycles administered to 106 patients with intra-ocular retinoblastoma from May 2006 to June 2011. Cycles were considered to be evaluable if (1) blood count results were available in the 7 to 14 days post-treatment interval and (2) concurrent intravenous chemotherapy was not administered. Toxicity was assessed via the Common Terminology Criteria for Adverse Events version 4.0.\n\nResults\n54 cycles (29%) were associated with grade 3 (n = 43) or grade 4 (n = 11) neutropenia. Multivariate stepwise logistic regression revealed that a higher melphalan dose (>0.40 mg/kg) was significantly associated with severe neutropenia during all 3 cycles (odds ratio during cycle one 4.11, 95% confidence interval 1.33–12.73, p = 0.01), but the addition of topotecan and/or carboplatin were not. Prior treatment with systemic chemotherapy was not associated with severe neutropenia risk in any analysis.\n\nConclusions\nIntra-arterial melphalan-based chemotherapy can cause severe neutropenia, especially when a dose of greater than 0.40 mg/kg is administered. Further study with a larger sample may be warranted.\n\nThis work was supported by Perry's Promise Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Body\nIntroduction\nRetinoblastoma is the most common primary ocular tumor of childhood. In the United States and other socio-economically advantaged parts of the world, the vast majority of patients have intra-ocular disease at diagnosis. During the past 15 to 20 years advanced intra-ocular disease has most often been treated with enucleation, but super selective intra-arterial chemotherapy appears to be a promising option [1]–[2]. It is generally well tolerated, but grade 3 and 4 neutropenia may occur. We performed this analysis to try to determine risk factors associated with the development of severe neutropenia and hypothesized that factors associated with development of grade 3 or 4 neutropenia would be (1) the melphalan dose, (2) administration of topotecan and/or carboplatin in addition to melphalan, and (3) prior treatment with systemic chemotherapy.\n\nMethods\nEthics statement\nThe Memorial Sloan-Kettering Cancer Center's Institutional Review Board/Privacy Board approved this retrospective review of existing data, granting a waiver for this to be done without obtaining consent from the subjects or their parents/legal guardians. All protected health information was handled in accordance with institutional policies that did not require the information to be anonymized and de-identified prior to analysis.\n\nPatients\nWe retrospectively reviewed the first 106 consecutive patients with intra-ocular retinoblastoma treated with intra-arterial chemotherapy at our centers from May 2006 to June 2011.\n\nPatients most frequently were treated with intra-arterial single-agent melphalan, but some cycles also included treatment with intra-arterial topotecan and/or carboplatin (Table 1). The number of agents to be used and the doses of chemotherapy administered were determined on a case by case basis. In general, patients received more than one agent if they had more severe disease or had been extensively pre-treated with intravenous chemotherapy and/or external beam radiation therapy, especially if we were treating the only remaining eye. In cycle 1, the dose was primarily determined by the patient's age. Patients 3 to 6 months of age generally received 2.5 mg of melphalan, 6 to 12 months of age, 3 mg of melphalan, 1 to 3 years of age, 4 mg of melphalan, and ≥3 years of age, 5 mg of melphalan [1]. In subsequent cycles we would consider increasing the dose(s) if the ophthalmic artery had large extra-ocular branches or if an inadequate response had been encountered without significant toxicity. We would consider decreasing the dose(s) if wedge flow was encountered or significant toxicity was encountered, such as an interval decrease in the eye's electroretinogram or an ocular inflammatory reaction. The median topotecan dose administered was 0.4 mg (range 0.2 to 2 mg) and the median carboplatin dose administered was 30 mg (range 25 to 80 mg).\n\n10.1371/journal.pone.0108692.t001Table 1 The number of patients treated per cycle with the various chemotherapy agents and the number of patients evaluable for analysis of neutropenia.\nCycle\tPatient\tM only\tM + T\tM+C\tM+T+C\tInevaluable\tEvaluable\t\n1\t106\t74\t21\t1\t10\t33\t73\t\n2\t100\t67\t25\t1\t7\t36\t64\t\n3\t86\t53\t24\t1\t8\t36\t50\t\n M: melphalan; T: topotecan; C: carboplatin.\n\nWe asked the parents to have a complete blood count performed 7 to 10 days after each dose of intra-arterial chemotherapy. However, many families did not reside in the New York area and returned home after the treatment, and so compliance was variable. Intra-arterial chemotherapy cycles were considered to be evaluable if (1) blood count results were available in the 7 to 14 days post-treatment interval, and (2) concurrent intravenous chemotherapy was not administered. However, if a blood count was not available within the 7 to 14 day post-treatment window, but grade 3 or 4 neutropenia was documented earlier or later in the cycle, the cycle was considered evaluable. Toxicity was assessed via the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.\n\nStatistics\nA binary melphalan dose is of interest in potential prediction. An optimal cut-off point of the dose was selected using Miller and Siegmund's minimum p-value approach and Altman, Lausen, Sauerbrei, and Schumacher's formula to adjust the minimum p-value selected from the systematic dependent multiple testing [3]–[4]. The highest and lowest 10% of the melphalan dose data were eliminated from the selection procedure. A univariate analysis of relationship between treatment factors and severe neutropenia (defined as grade 3 or 4 neutropenia) was performed using Chi-square, or Fisher's exact test. A multivariate analysis of the joint relationship was performed using a stepwise logistical regression method. Variables with p-value ≤0.20 on univariate analysis were candidates for the initial multivariate model. The statistical analysis was performed with the software SAS version 9.2 (SAS Institute Cary, NC) and r package ROCR (version 2.9.2). A p-value<0.05 was considered significant.\n\nAll analyses were based on evaluable cycles only. Grade 3 and 4 neutropenia were combined into the entity of severe neutropenia due to the small number of grade 4 neutropenia events (n = 5, 3, and 3 during cycles 1, 2 and 3, respectively).\n\nResults\nMelphalan dose and analysis of optimal cut-off point\nA preliminary analysis showed that a higher melphalan dose (continuous variable) was significantly associated with severe neutropenia during cycles 2 and cycle 3 (p<0.0001, p<0.0001 by t-test, respectively). The minimum p-value approach showed that 0.50 mg/kg was the best cut-off point during cycle 2 (>0.50 versus ≤50 mg/kg, χ2 = 18.55, adjusted p = 0.0007) and 0.40 mg/kg during cycle 3 (>0.40 versus ≤0.40 mg/kg, χ2 = 26.26, adjusted p<0.0001). Melphalan dose>0.40 mg/kg was also associated with severe neutropenia during cycle 2 (χ2 = 12.34, adjusted p = 0.01).\n\nAnalyses of treatment factors and severe neutropenia\nCycle 1\nA univariate analysis regarding cycle 1 showed that a higher dose of melphalan (>0.40 versus ≤0.40 mg/kg) was significantly associated with severe neutropenia (p = 0.01, Table 2). The univariate analysis also showed that the severe neutropenia rate was significantly different among patients treated with different chemotherapy regimens (melphalan alone versus melphalan and either topotecan or carboplatin versus melphalan, topotecan and carboplatin, p = 0.04). Further pairwise comparison showed that patients treated with three chemotherapy agents more frequently experienced severe neutropenia compared to those treated with two agents (50% versus 9%, p = 0.02). However, a stepwise logistic regression revealed that while higher melphalan dose remained associated with severe neutropenia (odds ratio (OR) 4.11, 95% CI 1.33–12.73, p = 0.01), the number of chemotherapy agents administered did not.\n\n10.1371/journal.pone.0108692.t002Table 2 Cycle 1: Univariate analysis of severe neutropenia.\nVariable\tSevere neutropenia (25%)\tp-value\t\n\tNo (n = 55)\tYes (n = 18)\t\t\nM dose, mg/kg (mean ± SD)\t0.39±0.14\t0.43±0.12\t\t\nMedian (range)\t0.35 (0.15–0.89)\t0.46 (0.27–0.68)\t\t\n≤0.40\t37 (67%)\t6 (33%)\t0.01\t\n>0.40\t18 (33%)\t12 (67%)\t\t\nChemotherapy agents\t\t\t0.04\t\nM only\t30 (55%)\t11 (61%)\t\t\nM+ T/C\t20 (36%)\t2 (11%)\t\t\nM+ T + C\t5 (9%)\t5 (28%)\t\t\nPrior treatmenta\n\t\t\t0.77\t\nNo\t24 (45%)\t7 (41%)\t\t\nYes\t29 (55%)\t10 (59%)\t\t\n M: melphalan; T: topotecan; C: carboplatin.\n\na Data not available for 3 patients (2 had and 1 did not have severe neutropenia).\n\nCycle 2\nA univariate analysis revealed that a higher cycle 2 melphalan dose (>0.50 versus ≤0.50 mg/kg) was significantly associated with severe neutropenia (p<0.0001 by Chi-square test, adjusted p = 0.0007, Table 3). A stepwise logistic regression showed melphalan dose remained associated with severe neutropenia during cycle 2 (p = 0.0005, OR 10.86, 95% CI 2.84–41.57).\n\n10.1371/journal.pone.0108692.t003Table 3 Cycle 2: Univariate analysis of severe neutropeniaa.\nVariable\tSevere neutropenia (30%)\tp-value\t\n\tNo (n = 45)\tYes (n = 19)\t\t\nM dose, mg/kg (mean ± SD)\t0.36±0.12\t0.51±0.13\t\t\nMedian (range)\t0.34 (0.04–0.57)\t0.52 (0.26–0.71)\t\t\n≤0.50\t40 (89)\t7 (37)\t<0.001c\n\t\n>0.50\t5 (11)\t12 (63)\t\t\n≤0.40\t31 (69%)\t4 (21%)\t0.01c\n\t\n>0.40\t14 (31%)\t15 (79%)\t\t\nChemotherapy agents\t\t\t0.26\t\nM only\t22 (49%)\t9 (47%)\t\t\nM+ T/C\t20 (44%)\t6 (32%)\t\t\nM+ T + C\t3 (7%)\t4 (21%)\t\t\nPrior treatmentb\n\t\t\t0.13\t\nNo\t22 (51%)\t5 (29%)\t\t\nYes\t21 (49%)\t12 (71%)\t\t\nCycle 1 grade 3 or 4 neutropenia\t\t\t0.66\t\nNo\t27 (60%)\t9 (47%)\t\t\nNo record\t10 (22%)\t5 (26%)\t\t\nYes\t8 (18%)\t5 (26%)\t\t\n M: melphalan; T: topotecan; C: carboplatin.\n\na Only one variable was associated with severe neutropenia at p≤0.05 on univariate analysis; multivariate analysis was not performed.\n\nb Data not available for 4 patients (2 had and 2 did not have severe neutropenia).\n\nc Cut-off point selection adjusted p-value.\n\nCycle 3\nA univariate analysis demonstrated that a higher cycle 3 melphalan dose (>0.40 versus ≤0.40 mg/kg) was once again significantly associated with severe neutropenia (p<0.0001, adjusted p<0.0001, Table 4). The univariate analysis and further pairwise comparison also showed that patients who had severe neutropenia during cycle 1 or 2 more frequently experienced severe neutropenia during cycle 3 compared to those who did not (yes versus unknown versus no, p = 0.02; yes versus no, p = 0.01). A stepwise multivariate logistic regression analysis revealed that while the higher melphalan dose remained associated with severe neutropenia (p = 0.0001, OR 72.0, 95% CI 7.93–653.4), severe neutropenia during cycle 1 or 2 did not.\n\n10.1371/journal.pone.0108692.t004Table 4 Cycle 3: Univariate analysis of severe neutropenia.\nVariable\tSevere neutropenia (34%)\tp-value\t\n\tNo (n = 33)\tYes (n = 17)\t\t\nM dose, mg/kg (mean ± SD)\t0.34±0.11\t0.50±0.08\t\t\nMedian (range)\t0.33 (0.13–0.70)\t0.50 (0.33–0.69)\t\t\n≤0.40\t27 (82%)\t1 (6%)\t<0.001b\n\t\n>0.40\t6 (18%)\t16 (94%)\t\t\nChemotherapy agents\t\t\t0.15\t\nM only\t13 (39%)\t4 (24%)\t\t\nM+ T/C\t17 (52%)\t8 (47%)\t\t\nM+ T + C\t3 (9%)\t5 (29%)\t\t\nPrior treatmenta\n\t\t\t0.83\t\nNo\t16 (50%)\t7 (47%)\t\t\nYes\t16 (50%)\t8 (53%)\t\t\nCycle 1 or 2, grade 3 or 4 neutropenia\t\t\t0.02\t\nNo\t14 (42%)\t3 (18%)\t\t\nNo record\t11 (33%)\t3 (18%)\t\t\nYes\t8 (24%)\t11 (65%)\t\t\n M: melphalan; T: topotecan; C: carboplatin.\n\na Data not available for 3 patients (1 had and 2 did not have severe neutropenia).\n\nb Cut-off point selection adjusted p-value.\n\nImpact of inevaluable cycles\nA greater proportion of later cycles were inevaluable (31%, 36%, and 42% in cycles 1, 2, and 3, respectively) and that could introduce bias on generalization. However, there was no significant difference in melphalan dose (continuous or binary>0.40 versus ≤0.40 mg/kg), chemotherapy regimen, prior treatment, and severe neutropenia during cycle 1, 2 or 3 between the patients who had or had no record (at cycle 1, 2, or 3, p = 0.11 to 0.95), except that patients with record received a higher mean melphalan dose during cycle 1 (0.40±0.14 versus 0.34±0.14, p = 0.04). In addition, patients with record received a higher binary melphalan dose (>0.50 versus ≤0.50 mg/kg) during cycle 2 (27% versus vs 8%, p = 0.03).\n\nClinical consequences of severe neutropenia\nMost patients who developed severe neutropenia were asymptomatic. Two patients were admitted to the hospital during three periods of severe neutropenia due to fever and/or mucositis. Both patients made complete recoveries.\n\nOther severe hematological toxicities\nSevere (grade 3 or 4) anemia or thrombocytopenia were encountered infrequently. Five patients suffered 1 episode each (5 episodes total) of grade 3 anemia and 2 patients suffered 1 episode each (2 episodes total) of grade 4 thrombocytopenia.\n\nDiscussion\nIntra-arterial chemotherapy was first introduced into the treatment regimen for patients with intra-ocular retinoblastoma by Reese and colleagues in 1955 when they administered triethylenemelamine via the internal carotid artery [2]. It then fell out of favor due to toxicity concerns (that included death) and lack of clear benefit over other treatments until 1987 when Kaneko and colleagues began to administer selective ophthalmic arterial injection of melphalan using a balloon catheter. Their group recently reported a retrospective series of 343 patients (408 eyes) treated with 1452 procedures from 1988 to 2007 [5]. They generally used single-agent melphalan at a dose of 5 to 7.5 mg/m2 and did not encounter any> grade 1 decrease of white blood cells. Using a 30∶1 conversion factor, these doses are approximately 0.17 to 0.25 mg/kg of melphalan.\n\nIn the patients reported in this series, we used a higher dose of melphalan (median dose of evaluable cycles 0.36 mg/kg, range 0.04 to 0.89 mg/kg) and have encountered severe neutropenia in 29% of the cycles. Fortunately, most of the episodes of severe neutropenia were grade 3 (n = 43) rather than grade 4 (n = 11) and were generally clinically insignificant. We counseled the parents about the risk of fever and neutropenia, but did not routinely prescribe filgrastim. We did not encounter any severe neutropenia during cycles in which the melphalan dose was ≤0.25 mg/kg (the approximate dose used in Japan). A limitation is that we may have overestimated the risk of neutropenia due to our decision to consider cycles with blood counts performed outside of the 7 to 14 day window without neutropenia to be inevaluable, but to consider cycles evaluable if grade 3 or 4 neutropenia was documented earlier or later in the cycle. We felt that potentially overestimating rather than underestimating the risk of neutropenia associated with the intra-arterial chemotherapy was the more conservative approach.\n\nWe hypothesized that (1) adding topotecan and/or carboplatin to the melphalan regimen and (2) a history of prior patient exposure to intravenous chemotherapy might be associated with increased risk for severe neutropenia, but that turned out not to be the case. The only factor that remained significant in analyses was melphalan dose, particularly when a dose of greater than 0.40 mg/kg was administered. Due to the relatively small number of events and sample size, we may not have enough power to detect some difference. We were also unable to select an optimal cut-off point of melphalan dose in a multivariate setting. Further study with a larger sample size may be warranted. This increased risk of neutropenia associated with a melphalan dose of greater than 0.40 mg/kg is comparable to the results in a small series reported by Argentine investigators. They noted that children receiving more than 0.48 mg/kg for bilateral tandem infusions had a significantly higher systemic area under the curve and a 50% probability of grade 3 or 4 neutropenia [6].\n\nThese data may help assist in the selection of safe intra-arterial chemotherapy doses for patients with intra-ocular retinoblastoma, but it is important to note that most patients who developed severe neutropenia were asymptomatic and did not require hospital admission for fever and neutropenia or an infection. To minimize the risk of severe neutropenia patients should be treated with a melphalan dose of 0.40 mg/kg or less, but should higher doses be required to adequately treat the retinoblastoma and cure the eye, the risk of severe neutropenia may be acceptable.\n\nA preliminary version of this work was presented at the 2009 International Congress of Ocular Oncology meeting in Cambridge, UK.\n==== Refs\nReferences\n1 \nGobin YP , Dunkel IJ , Marr BP , Brodie SE , Abramson DH (2011 ) Intra-arterial chemotherapy in the management of retinoblastoma: Four-year experience . Arch Ophthalmol \n129 : 732 –737 .21320950 \n2 \nReese AB , Hyman GA , Merriam GR Jr, Forrest AW , Kligerman MM (1954 ) Treatment of retinoblastoma by radiation and triethylenemelamine . AMA Arch Ophthalmol \n53 : 505 –513 .14360881 \n3 \nMiller R , Siegmund D (1982 ) Maximally selected chi square statistics . Biometrics \n38 : 1011 –1016 .\n4 \nAltman DG , Lausen B , Sauerbrei W , Schumacher M (1994 ) Dangers of using “optimal” cutpoints in the evaluation of prognostic factors . J Natl Cancer Inst \n86 : 829 –835 .8182763 \n5 \nSuzuki S , Yamane T , Mohri M , Kaneko A (2011 ) Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: The long term prognosis . Ophthalmology \n118 : 2081 –2087 .21715012 \n6 \nSchaiquevich P , Buitrago E , Taich P , Torbidoni A , Ceciliano A , et al (2012 ) Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients . Invest Ophthalmol Vis Sci \n53 : 4205 –4212 .22628208\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "9(10)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D008558:Melphalan; D009503:Neutropenia; D009504:Neutrophils; D012160:Retina; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies; D012307:Risk Factors", "nlm_unique_id": "101285081", "other_id": null, "pages": "e108692", "pmc": null, "pmid": "25303673", "pubdate": "2014", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "8182763;21715012;14360881;21320950;22628208", "title": "Risk factors for severe neutropenia following intra-arterial chemotherapy for intra-ocular retinoblastoma.", "title_normalized": "risk factors for severe neutropenia following intra arterial chemotherapy for intra ocular retinoblastoma" }

[ { "companynumb": "US-GLAXOSMITHKLINE-US2014GSK012727", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "014691", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPOTECAN\\TOPOTECAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPOTECAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUNKEL I, SHI W, SALVAGGIO K, MARR B, BRODIE S. RISK FACTORS FOR SEVERE NEUTROPENIA FOLLOWING INTRA-ARTERIAL CHEMOTHERAPY FOR INTRA-OCULAR RETINOBLASTOMA.. PLOS ONE. 2014;10", "literaturereference_normalized": "risk factors for severe neutropenia following intra arterial chemotherapy for intra ocular retinoblastoma", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141027", "receivedate": "20141027", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10544587, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]

{ "abstract": "We report a case of necrotizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia complicated by a bronchopleural fistula and treated by decortication and salvage lobectomy. Owing to the unknown characteristics of the underlying SARS-CoV-2 infection, treatment of the abscess and bronchopleural fistula was delayed. This may have resulted in further deterioration of the patient, with ensuing multiple organ dysfunction. Complications of SARS-CoV-2 pneumonia, such as a bacterial abscess and a bronchopleural fistula, should be treated as if the patient were not infected with SARS-CoV-2.", "affiliations": "Department of Thoracovascular Surgery, Ziekenhuis Oost-Limburg, Genk, Belgium. Electronic address: [email protected].;Department of Anesthesiology, Ziekenhuis Oost-Limburg, Genk, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium.;Department of Anesthesiology, Ziekenhuis Oost-Limburg, Genk, Belgium.;Department of Pathology, Ziekenhuis Oost-Limburg, Genk, Belgium.;Department of Thoracovascular Surgery, Ziekenhuis Oost-Limburg, Genk, Belgium.;Department of Thoracovascular Surgery, Ziekenhuis Oost-Limburg, Genk, Belgium.", "authors": "Peeters|Karen|K|;Mesotten|Dieter|D|;Willaert|Xavier|X|;Deraedt|Karen|K|;Nauwelaers|Sigi|S|;Lauwers|Geert|G|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.athoracsur.2020.10.038", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-4975", "issue": "111(4)", "journal": "The Annals of thoracic surgery", "keywords": null, "medline_ta": "Ann Thorac Surg", "mesh_terms": "D000328:Adult; D001983:Bronchial Fistula; D000086382:COVID-19; D005260:Female; D006801:Humans; D008168:Lung; D010995:Pleural Diseases; D011013:Pneumonectomy; D011024:Pneumonia, Viral; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "15030100R", "other_id": null, "pages": "e241-e243", "pmc": null, "pmid": "33279555", "pubdate": "2021-04", "publication_types": "D002363:Case Reports", "references": null, "title": "Salvage Lobectomy to Treat Necrotizing SARS-CoV-2 Pneumonia Complicated by a Bronchopleural Fistula.", "title_normalized": "salvage lobectomy to treat necrotizing sars cov 2 pneumonia complicated by a bronchopleural fistula" }

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SALVAGE LOBECTOMY TO TREAT NECROTIZING SARS?COV?2 PNEUMONIA COMPLICATED BY A BRONCHOPLEURAL FISTULA. 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"medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PEETERS K, MESOTTEN D, WILLAERT X, DERAEDT K, NAUWELAERS S, LAUWERS G. SALVAGE LOBECTOMY TO TREAT NECROTIZING SARS?COV?2 PNEUMONIA COMPLICATED BY A BRONCHOPLEURAL FISTULA. ANN THORAC SURG. 2021?111(4):E241?E243", "literaturereference_normalized": "salvage lobectomy to treat necrotizing sars cov 2 pneumonia complicated by a bronchopleural fistula", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20210423", "receivedate": "20210423", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19172323, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "OBJECTIVE\nAcute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment.\n\n\nMETHODS\nA 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250 mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10 U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76 L/min/m2). She developed acute renal failure, ischaemic hepatitis and disseminated intravascular coagulopathy. Inotropes and high-dose insulin were weaned over four days with complete recovery. Metoprolol was quantified with liquid chromatography-tandem mass spectrometry and concentration-time data were analysed using MONOLIX® vs 4.3 ( www.lixoft.com ). Admission metoprolol concentration was 2.39 μg/mL (therapeutic reference range: 0.035-0.5 μg/mL). Data best fitted a one compartmental model with Michaelis-Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4 L, maximum rate [Vm], 9.57 mg h-1, Michaelis constant [Km], 1.97 mg L-1. Predicted elimination half-life decreased from 20 h over time until there was first order elimination with a half-life 9 h.\n\n\nCONCLUSIONS\nThe time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes.", "affiliations": "a Clinical Toxicology Research Group , University of Newcastle , New South Wales , Australia.;b Department of Intensive Care , John Fawkner Private Hospital , Victoria , Australia.;b Department of Intensive Care , John Fawkner Private Hospital , Victoria , Australia.;a Clinical Toxicology Research Group , University of Newcastle , New South Wales , Australia.;c Department of Pharmaceutical Chemistry , Helwan University , Helwan , Egypt.;d Therapeutics Research Centre, School of Medicine , University of Queensland , Brisbane , Australia.", "authors": "Isbister|Geoffrey K|GK|;Ang|Karyn|K|;Gorman|Kieron|K|;Cooper|Joyce|J|;Mostafa|Ahmed|A|;Roberts|Michael S|MS|", "chemical_list": "D058672:Adrenergic beta-2 Receptor Antagonists; D007328:Insulin; D014662:Vasoconstrictor Agents; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol", "country": "England", "delete": false, "doi": "10.1080/15563650.2016.1209768", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-3650", "issue": "54(9)", "journal": "Clinical toxicology (Philadelphia, Pa.)", "keywords": "Beta-blocker; Michaelis–Menten; high-dose insulin therapy; pharmacokinetics; toxicity", "medline_ta": "Clin Toxicol (Phila)", "mesh_terms": "D058672:Adrenergic beta-2 Receptor Antagonists; D000369:Aged, 80 and over; D002853:Chromatography, Liquid; D019389:Cytochrome P-450 CYP2D6; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007022:Hypotension; D007328:Insulin; D008790:Metoprolol; D012770:Shock, Cardiogenic; D053719:Tandem Mass Spectrometry; D014662:Vasoconstrictor Agents", "nlm_unique_id": "101241654", "other_id": null, "pages": "881-885", "pmc": null, "pmid": "27442605", "pubdate": "2016-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Zero-order metoprolol pharmacokinetics after therapeutic doses: severe toxicity and cardiogenic shock.", "title_normalized": "zero order metoprolol pharmacokinetics after therapeutic doses severe toxicity and cardiogenic shock" }

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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALBUTAMOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ISBISTER GK, ANG K, GORMAN K, COOPER J, MOSTAFA A, ROBERTS MS. ZERO-ORDER METOPROLOL PHARMACOKINETICS AFTER THERAPEUTIC DOSES: SEVERE TOXICITY AND CARDIOGENIC SHOCK. CLIN-TOXICOL-(PHILA) 2016;54(9):881-885.", "literaturereference_normalized": "zero order metoprolol pharmacokinetics after therapeutic doses severe toxicity and cardiogenic shock", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20161121", "receivedate": "20161121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12962118, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "AU-ALEMBIC PHARMACUETICALS LIMITED-2016SCAL000908", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL TARTRATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202871", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG MORNING, 50 MG MID DAY, AND 100 MG AT NIGHT", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL TARTRATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", 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} ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ischaemic hepatitis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiac function test abnormal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lethargy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Malaise", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ISBISTER G K, ANG K, GORMAN K, COOPER J, MOSTAFA A, ROBERTS M S. ZERO-ORDER METOPROLOL PHARMACOKINETICS AFTER THERAPEUTIC DOSES: SEVERE TOXICITY AND CARDIOGENIC SHOCK. 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"reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cyanosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cyanosis central", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ISBISTER GK, ANG K, GORMAN K, COOPER J, MOSTAFA A, ROBERTS MS. ZERO-ORDER METOPROLOL PHARMACOKINETICS AFTER THERAPEUTIC DOSES: SEVERE TOXICITY AND CARDIOGENIC SHOCK. 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ZERO-ORDER METOPROLOL PHARMACOKINETICS AFTER THERAPEUTIC DOSES: SEVERE TOXICITY AND CARDIOGENIC SHOCK. 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{ "abstract": "The lack of a randomized trial comparing carfilzomib (K) versus elotuzumab (Elo) associated with lenalidomide and dexamethasone (Rd) prompted us to assess the relative usefulness of one triplet over the other. Five independent retrospective cohorts of 883 relapsed/refractory multiple myeloma (RRMM) patients, including 300 EloRd and 583 KRd cases, outside clinical trials, entered this non-randomized comparison. KRd cohort accounted for a higher incidence of younger patients, cases with ≥3 lines of therapy, already exposed to lenalidomide, International Staging System (ISS) stage III, and abnormal lactic dehydrogenase (LDH) level compared with EloRd cohort. Moreover, cytogenetic risk categories, detected in roughly one-third of cases, were equally distributed between the two therapy arms. The probability of CR+VGPR response was significantly higher in KRd (n = 314, 53.9%) than in EloRd patients (n = 111, 37.0%). Likewise, the cumulative incidence function of CR+VGPR, taking into account the competitive risk of death, was significantly higher in KRd arm patients than those in the EloRd arm (p = .003). Moreover, KRd treatment significantly reduced the progression or death risk by 46% in an adjusted multivariate analysis (HR: 0.54, 95% CI 0.42-0.69, p < .0001). Finally, in an adjusted illness-progression/death model, the effect of KRd versus EloRd was of higher magnitude among those who achieved CR+VGPR (-39% hazard ratio reduction, p = .02) than among those who achieved < VGPR (-29% hazard ratio reduction, p = .007). With limitations characteristic to any retrospective analysis, this current clinical practice study's overall results demonstrated potential benefits of KRd therapy compared with EloRd. This observation may help the daily clinical practice.", "affiliations": "Biothecnology Research Unit, AO of Cosenza, Cosenza, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, Catania, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Tricase (LE), Italy.;Hematology Unit, Ospedale Cardarelli, Napoli, Italy.;Division of Hematology, University of Torino, AOU Città della Salute e della Scienza di Torino, Torino, Italy.;Hematology and Bone Marrow Transplant Unit, Azienda Socio-Sanitaria Territoriale-Papa Giovanni XXIII, Bergamo, Italy.;Hematology Division, Department of Hematology-Oncology, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.;Department of Hematology, Businco Hospital, Cagliari, Italy.;Istituto di Ematologia, Università Cattolica, Fondazione Policlinico Gemelli IRCCS, Roma, Italy.;Department of Biomedical Science, University of Bari \"Aldo Moro\" Medical School, Internal Medicine \"G. Baccelli\", Policlinico, Bari, Italy.;AUOP \"Federico II\", Naples, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;Department of Hematology, Hospital Perrino, Brindisi, Italy.;Hematology Unit, Department of Hemato-Oncology and Radiotherapy, Great Metropolitan Hospital \"Bianchi-Melacrino-Morelli\", Reggio Calabria, Italy.;Hematology Unit AO of Cosenza, Cosenza, Italy.;Hematology Unit AO of Cosenza, Cosenza, Italy.;Hematology Unit AO of Cosenza, Cosenza, Italy.;Hematology Unit AO of Cosenza, Cosenza, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Tricase (LE), Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, Catania, Italy.;Department of Hematology and Bone Marrow Transplant, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;Institute of Haematology and Stem Cell transplantation, Ospedale Santa Maria della Misericordia, University of Perugia, Perugia, Italy.;Nephrology Center of National Research Institute of Biomedicine and Molecular Immunology, Reggio Calabria, Italy.;UOC Ematologia a Indirizzo Oncologico, AORN \"Sant'Anna e San Sebastiano\", Caserta, Italy.;Department of Hematology and Bone Marrow Transplant, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;U.O.C. Ematologia A. O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Department of Hematology, Hospital Vito Fazzi, Lecce, Italy.;UOC Ematologia a Indirizzo Oncologico, AORN \"Sant'Anna e San Sebastiano\", Caserta, Italy.;Onco-Hematology, \"Tortora\" Hospital, Pagani, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;Hematology Section, University of Bari, Italy.;Istituto di Ematologia, Università Cattolica, Fondazione Policlinico Gemelli IRCCS, Roma, Italy.;U.O.C. OncoEmatologia e TMO, Dipartimento Oncologico, La Maddalena, Palermo, Italy.;Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.;Hematology Unit, AOU Ospedali Riuniti di Ancona, Ancona, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.;Department of Hematology, Hospital Vito Fazzi, Lecce, Italy.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, Catania, Italy.;Division of Hematology, University of Torino, AOU Città della Salute e della Scienza di Torino, Torino, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.;Hematology Unit AO of Cosenza, Cosenza, Italy.", "authors": "Morabito|Fortunato|F|https://orcid.org/0000-0002-2585-7073;Zamagni|Elena|E|;Conticello|Concetta|C|;Pavone|Vincenzo|V|;Palmieri|Salvatore|S|;Bringhen|Sara|S|;Galli|Monica|M|;Mangiacavalli|Silvia|S|;Derudas|Daniele|D|;Rossi|Elena|E|;Ria|Roberto|R|;Catalano|Lucio|L|;Tacchetti|Paola|P|;Mele|Giuseppe|G|;Donatella Vincelli|Iolanda|I|;Antonia Martino|Enrica|E|;Vigna|Ernesto|E|;Botta|Cirino|C|https://orcid.org/0000-0002-1522-4504;Bruzzese|Antonella|A|;Mele|Anna|A|;Pantani|Lucia|L|;Rocchi|Serena|S|;Garibaldi|Bruno|B|;Cascavilla|Nicola|N|;Ballanti|Stelvio|S|;Tripepi|Giovanni|G|;Frigeri|Ferdinando|F|;Pia Falcone|Antonetta|A|;Cangialosi|Clotilde|C|;Reddiconto|Giovanni|G|;Farina|Giuliana|G|;Barone|Marialucia|M|;Rizzello|Ilaria|I|;Musto|Pellegrino|P|;De Stefano|Valerio|V|;Musso|Maurizio|M|;Teresa Petrucci|Maria|M|;Offidani|Massimo|M|;Neri|Antonino|A|;Di Renzo|Nicola|N|;Di Raimondo|Francesco|F|;Boccadoro|Mario|M|;Cavo|Michele|M|;Gentile|Massimo|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/ejh.13723", "fulltext": null, "fulltext_license": null, "issn_linking": "0902-4441", "issue": null, "journal": "European journal of haematology", "keywords": "carfilzomib; dexamethasone; elotuzumab; lenalidomide; multiple myeloma; salvage therapy", "medline_ta": "Eur J Haematol", "mesh_terms": null, "nlm_unique_id": "8703985", "other_id": null, "pages": null, "pmc": null, "pmid": "34716957", "pubdate": "2021-10-30", "publication_types": "D016428:Journal Article", "references": null, "title": "Adjusted comparison between elotuzumab and carfilzomib in combination with lenalidomide and dexamethasone as salvage therapy for multiple myeloma patients.", "title_normalized": "adjusted comparison between elotuzumab and carfilzomib in combination with lenalidomide and dexamethasone as salvage therapy for multiple myeloma patients" }

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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ELOTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM/KILOGRAM ON DAYS 1,8, 15, AND 22 DURING THE FIRST TWO CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELOTUZUMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": null, "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": "DIPHENHYDRAMINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RANITIDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM", "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": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANITIDINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": null, "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": "ACETAMINOPHEN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Morabito F. Adjusted comparison between elotuzumab and carfilzomib in combination with lenalidomide and dexamethasone as salvage therapy for multiple myeloma patients. European journal of haematology. 2021", "literaturereference_normalized": "adjusted comparison between elotuzumab and carfilzomib in combination with lenalidomide and dexamethasone as salvage therapy for multiple myeloma patients", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20211110", "receivedate": "20211110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20052065, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "Necrobiosis lipoidica (NL) is a rare granulomatous disease of unknown etiology. Multiple therapies may be used with varying efficacy. We report a pediatric patient with a history of type I diabetes mellitus and NL with minimal response to an ultrapotent topical steroid, topical calcineurin inhibitor, and intralesional triamcinolone, complicated by steroid atrophy, who rapidly responded after addition of doxycycline.", "affiliations": "Baylor College of Medicine, Houston, TX, USA.;Department of Dermatology, Baylor College of Medicine, Houston, TX, USA.;Department of Dermatology, Baylor College of Medicine, Houston, TX, USA.", "authors": "Burns|Emily|E|https://orcid.org/0000-0002-9532-5339;Ukoha|Uzoamaka|U|;Chan|Audrey|A|", "chemical_list": "D065095:Calcineurin Inhibitors; D014221:Triamcinolone; D004318:Doxycycline", "country": "United States", "delete": false, "doi": "10.1111/pde.14295", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-8046", "issue": "37(5)", "journal": "Pediatric dermatology", "keywords": "doxycycline; necrobiosis lipoidica", "medline_ta": "Pediatr Dermatol", "mesh_terms": "D065095:Calcineurin Inhibitors; D002648:Child; D003922:Diabetes Mellitus, Type 1; D004318:Doxycycline; D006801:Humans; D009335:Necrobiosis Lipoidica; D014221:Triamcinolone", "nlm_unique_id": "8406799", "other_id": null, "pages": "981-982", "pmc": null, "pmid": "32681529", "pubdate": "2020-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Necrobiosis lipoidica with rapid response to doxycycline.", "title_normalized": "necrobiosis lipoidica with rapid response to doxycycline" }

[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-062160", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "012041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "7.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROBIOSIS LIPOIDICA DIABETICORUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "012041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OINTMENT", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROBIOSIS LIPOIDICA DIABETICORUM", "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": "3", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "012041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "15 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOBETASOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OINTMENT", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROBIOSIS LIPOIDICA DIABETICORUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBETASOL" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "012041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "30 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin atrophy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BURNS E, UKOHA U, CHAN A. NECROBIOSIS LIPOIDICA WITH RAPID RESPONSE TO DOXYCYCLINE. PEDIATRIC DERMATOLOGY. 2020", "literaturereference_normalized": "necrobiosis lipoidica with rapid response to doxycycline", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200820", "receivedate": "20200806", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18117543, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]

{ "abstract": "Asthma is a highly prevalent chronic respiratory disease\naffecting millions of people worldwide. Short-acting\nbeta 2-agonists induce bronchodilation and usually are\nprescribed as a rescue medication. They are recognized\nas a cause of hyperlactatemia and, less frequently,\nlactic acidosis. Short-acting beta 2-agonists are also\nknown for their potentially adverse cardiovascular\neffects, such as atrial fibrillation. Differential diagnosis\nand subsequent treatment of the latter entity are\nimportant due to the adverse prognosis related to it. In\nthis case report, we describe the unusual association\nbetween albuterol-induced lactic acidosis and atrial\nfibrillation in a patient with an asthma exacerbation.", "affiliations": null, "authors": "Reyes-Mondragon|Alan|A|;Delgado-García|Guillermo|G|;Pacheco-Cantú|Adán|A|;Contreras-Garza|Nancy|N|;Galarza-Delgado|Dionicio Ángel|DÁ|;González-Aguirre|Julio|J|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D001993:Bronchodilator Agents; D014700:Verapamil; D000420:Albuterol", "country": "Romania", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "2067-2993", "issue": "65(3)", "journal": "Pneumologia (Bucharest, Romania)", "keywords": null, "medline_ta": "Pneumologia", "mesh_terms": "D000140:Acidosis, Lactic; D000420:Albuterol; D000889:Anti-Arrhythmia Agents; D001249:Asthma; D001281:Atrial Fibrillation; D001993:Bronchodilator Agents; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014700:Verapamil", "nlm_unique_id": "100941067", "other_id": null, "pages": "150-1", "pmc": null, "pmid": "29542893", "pubdate": "2016", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Atrial fibrillation in an asthmatic patient with albuterol-induced lactic acidosis.", "title_normalized": "atrial fibrillation in an asthmatic patient with albuterol induced lactic acidosis" }

[ { "companynumb": "MX-BAUSCH-BL-2018-013792", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL SULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75358", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PATIENT RECEIVED FIVE DOSES OF NEBULIZED ALBUTEROL THROUGH A MOUTHPIECE (TOTAL DOSE OF 32.5 MG)", "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": "ALBUTEROL SULFATE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75835", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NEBULIZED IPRATROPIUM BROMIDE (0.5 MG EVERY 4 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "4", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75835", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THREE OR FOUR PUFFS OF IPRATROPIUM BROMIDE PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL SULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75358", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THREE OR FOUR PUFFS OF ALBUTEROL SULFATE PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALBUTEROL SULFATE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75835", "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "REYES-MONDRAGON A, DELGADO-GARCIA G, PACHECO-CANTU A, CONTRERAS-GARZA N, GALARZA-DELGADO D, GONZALEZ-AGUIRRE J. ATRIAL FIBRILLATION IN AN ASTHMATIC PATIENT WITH ALBUTEROL-INDUCED LACTIC ACIDOSIS. ARTICLE IN PNEUMOLOGIA. 2016 OCT?65 (3):150-151.", "literaturereference_normalized": "atrial fibrillation in an asthmatic patient with albuterol induced lactic acidosis", "qualification": "3", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180518", "receivedate": "20180518", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14915404, "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": "MX-MYLANLABS-2018M1030448", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL\\IPRATROPIUM BROMIDE" }, "drugadditional": "1", "drugadministrationroute": "055", "drugauthorizationnumb": "020950", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "IPRATROPIUM BROMIDE/SALBUTAMOL SULFATE: 0.5MG/32.5MG; 3-4 PUFFS PER DAY, THROUGH A MOUTH PIECE; F...", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM/SALBUTAMOL" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "REYES-MONDRAGON A, DELGADO-GARCIA G, PACHECO-CANTU A, CONTRERAS-GARZA N, GALARZA-DELGADO DA, GONZALEZ-AGUIRRE J. ATRIAL FIBRILLATION IN AN ASTHMATIC PATIENT WITH ALBUTEROL-INDUCED LACTIC ACIDOSIS. PNEUMOLOGIA 2016?65(3):150-1.", "literaturereference_normalized": "atrial fibrillation in an asthmatic patient with albuterol induced lactic acidosis", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180509", "receivedate": "20180509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14870666, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "MX-VISTAPHARM, INC.-VER201804-000618", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "077788", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALBUTEROL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "077788", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FIVE DOSES OF NEBULIZED ALBUTEROL THROUGH A MOUTHPIECE (TOTAL DOSE OF 32.5 MG)", "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": "ALBUTEROL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IPRATROPIUM BROMIDE" }, "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM BROMIDE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DELGADO-GARCIA G,REYES-MONDRAGON A,PACHECO-CANTU A,CONTRERAS-GARZA N,GALARZA-DELGADO D,GONZALEZ-AGUIRRE J. ATRIAL FIBRILLATION IN AN ASTHMATIC PATIENT WITH ALBUTEROL-INDUCED LACTIC ACIDOSIS. PNEUMOLOGIA 2016?65(3):150-1.", "literaturereference_normalized": "atrial fibrillation in an asthmatic patient with albuterol induced lactic acidosis", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180503", "receivedate": "20180503", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14840372, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "MX-TEVA-2018-MX-891926", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL\\IPRATROPIUM" }, "drugadditional": "1", "drugadministrationroute": "055", "drugauthorizationnumb": "76724", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "IPRATROPIUM BROMIDE/SALBUTAMOL SULFATE: 0.5MG/32.5MG; 3-4 PUFFS PER DAY, THROUGH A MOUTH PIECE; F...", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALBUTAMOL W/IPRATROPIUM" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "REYES-MONDRAGON A, DELGADO-GARCIA G, PACHECO-CANTU A, CONTRERAS-GARZA N, GALARZA-DELGADO DA, GONZALEZ-AGUIRRE J. ATRIAL FIBRILLATION IN AN ASTHMATIC PATIENT WITH ALBUTEROL-INDUCED LACTIC ACIDOSIS. PNEUMOLOGIA 2016?65(3):150-1.", "literaturereference_normalized": "atrial fibrillation in an asthmatic patient with albuterol induced lactic acidosis", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180609", "receivedate": "20180522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14921962, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" } ]

{ "abstract": "OBJECTIVE\nThe present study was designed to determine the toxicity and maximum tolerated doses of oral intermittent oral capecitabine and subcutaneous (s.c.) rHuIFNalpha2a in patients with metastatic renal cell carcinoma (RCC). The pharmacokinetics of capecitabine and its metabolites were also investigated.\n\n\nMETHODS\nA total of 27 patients were treated at four dose levels of capecitabine (825 or 1000 mg/m2 twice daily orally, days 1-14, 22-36) and rHuIFNalpha2a (1.5 or 3.0 MU/m2 s.c. three times weekly). Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chroatography/mass spectrometry in ten patients.\n\n\nRESULTS\nThe toxicity of combined capecitabine and rHuIFNalpha2a was moderate. Patients experienced mild nausea/vomiting (70%) and diarrhea (63%). The hand-foot syndrome was seen in 67% of patients and was generally mild, as was hematologic toxicity. Dose-limiting toxicity included diarrhea, mucositis, neutropenia and the hand-foot syndrome. The dose level recommended for further trials included capecitabine 1000 mg/m2 twice daily and rHuIFNalpha2a 3.0 MU/m2 three times weekly. One patient had a partial response of a liver lesion (duration > 200 days). Pharmacokinetic parameters of capecitabine and its metabolites (5'-deoxy-5-fluorouridine, 5-fluorouracil and alpha-fluoro-beta-alanine) were similar to those reported by other authors. There was rapid conversion to 5'-deoxyuridine. The peak plasma concentrations of capecitabine occurred between 0.5 and 3.0 h.\n\n\nCONCLUSIONS\nThe combination of capecitabine and rHuIFNalpha2a was well tolerated. The recommended dose levels for phase II trials are: rHuIFNalpha2a 3.0 MU/m2 s.c. three times weekly and oral capecitabine 1000 mg/m2 twice daily for 2 weeks. No evidence of an effect of rHuIFNalpha2a on the pharmacokinetics of capecitabine or its metabolites was apparent. A phase II trial in untreated patients with metastatic RCC is planned.", "affiliations": "Experimental Therapeutics Program, Cleveland Clinic Taussig Cancer Center, OH 44195, USA.", "authors": "Chang|D Z|DZ|;Olencki|T|T|;Budd|G T|GT|;Peereboom|D|D|;Ganapathi|R|R|;Osterwalder|B|B|;Bukowski|R|R|", "chemical_list": "D016898:Interferon-alpha; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil", "country": "Germany", "delete": false, "doi": "10.1007/s002800100366", "fulltext": null, "fulltext_license": null, "issn_linking": "0344-5704", "issue": "48(6)", "journal": "Cancer chemotherapy and pharmacology", "keywords": null, "medline_ta": "Cancer Chemother Pharmacol", "mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002853:Chromatography, Liquid; D003841:Deoxycytidine; D003967:Diarrhea; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007279:Injections, Subcutaneous; D016898:Interferon-alpha; D007680:Kidney Neoplasms; D008297:Male; D013058:Mass Spectrometry; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms; D009503:Neutropenia; D010523:Peripheral Nervous System Diseases", "nlm_unique_id": "7806519", "other_id": null, "pages": "493-8", "pmc": null, "pmid": "11800031", "pubdate": "2001-12", "publication_types": "D016430:Clinical Trial; D017426:Clinical Trial, Phase I; D016428:Journal Article", "references": null, "title": "Phase I trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer: toxicity and pharmacokinetics.", "title_normalized": "phase i trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer toxicity and pharmacokinetics" }

[ { "companynumb": "US-ROCHE-2411765", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INTERFERON ALFA-2A" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3.0 MU/M2 THREE TIMES WEEKLY ON MONDAY-WEDNESDAY-FRIDAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL CANCER METASTATIC", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERFERON ALFA-2A" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "020896", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "DAYS 1-14 AND 22-36, CYCLES REPEATED EVERY 6 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL CANCER METASTATIC", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHANG D, OLENCKI T, BUDD G, PEEREBOOM D, GANAPATHI R, OSTERWALDER B AND BUKOWSKI R. PHASE I TRIAL OF CAPECITABINE IN COMBINATION WITH INTERFERON ALPHA IN PATIENTS WITH METASTATIC RENAL CANCER: TOXICITY AND PHARMACOKINETICS. CANCER CHEMOTHERAPY AND PHARMACOLOGY 2001 DEC?48 (6):493-8.", "literaturereference_normalized": "phase i trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer toxicity and pharmacokinetics", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190916", "receivedate": "20190916", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16808743, "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": "Antimuscarinic agents are now widely used as the pharmacological therapy for overactive bladder (OAB) because neuronal (parasympathetic nerve) and non-neuronal acetylcholine play a significant role for the bladder function. In this review, we will highlight basic and clinical aspects of eight antimuscarinic agents (oxybutynin, propiverine, tolterodine, solifenacin, darifenacin, trospium, imidafenacin, and fesoterodine) clinically used to treat urinary dysfunction in patients with OAB. The basic pharmacological characteristics of these eight antimuscarinic agents include muscarinic receptor subtype selectivity, functional bladder selectivity, and muscarinic receptor binding in the bladder and other tissues. The measurement of drug-receptor binding after oral administration of these agents allows for clearer understanding of bladder selectivity by the integration of pharmacodynamics and pharmacokinetics under in vivo conditions. Their central nervous system (CNS) penetration potentials are also discussed in terms of the feasibility of impairments in memory and cognitive function in elderly patients with OAB. The clinical aspects of efficacy focus on improvements in the daytime urinary frequency, nocturia, bladder capacity, the frequency of urgency, severity of urgency, number of incontinence episodes, OAB symptom score, and quality of life (QOL) score by antimuscarinic agents in patients with OAB. The safety of and adverse events caused by treatments with antimuscarinic agents such as dry mouth, constipation, blurred vision, erythema, fatigue, increased sweating, urinary retention, and CNS adverse events are discussed. A dose-dependent relationship was observed with adverse events, because the risk ratio generally increased with elevations in the drug dose of antimuscarinic agents. Side effect profiles may be additive to or contraindicated by other medications.", "affiliations": "Center for Pharma-Food Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. Electronic address: [email protected].;Center for Pharma-Food Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.;Southern Knights' Laboratory, 1-1-823 Miyagi, Chatan, Okinawa, 904-0113, Japan.;Southern Knights' Laboratory, 1-1-823 Miyagi, Chatan, Okinawa, 904-0113, Japan.;Southern Knights' Laboratory, 1-1-823 Miyagi, Chatan, Okinawa, 904-0113, Japan.", "authors": "Yamada|Shizuo|S|;Ito|Yoshihiko|Y|;Nishijima|Saori|S|;Kadekawa|Katsumi|K|;Sugaya|Kimio|K|", "chemical_list": "D018727:Muscarinic Antagonists", "country": "England", "delete": false, "doi": "10.1016/j.pharmthera.2018.04.010", "fulltext": null, "fulltext_license": null, "issn_linking": "0163-7258", "issue": "189()", "journal": "Pharmacology & therapeutics", "keywords": "Antimuscarinics; Basic pharmacology; Bladder selectivity; Clinical efficacy and tolerability; Muscarinic receptor binding; Overactive bladder", "medline_ta": "Pharmacol Ther", "mesh_terms": "D000818:Animals; D001921:Brain; D006801:Humans; D018727:Muscarinic Antagonists; D053201:Urinary Bladder, Overactive", "nlm_unique_id": "7905840", "other_id": null, "pages": "130-148", "pmc": null, "pmid": "29709423", "pubdate": "2018-09", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder.", "title_normalized": "basic and clinical aspects of antimuscarinic agents used to treat overactive bladder" }

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BASIC AND CLINICAL ASPECTS OF ANTIMUSCARINIC AGENTS USED TO TREAT OVERACTIVE BLADDER.. PHARMACOLOGY + THERAPEUTICS. 2018?189:130-148", "literaturereference_normalized": "basic and clinical aspects of antimuscarinic agents used to treat overactive bladder", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "CA", "receiptdate": "20190107", "receivedate": "20190107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15792667, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2018-07682", "fulfillexpeditecriteria": "2", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTONIC BLADDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YAMADA S, ITO Y, NISHIJIMA S, KADEKAWA K, ET AL. BASIC AND CLINICAL ASPECTS OF ANTIMUSCARINIC AGENTS USED TO TREAT OVERACTIVE BLADDER.. 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BASIC AND CLINICAL ASPECTS OF ANTIMUSCARINIC AGENTS USED TO TREAT OVERACTIVE BLADDER.. PHARMACOLOGY + THERAPEUTICS. 2018?189:130?148", "literaturereference_normalized": "basic and clinical aspects of antimuscarinic agents used to treat overactive bladder", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "CA", "receiptdate": "20190107", "receivedate": "20190107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15792669, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2018-07679", "fulfillexpeditecriteria": "2", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FESOTERODINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204827", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTONIC BLADDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FESOTERODINE FUMARATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YAMADA S, ITO Y, NISHIJIMA S, KADEKAWA K, ET AL. BASIC AND CLINICAL ASPECTS OF ANTIMUSCARINIC AGENTS USED TO TREAT OVERACTIVE BLADDER.. PHARMACOLOGY + THERAPEUTICS. 2018?189:130-148", "literaturereference_normalized": "basic and clinical aspects of antimuscarinic agents used to treat overactive bladder", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "CA", "receiptdate": "20190107", "receivedate": "20190107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15792665, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" } ]

{ "abstract": "BACKGROUND\nThe risk of gastrointestinal (GI) bleeding of dabigatran and rivaroxaban is relatively unexplored. The aim of our study was to compare this risk in both drugs.\n\n\nMETHODS\nWe examined the medical records of patients on either dabigatran or rivaroxaban from October 2010 to April 2013 in two hospitals.\n\n\nRESULTS\nA total of 374 patients (147 rivaroxaban vs. 227 dabigatran) were identified. GI bleeding occurred in 5.3% in the dabigatran when compared to 4.8% in the rivaroxaban group (p = 0.8215). Multivariate analysis showed that the odds of GI bleeding while on dabigatran for ≤40 days when compared to ≥40 days was 8.3 (p < 0.0001). In the rivaroxaban group, patients who were on the drug for ≤40 days had a higher incidence of bleeding when compared to those >40 days (OR = 2.8, p = 0.023). Concomitant use of antiplatelets (single or dual) or non-steroidal anti-inflammatory drugs was not associated with increased bleeding in the dabigatran group; however, the use of dual antiplatelet agents with rivaroxaban was associated with an increased risk of GI bleeding (OR = 7.4, p = 0.0378). Prior GI bleeding had a higher risk of bleeding in the rivaroxaban group (OR = 15.5, p = 0.0002).\n\n\nCONCLUSIONS\nDabigatran was not associated with a higher incidence of GI bleeding. Both drugs had a higher bleeding risk in the first 40 days.", "affiliations": "Section of Gastroenterology and Hepatology, Georgia Regents University, Augusta, Ga., USA.", "authors": "Sherid|Muhammed|M|;Sifuentes|Humberto|H|;Sulaiman|Samian|S|;Samo|Salih|S|;Husein|Husein|H|;Tupper|Ruth|R|;Thiruvaiyaru|Dharma|D|;Spurr|Charles|C|;Sridhar|Subbaramiah|S|", "chemical_list": "D000991:Antithrombins; D001562:Benzimidazoles; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D015091:beta-Alanine; D000069552:Rivaroxaban; D000069604:Dabigatran", "country": "Switzerland", "delete": false, "doi": "10.1159/000365967", "fulltext": null, "fulltext_license": null, "issn_linking": "0012-2823", "issue": "90(2)", "journal": "Digestion", "keywords": null, "medline_ta": "Digestion", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001562:Benzimidazoles; D000069604:Dabigatran; D065427:Factor Xa Inhibitors; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D012189:Retrospective Studies; D012307:Risk Factors; D000069552:Rivaroxaban; D013876:Thiophenes; D015091:beta-Alanine", "nlm_unique_id": "0150472", "other_id": null, "pages": "137-46", "pmc": null, "pmid": "25278002", "pubdate": "2014", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Risk of gastrointestinal bleeding with dabigatran: a head-to-head comparative study with rivaroxaban.", "title_normalized": "risk of gastrointestinal bleeding with dabigatran a head to head comparative study with rivaroxaban" }

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{ "abstract": "BACKGROUND\nThe calcineurin (CaN) inhibitor, tacrolimus, is widely used in patients undergoing allogeneic organ transplantation and in those with certain allergic diseases. Recently, several reports have suggested that CaN is also associated with schizophrenia. However, little data are currently available on the direct effect of tacrolimus on the human brain.\n\n\nMETHODS\nA 23-year-old Japanese female experienced severe delusion of persecution, delusional mood, suspiciousness, aggression, and excitement. She visited our hospital and was diagnosed with schizophrenia. When she was 27 years old, she had severe general fatigue, persistent fever, systemic joint pain, gingival bleeding, and breathlessness and was diagnosed with acute myelomonocytic leukemia. Later she underwent bone marrow transplantation (BMT), she was administered methotrexate and cyclosporin A to prevent graft versus host disease (GVHD). Three weeks after BMT, she showed initial symptoms of GVHD and was prescribed tacrolimus instead of cyclosporin A. Seven months after BMT at the age of 31 years, she died of progression of GVHD. Pathological anatomy was examined after her death, including immunohistochemical analysis of her brain using anti-CaN antibodies. For comparison, we used our previous data from both a schizophrenia group and a healthy control group. No significant differences were observed in the percentage of CaN-immunoreactive neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-immunoreactive neurons in layers III-VI of the BA46 and the putamen tended to be lower in the tacrolimus case.\n\n\nCONCLUSIONS\nTacrolimus may decrease CaN immunoreactivity in some regions of the human brain. Thus, tacrolimus may introduce side effects such as cognitive dysfunction and extrapyramidal symptoms. In addition, we also found that the effect of tacrolimus on CaN immunore-activity in human brain was stronger than the effect of schizophrenia.", "affiliations": "Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima; Department of Neuropsychiatry, The University of Tokyo Hospital, Bunkyo-ku, Tokyo.;Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima.;Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima.;Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima.;Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima.;Department of Psychiatry, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu City, Fukushima, Japan.;Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima.", "authors": "Wada|Akira|A|;Kunii|Yasuto|Y|;Matsumoto|Jyunya|J|;Hino|Mizuki|M|;Nagaoka|Atsuko|A|;Niwa|Shin-Ichi|S|;Yabe|Hirooki|H|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/NDT.S106371", "fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S106371ndt-12-1645Case ReportDecreased calcineurin immunoreactivity in the postmortem brain of a patient with schizophrenia who had been prescribed the calcineurin inhibitor, tacrolimus, for leukemia Wada Akira 12Kunii Yasuto 1Matsumoto Jyunya 1Hino Mizuki 1Nagaoka Atsuko 1Niwa Shin-ichi 3Yabe Hirooki 11 Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima2 Department of Neuropsychiatry, The University of Tokyo Hospital, Bunkyo-ku, Tokyo3 Department of Psychiatry, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu City, Fukushima, JapanCorrespondence: Akira Wada, Department of Neuropsychiatry, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan, Tel +81 24 547 1331, Fax +81 24 548 6735, Email [email protected] 06 7 2016 12 1645 1650 © 2016 Wada et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background\nThe calcineurin (CaN) inhibitor, tacrolimus, is widely used in patients undergoing allogeneic organ transplantation and in those with certain allergic diseases. Recently, several reports have suggested that CaN is also associated with schizophrenia. However, little data are currently available on the direct effect of tacrolimus on the human brain.\n\nCase\nA 23-year-old Japanese female experienced severe delusion of persecution, delusional mood, suspiciousness, aggression, and excitement. She visited our hospital and was diagnosed with schizophrenia. When she was 27 years old, she had severe general fatigue, persistent fever, systemic joint pain, gingival bleeding, and breathlessness and was diagnosed with acute myelomonocytic leukemia. Later she underwent bone marrow transplantation (BMT), she was administered methotrexate and cyclosporin A to prevent graft versus host disease (GVHD). Three weeks after BMT, she showed initial symptoms of GVHD and was prescribed tacrolimus instead of cyclosporin A. Seven months after BMT at the age of 31 years, she died of progression of GVHD. Pathological anatomy was examined after her death, including immunohistochemical analysis of her brain using anti-CaN antibodies. For comparison, we used our previous data from both a schizophrenia group and a healthy control group. No significant differences were observed in the percentage of CaN-immunoreactive neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-immunoreactive neurons in layers III–VI of the BA46 and the putamen tended to be lower in the tacrolimus case.\n\nConclusion\nTacrolimus may decrease CaN immunoreactivity in some regions of the human brain. Thus, tacrolimus may introduce side effects such as cognitive dysfunction and extrapyramidal symptoms. In addition, we also found that the effect of tacrolimus on CaN immunore-activity in human brain was stronger than the effect of schizophrenia.\n\nKeywords\ncalcineurincalcineurin inhibitorsschizophreniapostmortem brainimmunohistochemistry\n==== Body\nIntroduction\nThe calcineurin (CaN) inhibitor, tacrolimus, is a nonsteroidal, anti-inflammatory immunosuppressive drug mainly used to treat patients undergoing allogeneic organ transplantation and those with atopic dermatitis.1 CaN is a heterodimeric calcium-dependent serine/threonine protein phosphatase, consisting of a catalytic (CaN A) and a regulatory (CaN B) subunits, and plays a critical role in cellular responses and calcium signaling.2 Tacrolimus induces not only mild neurological side effects such as tremor but also psychiatric side effects such as manic-like psychosis and relapse of schizophrenia.3,4 On the other hand, several reports suggested that CaN dysfunction may be a risk factor for schizophrenia. Forebrain-specific PPP3CC (encodes the CaN A γ-catalytic subunit) knockout mice display multiple abnormal activities related to schizophrenia, such as increased locomotor activity, decreased social interaction, impairments in prepulse inhibition, and latent inhibition.5,6 Another report showed decreased CaN A protein levels and decreased mRNA of the three subunits of CaN A in the hippocampus of schizophrenia patients.7\n\nChang et al8 reported on the B-cell lymphoma-2 (Bcl-2)–CaN–dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) feedback mechanism in regulating serine 1755 phosphorylation and apoptosis in primary human chronic lymphocytic leukemia cells. However, there were no previous reports that acute myelomonocytic leukemia (AML) itself has direct influence on CaN in the brain.\n\nTo investigate the effect of tacrolimus in the brain, we examined the immunoreactivity of CaN using immunohistochemistry in the dorsolateral prefrontal cortex, hippocampus, caudate, and putamen of a postmortem brain of a patient with schizophrenia who had been treated with tacrolimus. As healthy and disease controls, we used our previously reported data.9 There were no previous reports of AML itself having a direct influence on CaN in the brain. If we only aimed to investigate the effect of tacrolimus on the brain, we would have focused on characterizing the effect of tacrolimus in AML patients without prior history of schizophrenia. We aimed to investigate whether tacrolimus treatment or acquiring schizophrenia had a stronger effect on the CaN immunoreactivity in the brain.\n\nCase report\nA 23-year-old Japanese female visited a local psychiatric clinic in May 1990 due to nonspecific physical symptoms. She had poor premorbid functioning, and her mother had been diagnosed with schizophrenia. She had no history of neurological disorders or substance abuse. She first received a diagnosis of psychogenic reaction. Several months after she first visited that clinic, she experienced severe delusion of persecution, delusional mood, suspiciousness, aggression, and excitement. She first visited our hospital in November 1992 and was diagnosed with schizophrenia. She was prescribed antipsychotics, but she initially refused them. She and her mother had “shared psychotic disorder”. Because they shared the same delusion of persecution, they moved together many times to various places based on delusions. In November 1992, she began to take haloperidol (4.5 mg/d) and chlorpromazine (200 mg/d) for her psychotic symptoms. Five months after starting antipsychotics, her psychotic symptoms had improved.\n\nIn June 1996, she experienced severe general fatigue, persistent fever (≥38°C), systemic joint pain, gingival bleeding, and breathlessness. Her blood tests showed pancytopenia (white blood cells, 3.1×103/mm2; red blood cells, 2.6×106/μL; hemoglobin, 7.5 g/dL; and platelets, 8.8×104/μL) and the presence of blast cells. We consulted a hematologist, and she was diagnosed with AML. In September 1996, she underwent bone marrow transplantation (BMT). After BMT, she was administered methotrexate and cyclosporin A to prevent graft versus host disease (GVHD). At the same time, we stopped prescribing antipsychotics. Three weeks after BMT, she had diarrhea and systemic eruption. We judged that she had initial symptoms of GVHD, and the hematologist prescribed tacrolimus instead of cyclosporine A. In December 1996, her auditory hallucination, delusions, and excitement recurred. We needed to prescribe risperidone so that she could continue her treatment safely. Her general condition gradually worsened. In February 1997, she experienced disturbance of consciousness, hypotension, and respiratory failure. In April 1997, she died of progression of GVHD at the age of 31 years.\n\nPathological anatomy was examined after her death. The use of postmortem human brain tissues for the present study was approved by the Ethics Committee of Fukushima Medical University (FMU) and complied with the Declaration of Helsinki. All procedures were carried out with the informed written consent of the next of kin. The postmortem interval was 9.5 hours. Her brain weight was 1,232 g with no indication of gross neurological pathology. Brain tissue blocks were obtained from the right hemisphere of the dorsolateral prefrontal cortex (BA46), hippocampus, caudate, and putamen and fixed in 10% formalin, embedded in paraffin, and sliced into 5 μm sections. We obtained ten sections and used one section in this analysis. Immunohistochemistry was performed in accordance with our previous protocol.9–11 The sections were deparaffinized in xylene and rehydrated through a decreasing alcohol series (100%, 90%, 80%, and 70% ethanol). Endogenous peroxidase activity was quenched by incubating in 0.3% hydrogen peroxide in methanol at room temperature for 20 minutes. The sections were washed with phosphate-buffered saline (PBS: 0.01 M sodium phosphate, pH 7.3), microwaved for 15 minutes in 10 mM citrate buffer for antigen recovery, and washed with PBS. The sections were incubated in 5% skim milk in PBS for 30 minutes at room temperature to reduce nonspecific binding, incubated overnight at 4°C in rabbit polyclonal antibodies against human CaN (1717-0909; AbD Serotec, Oxford, UK, 1:50), which recognizes the 60 kDa mammalian CaN catalytic subunit (CaN A), in PBS, and washed in PBS three times for 5 minutes each. We used normal rabbit serum instead of the primary antibody as a negative control. The sections were incubated with the second antibody (biotinylated anti-rabbit IgG; Nichirei Corporation, Tokyo, Japan) for 20 minutes at room temperature and washed in PBS three times for 5 minutes each. Subsequently, the sections were incubated with peroxidase-labeled streptavidin for 15 minutes at room temperature and washed in PBS three times for 5 minutes each. The sections were treated with diaminobenzidine (Wako Pure Chemical Industries, Ltd., Osaka, Japan) for 5 minutes at room temperature to visualize the immunoreaction products and then washed with PBS to terminate the reaction. For nuclear counterstaining, the sections were treated with Carracci’s hematoxylin for 20 seconds. CaN-immunoreactive (CaN-IR) cells were examined under a microscope equipped with a digital camera (Olympus BX51; Olympus Corporation, Tokyo, Japan) at 100× magnification, and parenchymal cell numbers were counted using WinROOF Version 5.5 (Mitani Corporation, Tokyo, Japan). Neurons and neuroglial cells were distinguished by morphology, nuclear size, nuclear membrane thickness, and chromatin homogeneity.10–12 We defined neurons in which staining was more intense than background as CaN-IR. Image acquisition was performed to show the representative staining pattern of each region and to include approximately the same number of total neurons. In the BA46, three images were randomly selected from each of layers II–VI. The mean percentage of CaN-IR neurons (number of CaN-IR neurons/number of total neurons) was calculated for each layer. In the hippocampus, the CA1, CA2, CA3, and CA4 subfields and dentate gyrus were investigated by randomly selecting three, one, one, three, and two images, respectively. The caudate and putamen were analyzed separately by randomly selecting three images each. A single researcher blinded to the tissue source was responsible for all cell counting and data analyses.\n\nThe percentages of CaN-IR neurons in the BA46, hippocampus, caudate nucleus, and putamen are shown in Figure 1A–C. To compare this patient with a schizophrenia group and healthy control group, we used previously reported data.9 No significant differences were observed in the percentage of CaN-IR neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-IR neurons in layers III–VI of the BA46 and the putamen tended to be lower in the tacrolimus case (Figure 1A and C). Representative images of CaN-IR neurons in the prefrontal cortex (BA46, layers V–VI) are shown in Figure 2.\n\nFirst, we considered the possibility of an association between our patient’s psychiatric symptoms and tacrolimus. The percentage of CaN-IR neurons in layers III–VI of the BA46 tended to be lower in patients with schizophrenia compared with the healthy control group. Furthermore, the percentage of CaN-IR neurons was even lower in the tacrolimus patient compared with the schizophrenia alone group. Cognitive dysfunction due to hypofunction of the frontal lobe is well known in schizophrenia.13 In addition, a side effect of tacrolimus is delirium, and this form of cognitive dysfunction is more severe than schizophrenia without delirium. Thus, the decrease in CaN immunoreactivity in the frontal lobe may reflect cognitive dysfunction.\n\nNext, we considered the results from the caudate and putamen. The percentage of CaN-IR neurons in the putamen tended to be higher in patients with schizophrenia compared with healthy subjects, but the percentage of CaN-IR neurons was lower in the tacrolimus case than in the schizophrenia group. Tacrolimus may cause side effects of tremor and dysarthria, which occur when a patient has dysfunction of the striatum. Lower immunoreactivity of CaN induced by tacrolimus in the striatum may mediate these extrapyramidal symptoms.\n\nLee et al14 reported that tacrolimus reduces nuclear expression of CaN in a renal ischemia–reperfusion injury mouse model. They suggested that tacrolimus decreases CaN expression both in the cytoplasm and in the nucleus. Our data indicated that the percentages of CaN-IR neurons in layers III–VI of the BA46 and putamen tended to be lower in the tacrolimus case compared with the schizophrenia group. As in the report by Lee et al, tacrolimus may decrease the expression of CaN in some regions of the human brain. Overall, when we considered the results from the frontal, caudate, and putamen together, we found that the effect of tacrolimus in the human brain may be stronger than the effect of schizophrenia.\n\nEastwood et al7 reported decreased CaN A protein levels and decreased mRNA of the three subunits of CaN A in the hippocampus of schizophrenia patients. This report does not support our findings in the hippocampus. This discrepancy could be attributed to the small sample numbers in our study.\n\nOur study has a number of limitations. Only one tacrolimus case was included in this report. The effect of tacrolimus on the human brain might be subject to intersubject differences in CaN immunoreactivity and thus generalization of these findings might be difficult. In addition, the lack of a control group (patients with leukemia but without tacrolimus treatment and schizophrenia, patients with leukemia treated using tacrolimus but without schizophrenia) makes drawing firm conclusion regarding efficacy difficult. It is also possible that the AML might have directly influenced CaN immunoreactivity in the brain. Further studies using a larger sample size are warranted to investigate CaN immunoreactivity in the postmortem brains of leukemia patients without tacrolimus treatment and schizophrenia, leukemia patients treated with tacrolimus but without schizophrenia, and schizophrenia patients with tacrolimus-treated AML. Second, this research was conducted using immunohistochemical analysis only. Further studies using other methods, such as in situ hybridization, are warranted. Third, CaN-IR neurons were defined as having greater staining intensity compared to background. This method allows for ambiguity because it is dependent on human assessment. In this context, the use of in situ hybridization for future studies is warranted. Finally, if the patient carried the PPP3CC SNP, the level of CaN might have already been low, instead of attributable to the tacrolimus treatment. However, we could not obtain the SNPs data because we were unable to use frozen brain samples in the tacrolimus case. Further studies are needed to obtain the SNPs data from frozen samples.\n\nConclusion\nWe performed immunohistochemical analysis using human brain tissue from a patient with schizophrenia and AML treated with tacrolimus. Our data suggested that tacrolimus may decrease the immunoreactivity of CaN in some regions of the human brain. In addition, the percentage of CaN-IR neurons in layers III–VI of the BA46, caudate, and putamen tended to be lower in patients with schizophrenia complicated by tacrolimus-treated AML compared to the schizophrenia group. These data also suggested that the effect of tacrolimus in the human brain was stronger than the effect of schizophrenia.\n\nAcknowledgments\nWe thank Hiromi Onuma for her assistance with coordinating tissue donations. We also thank the families of the deceased for the donations of brain tissue and the time and effort devoted to the consent process and interviews.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Quantitative analysis of CaN-IR neurons: layers II–VI of the prefrontal cortex (BA46), hippocampus, caudate nucleus, and putamen.\n\nNotes: In each histogram, “Sz” indicates the schizophrenia group, “cont” indicates the control group, and “tacrolimus” indicates the tacrolimus case. Analysis of covariance was used to compare the percentage of CaN-IR neurons among the three groups. (A) Percentage of CaN-IR neurons in each layer of the prefrontal cortex (BA46). (B) Percentage of CaN-IR neurons in each subfield of the hippocampus. (C) Percentage of CaN-IR neurons in the caudate and putamen.\n\nAbbreviations: CaN-IR, calcineurin-immunoreactive; DG, dentate gyrus.\n\nFigure 2 CaN-IR neurons in brain sections from controls, patients with schizophrenia, and a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus.\n\nNotes: (A) Calcineurin-immunoreactive (CaN-IR) cells in the prefrontal cortex (BA46, layers V–VI) of a control brain (72-year-old male with a postmortem interval [PMI] of 12.5 hours). (B) CaN-IR cells in the prefrontal cortex (BA46, layers V–VI) of the brain of a patient with schizophrenia (48-year-old male with a PMI of 10 hours). (C) CaN-IR cells in prefrontal cortex (BA46, layers V–VI) in the brain of a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus (31-year-old female with a PMI of 9.5 hours). Immunopositive neurons are indicated by arrows, and immunonegative neurons are indicated by arrowheads. Magnification ×200.\n==== Refs\nReferences\n1 Miyata S Ohkubo Y Mutoh S A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis Inflamm Res 2005 54 1 1 9 15723198 \n2 Rusnak F Mertz P Calcineurin: form and function Physiol Rev 2000 80 4 1483 1521 11015619 \n3 Bersani G Marino P Valeriani G Manic-like psychosis associated with elevated trough tacrolimus blood concentrations 17 years after kidney transplant Case Rep Psychiatry 2013 2013 926395 23762723 \n4 Lin Y Sun IW Liu SI Loh el-W Lin YC Tacrolimus ointment-induced relapse of schizophrenia: a case report Int J Neuropsychopharmacol 2007 10 6 851 854 18077846 \n5 Miyakawa T Leiter LM Gerber DJ Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia Proc Natl Acad Sci U S A 2003 100 15 8987 8992 12851457 \n6 Zeng H Chattarji S Barbarosie M Forebrain-specific calcineu-rin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory Cell 2001 107 5 617 629 11733061 \n7 Eastwood SL Burnet PW Harrison PJ Decreased hippocampal expression of the susceptibility gene PPP3CC and other calcineurin subunits in schizophrenia Biol Psychiatry 2005 57 7 702 710 15820226 \n8 Chang MJ Zhong F Lavik AR Parys JB Berridge MJ Distelhorst CW Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival Proc Natl Acad Sci U S A 2014 111 3 1186 1191 24395794 \n9 Wada A Kunii Y Ikemoto K Increased ratio of calcineurin immunoreactive neurons in the caudate nucleus of patients with schizophrenia Prog Neuropsychopharmacol Biol Psychiatry 2012 37 1 8 14 22285318 \n10 Kunii Y Ikemoto K Wada A Detailed DARPP-32 expression profiles in postmortem brains from patients with schizophrenia: an immunohistochemical study Med Mol Morphol 2011 44 4 190 199 22179181 \n11 Kunii Y Yabe H Wada A Yang Q Nishiura K Niwa S Altered DARPP-32 expression in the superior temporal gyrus in schizophrenia Prog Neuropsychopharmacol Biol Psychiatry 2011 35 4 1139 1143 21453742 \n12 Selemon LD Rajkowska G Goldman-Rakic PS Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17 Arch Gen Psychiatry 1995 52 10 805 818 discussion 819–820 7575100 \n13 Yoon JH Minzenberg MJ Ursu S Association of dorsolateral prefrontal cortex dysfunction with disrupted coordinated brain activity in schizophrenia: relationship with impaired cognition, behavioral disorganization, and global function Am J Psychiatry 2008 165 8 1006 1014 18519527 \n14 Lee SH Choi J Kim H FK506 reduces calpain-regulated calcineurin activity in both the cytoplasm and the nucleus Anat Cell Biol 2014 47 2 91 100 24987545\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1176-6328", "issue": "12()", "journal": "Neuropsychiatric disease and treatment", "keywords": "calcineurin; calcineurin inhibitors; immunohistochemistry; postmortem brain; schizophrenia", "medline_ta": "Neuropsychiatr Dis Treat", "mesh_terms": null, "nlm_unique_id": "101240304", "other_id": null, "pages": "1645-50", "pmc": null, "pmid": "27462157", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "24395794;24987545;7575100;11733061;11015619;22179181;18519527;15820226;22285318;23762723;12851457;18077846;21453742;15723198", "title": "Decreased calcineurin immunoreactivity in the postmortem brain of a patient with schizophrenia who had been prescribed the calcineurin inhibitor, tacrolimus, for leukemia.", "title_normalized": "decreased calcineurin immunoreactivity in the postmortem brain of a patient with schizophrenia who had been prescribed the calcineurin inhibitor tacrolimus for leukemia" }

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"SCHIZOPHRENIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "199211", "drugstartdateformat": "610", "drugstructuredosagenumb": "4.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PER ORAL NOS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AGITATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": "1996", "drugenddateformat": "602", "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1996", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PER ORAL NOS", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "HALLUCINATION, AUDITORY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "199612", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PER ORAL NOS", "drugdosagetext": null, "drugenddate": "199701", "drugenddateformat": "610", "drugindication": "DELUSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hallucination, auditory", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delusion", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft versus host disease", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 1996" } }, "primarysource": { "literaturereference": "WADA A, KUNII Y, MATSUMOTO J, HINO M, NAGAOKA A, NIWA S, ET AL.. DECREASED CALCINEURIN IMMUNOREACTIVITY IN THE POSTMORTEM BRAIN OF A PATIENT WITH SCHIZOPHRENIA WHO HAD BEEN PRESCRIBED THE CALCINEURIN INHIBITOR, TACROLIMUS, FOR LEUKEMIA. NEUROPSYCHIATRIC DISEASE AND TREATMENT. 2016;12:1645-50", "literaturereference_normalized": "decreased calcineurin immunoreactivity in the postmortem brain of a patient with schizophrenia who had been prescribed the calcineurin inhibitor tacrolimus for leukemia", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "JP", "receiptdate": "20160815", "receivedate": "20120514", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8559795, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "Acetaminophen or paracetamol, a commonly used over-the-counter analgesic, is known to elicit severe adverse reactions when taken in overdose, chronically at therapeutic dosage or, sporadically, following single assumptions of a therapeutic dose. Damage patterns including liver damage and, rarely, acute tubular necrosis or a fixed drug exanthema. We present a case of fatal acetaminophen toxicity with postmortem blood concentration 78 μg/mL and unusual clinical features, including a visually striking and massive epidermolysis and rhabdomyolysis, disseminated intravascular coagulation and myocardial ischemia. This case is compared with the most similar previous reports in terms of organ damage, clinical presentation, and cause of death. We conclude that a number of severe patterns of adverse effects to acetaminophen are emerging that were previously greatly underestimated, thus questioning the adequacy of the clinical spectrum traditionally associated with acetaminophen intoxication and leading to the need to review this spectrum and the associated diagnostic criteria.", "affiliations": "Institute of Legal Medicine Catholic University, School of Medicine, L.go F. Vito, 1 00168, Rome, Italy. [email protected]", "authors": "De-Giorgio|Fabio|F|;Lodise|Maria|M|;Chiarotti|Marcello|M|;d'Aloja|Ernesto|E|;Carbone|Arnaldo|A|;Valerio|Luca|L|", "chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen", "country": "United States", "delete": false, "doi": "10.1111/1556-4029.12205", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-1198", "issue": "58(5)", "journal": "Journal of forensic sciences", "keywords": "acetaminophen; epidermolysis; forensic pathology; forensic science; forensic toxicology; intoxication; paracetamol; rhabdomyolysis; skin necrosis", "medline_ta": "J Forensic Sci", "mesh_terms": "D000082:Acetaminophen; D058186:Acute Kidney Injury; D018712:Analgesics, Non-Narcotic; D004211:Disseminated Intravascular Coagulation; D004820:Epidermolysis Bullosa; D005260:Female; D049429:Forensic Pathology; D053593:Forensic Toxicology; D006801:Humans; D007668:Kidney; D008099:Liver; D008875:Middle Aged; D018482:Muscle, Skeletal; D017202:Myocardial Ischemia; D012206:Rhabdomyolysis; D012867:Skin", "nlm_unique_id": "0375370", "other_id": null, "pages": "1397-400", "pmc": null, "pmid": "23822653", "pubdate": "2013-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Possible fatal acetaminophen intoxication with atypical clinical presentation.", "title_normalized": "possible fatal acetaminophen intoxication with atypical clinical presentation" }

[ { "companynumb": "IT-JNJFOC-20130908820", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myocardial ischaemia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epidermolysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DE-GIORGIO F, LODISE M, CHIAROTTI M, D^ALOJA E, CARBONE A, VALERIO L. POSSIBLE FATAL ACETAMINOPHEN INTOXICATION WITH ATYPICAL CLINICAL PRESENTATION. JOURNAL FORENSIC SCIENCES SEP-2013;58(5):1397-400.", "literaturereference_normalized": "possible fatal acetaminophen intoxication with atypical clinical presentation", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20150224", "receivedate": "20130919", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9536562, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "IT-RANBAXY-2014RR-88431", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076200", "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": "PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Epidermolysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myocardial ischaemia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Liver injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DE-GIORGIO F, LODISE M, CHIAROTTI M, D^ALOJA E, CARBONE A, VALERIO L. POSSIBLE FATAL ACETAMINOPHEN INTOXICATION WITH ATYPICAL CLINICAL PRESENTATION. J-FORENSIC-SCI. 2013;58 (5):1397-400", "literaturereference_normalized": "possible fatal acetaminophen intoxication with atypical clinical presentation", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20141215", "receivedate": "20141204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10627360, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" } ]

{ "abstract": "The impact of genomic profiling on the outcomes of patients with advanced gastrointestinal (GI) malignancies remains unknown. The primary objectives of the study were to investigate the clinical benefit of genomic-guided therapy, defined as complete response (CR), partial response (PR), or stable disease (SD) at 3 months, and its impact on progression-free survival (PFS) in patients with advanced GI malignancies. Clinical and genomic data of all consecutive GI tumor samples from April, 2013 to April, 2016 sequenced by FoundationOne were obtained and analyzed. A total of 101 samples from 97 patients were analyzed. Ninety-eight samples from 95 patients could be amplified making this approach feasible in 97% of the samples. After removing duplicates, 95 samples from 95 patients were included in the further analysis. Median time from specimen collection to reporting was 11 days. Genomic alteration-guided treatment recommendations were considered new and clinically relevant in 38% (36/95) of the patients. Rapid decline in functional status was noted in 25% (9/36) of these patients who could therefore not receive genomic-guided therapy. Genomic-guided therapy was utilized in 13 patients (13.7%) and 7 patients (7.4%) experienced clinical benefit (6 PR and 1 SD). Among these seven patients, median PFS was 10 months with some ongoing durable responses. Genomic profiling-guided therapy can lead to clinical benefit in a subset of patients with advanced GI malignancies. Attempting genomic profiling earlier in the course of treatment prior to functional decline may allow more patients to benefit from these therapies.", "affiliations": "Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Gastrointestinal Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.;Division of Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15232.", "authors": "Dhir|Mashaal|M|0000-0002-1426-1098;Choudry|Haroon A|HA|;Holtzman|Matthew P|MP|;Pingpank|James F|JF|;Ahrendt|Steven A|SA|;Zureikat|Amer H|AH|;Hogg|Melissa E|ME|;Bartlett|David L|DL|;Zeh|Herbert J|HJ|;Singhi|Aatur D|AD|;Bahary|Nathan|N|", "chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077146:Irinotecan; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin", "country": "United States", "delete": false, "doi": "10.1002/cam4.992", "fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 10.1002/cam4.992CAM4992Original ResearchClinical Cancer ResearchOriginal ResearchImpact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies Dhir Mashaal http://orcid.org/0000-0002-1426-1098\n1\nChoudry Haroon A. \n1\nHoltzman Matthew P. \n1\nPingpank James F. \n1\nAhrendt Steven A. \n1\nZureikat Amer H. \n1\nHogg Melissa E. \n1\nBartlett David L. \n1\nZeh Herbert J. \n1\nSinghi Aatur D. \n2\nBahary Nathan [email protected] \n3\n1 Division of Surgical OncologyUniversity of Pittsburgh Medical CenterPittsburghPennsylvania152322 Division of Gastrointestinal PathologyUniversity of Pittsburgh Medical CenterPittsburghPennsylvania152323 Division of OncologyUniversity of Pittsburgh Medical CenterPittsburghPennsylvania15232* Correspondence\n\nNathan Bahary, Division of Oncology, Co‐Director UPMC Pancreatic Cancer Center of Excellence, UPMC Cancer Pavilion, 5150 Centre Avenue, 5th floor, Pittsburgh, PA 15232. Tel: 412‐864‐7764; Fax: 412‐648‐6579; E‐mail: [email protected]\n28 12 2016 1 2017 6 1 10.1002/cam4.2017.6.issue-1195 206 07 8 2016 28 9 2016 12 11 2016 © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.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\nThe impact of genomic profiling on the outcomes of patients with advanced gastrointestinal (GI) malignancies remains unknown. The primary objectives of the study were to investigate the clinical benefit of genomic‐guided therapy, defined as complete response (CR), partial response (PR), or stable disease (SD) at 3 months, and its impact on progression‐free survival (PFS) in patients with advanced GI malignancies. Clinical and genomic data of all consecutive GI tumor samples from April, 2013 to April, 2016 sequenced by FoundationOne were obtained and analyzed. A total of 101 samples from 97 patients were analyzed. Ninety‐eight samples from 95 patients could be amplified making this approach feasible in 97% of the samples. After removing duplicates, 95 samples from 95 patients were included in the further analysis. Median time from specimen collection to reporting was 11 days. Genomic alteration‐guided treatment recommendations were considered new and clinically relevant in 38% (36/95) of the patients. Rapid decline in functional status was noted in 25% (9/36) of these patients who could therefore not receive genomic‐guided therapy. Genomic‐guided therapy was utilized in 13 patients (13.7%) and 7 patients (7.4%) experienced clinical benefit (6 PR and 1 SD). Among these seven patients, median PFS was 10 months with some ongoing durable responses. Genomic profiling‐guided therapy can lead to clinical benefit in a subset of patients with advanced GI malignancies. Attempting genomic profiling earlier in the course of treatment prior to functional decline may allow more patients to benefit from these therapies.\n\nClinical benefitgastrointestinal malignanciesgenomic‐guided therapygenomicsprecision medicine source-schema-version-number2.0component-idcam4992cover-dateJanuary 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.0.3 mode:remove_FC converted:27.01.2017\n\nCancer Medicine \n2017 , 6 (1 ):195 –206\n==== Body\nIntroduction\nGenomics‐driven cancer treatments have provided new hope to cancer patients with advanced malignancies. This approach is often termed as precision oncology or personalized cancer care 1, 2. Although oncologists have been customizing the treatment of various malignancies based on site, stage, and tolerability, etc., genetic guidance in selection of therapies has added another level of complexity. Data from retrospective analyses and early‐phase clinical trials have demonstrated that strategy of matching targeted agents with genomic alterations is associated with encouraging results in the treatment of patients with various cancers 3, 4, 5, 6. Schwaederle et al. in their meta‐analysis of phase II clinical trials noted that, across various malignancies, a personalized strategy was an independent predictor of better outcomes and fewer toxicity‐related deaths 6.\n\nHowever, integration of genomics‐driven care into routine oncology practice remains challenging given the practical and cost implications 1, 2, 7. At the time of their genomic evaluation, many of these patients have advanced refractory disease and a rapidly declining clinical course, disqualifying them from participating in molecular target‐driven clinical trials. There are few prospective studies validating the feasibility of a genomics‐driven approach in solid tumors including single‐disease and multidisease settings 8, 9. Sohal et al. in their prospective study of solid tumors reported that 49% of the 223 evaluable patients were recommended a specific therapy, but only 11% received such therapy 9. However, data evaluating genomics‐driven therapy specifically for advanced gastrointestinal (GI) malignancies are limited. In addition, it remains unknown whether such therapy would impact outcomes as mutations detected late in the treatment course of the disease may not be the current disease drivers. Therefore, the percentage of patients with advanced GI malignancies whose treatment plan is altered after genomic testing remains unknown. Consequently, the aim of this study was to evaluate the impact of next‐generation sequencing on the treatment plan and outcomes in patients with advanced gastrointestinal malignancies.\n\nPatients and Methods\nThe study was approved by the University of Pittsburgh Institutional Review Board (PRO16020064). All patients with advanced gastrointestinal malignancies treated at University of Pittsburgh Cancer Institute and allied cancer centers who underwent next‐generation sequencing (NGS) were included in this study. The unique setup of the University of Pittsburgh Medical Center—Cancer Centers Network connects the main institution with >40 network community sites covering a geographic area of >200 miles around greater Pittsburgh allowing us to include patients treated at both academic and community oncology centers.\n\nTumor specimens were shipped to Foundation Medicine, Inc. (Cambridge, MA), for sequencing using the FoundationOne platform. This platform is designed to include all genes known to be somatically altered in human solid tumors that are validated targets for therapy, either approved or in clinical trials, and/or that are unambiguous drivers of oncogenesis based on current knowledge 10. Technical specifications for the test are provided at the FoundationOne website (http://foundationone.com/learn.php#4). Briefly, FoundationOne applied next‐generation sequencing to identify all four types [base substitutions, insertions and deletions (indels), copy number alterations (CNAs), and rearrangements] of genomic alterations across the coding region of 315 cancer‐related genes plus introns from 28 genes. Funding for testing was borne as standard of care through each individual's insurance plan.\n\nGenomic data were collected from the standard FoundationOne patient reports. Alterations which have been previously characterized in the literature were categorized as gene alterations (GAs), whereas the alterations which have not been characterized in the literature were referred to as variants of unknown significance (VUS). VUSs were not considered to make any therapeutic decisions in this study. Electronic chart review was performed to evaluate for demographic variables of the patients as well as to ascertain if the genomics‐guided therapy was utilized in the treatment of the patients. Statistical analyses were performed using STATA 14.1 (Statacorp, 4905 Lakeway Drive, College Station, Texas, US). Continuous variables were summarized as medians with interquartile range (IQR) and categorical variables were summarized as frequencies and percentages. Progression‐free survival was calculated from the start of genomic‐guided therapy until evidence of disease progression by imaging or tumor markers. Kaplan–Meier method was used to estimate the probability of progression‐free survival. Clinical benefit was defined as complete response (CR) or partial response (PR) or stable disease (SD) at 3 months.\n\nResults\nA total of 101 consecutive samples from 97 patients consisting of all samples sent from the University of Pittsburgh Medical Center—Cancer Centers Network to FoundationOne from April, 2013 to April, 2016 were analyzed. Ninety‐eight samples from 95 patients could be amplified to provide meaningful genetic information making this approach feasible in 97% of the samples. Three patients had two samples each sent for testing; only one sample was included in the analysis to avoid duplication of the genetic information. Therefore, 95 samples from 95 patients were included in the further analysis.\n\nThe median age of the studied patients was 50 years; women comprised 40% of patients. Table 1 summarizes the baseline characteristics of the patients and tested samples. Colorectal adenocarcinoma (36%), pancreatic adenocarcinoma (20%), and appendiceal adenocarcinoma (9.5%) were the most common diagnoses. Approximately 28% of the reports were qualified, that is, genomic alterations could be confirmed, but the data obtained may have been insufficient for comprehensive detection of genomic alterations due to poor specimen quality. Median time from specimen receipt to reporting of the genomic data was 11 days and 75% of the samples were reported within 2 weeks. Median number of GAs (excluding VUS) detected per sample were 4 and median number of VUS per sample were 7. Median time from the original diagnosis to genomic profiling was 20 months. A median of 1 FDA‐approved therapy in other tumor types which could be implicated in the tumor being sequenced was suggested. A median of six clinical trials, mainly phase I trials, based on GAs were suggested.\n\nTable 1 Baseline characteristics of the patients/samples N = 95\n\n\t\nN (%)/median (iqr)\t\nAge, year\t50 (39–61)\t\nFemales\t38 (40)\t\nDiagnosis\t\nPancreatic Adenocarcinoma\t19 (20)\t\nColorectal Adenocarcinoma\t34 (35.8)\t\nAppendiceal Adenocarcinoma\t9 (9.5)\t\nNET—pancreas/small bowel\t6 (6.3)\t\nUnknown primary adenocarcinoma including PB/UGI type\t5 (5.3)\t\nCholangiocarcinoma\t5 (5.3)\t\nUnknown primary—neuroendocrine carcinoma\t3 (3.1)\t\nOther\t14 (14.7)\t\nTime from specimen collection to receipt, days\t0\t\nTime from receipt to reporting, days\t11 (9–13)\t\nTime since cancer diagnosis, months\t20 (10–39)\t\nQualified reports\t27 (28.4)\t\nGene Alterations per sample\t4 (2–6)\t\nVUS per sample\t7 (5–11)\t\nNumber of FDA‐approved therapies in the tested tumor type suggested based on genetic testing\t0 (0)\t\nNumber of FDA‐approved therapies in other tumor types implicated in treatment\t1 (0–3)\t\nNumber of suggested clinical trials\t6 (3–10)\t\nPrediction of lack of response to standard therapies\t15 (16)\t\nNET, Neuroendocrine tumor; PB, pancreaticobiliary; UGI, Upper gastrointestinal; VUS, Variants of unknown significance; FDA, Food and drug administration.\n\nJohn Wiley & Sons, LtdTP53, APC, KRAS, and SMAD4 were the most frequently mutated genes in colorectal adenocarcinoma. KRAS, CDKN2A, and TP53 were frequently mutated in pancreatic adenocarcinoma. Interestingly, 25% of tumors from patients with pancreatic adenocarcinoma harbored a BRCA2 mutation. GNAS, KRAS, TP53, and ATM were frequently mutated in appendiceal adenocarcinoma tumors. Figure 1 provides a summary of genetic alterations discovered in the three most common tumor types, that is, colorectal adenocarcinoma, pancreatic adenocarcinoma, and appendiceal adenocarcinoma.\n\nFigure 1 Mutation frequencies of genes in colorectal, pancreatic, and appendiceal adenocarcinoma.\n\nTreatment recommendations based on GAs were suggested for 75% (71/95) of the patients (Fig. 2). However, in our institution, KRAS and BRAF mutations were not considered clinically relevant as most patients with CRC already had these tests performed as a matter of protocol, and no directed KRAS therapies exist. Therefore, recommendations were considered new and clinically relevant in 38% (36/95) of the patients. In approximately two thirds of these patients (23/36), genomic‐guided therapy was not instituted due to several reasons including: (1) rapid functional decline in the patient (N = 9), (2) use of alternative standard of care therapies (N = 5), (3) enrollment in other clinical trials (N = 4), (4) observation/no evidence of disease (NED) after only site of disease was resected (N = 2), (5) lost to follow‐up (N = 2) and (6) insurance denial of therapy (N = 1). Genomic‐driven therapy was utilized in 13 patients (13.7%, 13/95). A summary of these patients is provided in Table S1. Only one patient received such therapy under a clinical trial (described below).\n\nFigure 2 Flow diagram providing a summary of samples.\n\nMany of the patients who responded to treatment based on a GA had alterations in the DNA damage repair pathway. Four patients with metastatic pancreatic cancer were found to have BRCA2 mutations. Two of these patients had a partial radiologic response and normalization of their CA 19‐9 in response to irinotecan and cisplatin. A third patient in this group received 5‐Fluorouracil and mitomycin C–based therapy due to chronic renal insufficiency and also had an excellent partial radiological response with necrosis in areas of disease and CA 19‐9 normalization. A fourth patient with a BRCA2 mutation and metastatic pancreatic cancer only recently started platinum‐based therapy and was not evaluable. Given limited open regional protocols, we have reserved therapy with PARP inhibitors for a later time point. A 30‐year‐old woman with a past history of treated early‐stage colon cancer at age 17 presented with recurrent metastatic colon cancer. Tumor analysis revealed a hypermutator phenotype; her tumor harbored more than 600 mutations/Megabase (Mb). Further evaluation of her tumor failed to reveal an underlying mismatch repair (MMR), DNA excision repair, and POLE or POLD mutations. Having failed all standard previous therapies (multiple surgeries including left colectomies, three cytoreductive procedures; two of which were accompanied with intraperitoneal hyperthermic chemoperfusion with mitomycin C, FOLFOX, FOLFIRI, and FOLFIRINOX with cetuximab) she was approved for, and responded to the anti‐PD‐1 agent nivolumab 11. Three patients with mutations in the MMR genes were treated with PD‐1 inhibitors: (1) one patients with unresectable cholangiocarcinoma who had an MLH1 mutation had a near‐complete and persistent response to pembrolizumab (discussed below), and (2) another heavily pretreated patient's metastatic CRC tumor had an MSH6 mutation and another patient's metastatic well‐differentiated high‐grade pancreatic neuroendocrine tumor harbored an MSH2 mutation (this patient's microsatellite status could not be confirmed by IHC). However, as they had exhausted all standard treatments options (mCRC KRAS mut—FOLFOX and bevacizumab, NET—interferon, long‐acting octreotide analogues, everolimus, peptide receptor radiotherapy ×2, multiple chemoembolizations, combination of everolimus and bevacizumab, temozolamide and capecitabine, XELOX, sunitinib alone, and in combination with hydroxychloroquine) they were treated with, but failed to respond to Nivolumab and ultimately succumbed to their disease. Interestingly, one patient with metastatic pancreatic cancer was found to have an ALK translocation and responded to ALK inhibition. Additionally, one patient with metastatic adenocarcinoma of unknown primary was found to have FGFR amplification and was treated with the FGFR inhibitor dovitinib on a clinical trial, resulting in stabilization of disease. In addition to the two patients with defects in mismatch repair genes (MHS2 and MSH6) who did not respond to nivolumab, three patients with therapies guided by ERBB3 amplification, NF1 mutation, and PDGFRA amplification failed to respond to directed therapy. Figure 3 provides summary of all the study patients. Median progression‐free survival (PFS) was approximately 4 months in all patients who received genomic‐guided therapy and was 10 months among those who derived any clinical benefit. A description of three patients who derived benefit from genomic‐guided therapy is provided below. These three patients were chosen as they had both a biochemical and radiologic response for illustration.\n\nFigure 3 Summary of patients treated with genomic‐guided therapy and progression‐free survival. One patient with BRCA2 mutation and metastatic pancreatic cancer recently started irinotecan and cisplatin and was not evaluable.\n\nCase 1—BRCA2 mutation and use of irinotecan with cisplatin in metastatic pancreatic cancer\nThe patient was a 38‐year‐old man, with no family history of cancer, initially diagnosed with biopsy‐proven locally advanced unresectable pancreatic (head/body) adenocarcinoma in 2013. He was treated with 8 months of FOLFIRINOX (5‐Fluorouracil, Leucovorin, Irinotecan, and Oxaliplatin) therapy and had a partial response to therapy. He subsequently underwent total pancreatectomy with portal vein resection with negative margins. Final pathology revealed a 6.5‐cm tumor, ypT3N1, and 13/47 lymph nodes positive for adenocarcinoma. No adjuvant therapy was given due to decline in functional status at that time. Eighteen months postresection, an elevation in CA 19‐9 was noted along with soft tissue thickening around the celiac axis, gastrohepatic ligament, subtle hypodensity in the segment 7 of the liver, and omental nodularity suggestive of early carcinomatosis. An endoscopic ultrasound‐guided biopsy of the celiac region was positive for adenocarcinoma and this specimen was submitted for genomic analysis. Genomic analysis identified biallelic BRCA2 mutation along with KRAS, SMAD4, and CDKN2A mutations. He was started on irinotecan and cisplatin. Pretherapy CA 19‐9 was 1673 IU/L and after four cycles CA 19‐9 decreased to 52.9 IU/L (Fig. 4A). He is currently continuing on therapy with continued response at 4 months.\n\nFigure 4 (A) CA 19‐9 and radiologic response in a patient with metastatic pancreatic cancer found to have BRCA2 mutation and treated with irinotecan and cisplatin; (B) CA 19‐9 and radiologic response in a patient with metastatic pancreatic cancer treated with ALK inhibitors crizotinib and ceritinib; (C) CA 19‐9 and radiologic response in a patient with unresectable cholangiocarcinoma treated with pembrolizumab. Pre and Post indicate pretherapy and posttherapy scans. Arrows mark the index lesions that were most easy to demonstrate and compare on the scans.\n\nCase 2—ALK translocation and use of ceritinib in metastatic pancreatic cancer\nThis patient was a 35‐year‐old man diagnosed with biopsy‐proven locally advanced pancreatic head adenocarcinoma in 2012 and underwent 3 months of therapy with FOLFIRINOX. Therapy was subsequently switched to gemcitabine and nab‐paclitaxel due to lack of response. He underwent another 3 months of gemcitabine and nab‐paclitaxel followed by pancraticoduodenectomy with negative margins. Final pathology revealed a 2‐cm tumor, ypT3N1, and 2/56 lymph nodes positive for adenocarcinoma. Postoperative adjuvant therapy was deferred due to poor functional and nutritional status. Ten months postresection CA 19‐9 was noted to be 585 U/mL and CT imaging revealed multiple newly enlarged retroperitoneal, periaortic, and retrocaval lymph nodes. At this time gemcitabine and nab‐paclitaxel were reinstituted. His CA 19‐9 normalized, but therapy was discontinued after 3 months secondary to severe neuropathy and fatigue. At that time, tumor from his resection specimen was sent for genomic analysis revealing an ALK‐EML4 translocation. He was started on Crizotinib without significant biochemical response possibly due to multiple needed dose reductions for hematologic toxicity. Treatment was then subsequently changed to Ceritinib leading to normalization of his CA 19‐9 as well as radiographic response and clinical improvement until progression after approximately 6 months of therapy (Fig. 4B). At this time repeat genomic analysis was performed which revealed the same ALK translocation. A recommendation was made for changing to an alternative ALK inhibitor—alectinib and insurance approval is currently pending.\n\nCase 3—MLHI mutation and use of pembrolizumab in unresectable cholangiocarcinoma\nA 60‐year‐old man presented in October 2012 with abdominal pain. A CT scan demonstrated a 4.6‐cm mass in the left liver with extension into the portahepatis and encasement of the common hepatic artery and portal vein; biopsy was consistent with cholangiocarcinoma. Within a month he developed jaundice. His EUS confirmed T4N0 disease and ERCP was performed with placement of a stent. The patient underwent eight cycles of gemcitabine and cisplatin, which was discontinued due to toxicity. A repeat CT scan in June, 2013, revealed stable disease. He then underwent six cycles of irinotecan and cetuximab followed by a CT scan in September 2013, which demonstrated progression of disease. His therapy was changed to FOLFOX, which was discontinued after 13 cycles due to thrombocytopenia and progressive peripheral neuropathy. In July, 2014, NGS/FoundationOne testing identified biallelic MLH1 loss. The patient subsequently enrolled in a clinical trial with pembrolizumab. After approximately 6 months, he had an excellent partial response to therapy and is currently continuing treatment on pembrolizumab (Fig. 4C).\n\nDiscussion\nThis study highlights the role of genomic profiling using a commercially available platform in patients with advanced GI malignancies being treated in a GI oncology practice including both academic and community cancer centers. Our data suggest that this approach is feasible as 97% of the samples could be successfully amplified and median time to reporting was 11 days. Recommendations for therapy were new and clinically relevant in 38% of the patients, but only 13.7% eventually received genomic‐guided therapy. The majority of these patients had advanced disease and a rapid clinical decline that prevented them from receiving genomic‐guided therapy off‐label or enrollment in an appropriate clinical trial. This suggests that undertaking genomic tumor profiling earlier in a patient's disease course may facilitate the identification and utility of directed protocol therapies. Of those screened in this analysis, however, approximately 7% of the patients eventually experienced clinical benefit. The most common single targetable alteration identified was a previously undetected BRCA2 mutations in pancreatic cancers. Multiple specific chemotherapy regimens can target this mutational landscape and we present responses with both platinum‐ and mitomycin C‐based regimens in BRCA2‐mutated patients. Trials with PARP inhibition in patients with BRCA2 mutations are also underway. Given the prevalence of BRCA pathway mutations in pancreatic adenocarcinoma (PDAC), we believe that BRCA pathway testing should be routinely undertaken in PDAC. The next most common clinically useful alteration was in the pathway of genomic instability; including one patient with metastatic CRC and hypermutator phenotype of unknown source and another patient with unresectable cholangiocarcinoma and MLH1 mutation who is responding to pembrolizumab. However, other unique molecular alterations were also identified that proved useful in offering targeted treatments (Fig. 3).\n\nThe potential for molecular‐guided therapy to affect the treatment of an individual patient has been recognized 12, 13. Initial studies by Sjoblom et al. defined the genetic landscapes of breast and colorectal cancer in 2006 and not only described several novel genes but also identified some of the key dysregulated pathways which could be the targets of therapy in future 14. Since then a team approach to defining the mutational landscape of various cancers have been taken by The Cancer Genome Atlas Project and International Cancer Genome Consortium, and new mutations and dysregulated pathways have been defined in several cancers 15, 16. Several authors have previously reported cases where drugable targets were identified and significant improvement in progression‐free survival was observed 5, 17. Others have verified the feasibility of high‐throughput testing of clinical samples for various mutations 18. Boland et al. reported their results of 500 patients who underwent next‐generation sequencing of a panel of 46 genes in a phase I clinical trials program 19. Seventy‐two percent of these patients had a mutation or variant among the 46 tested genes and 30% of the patients had alterations which were potentially actionable 19. Additionally, a recent meta‐analysis of phase II clinical trials suggested that a personalized approach compared to a nonpersonalized approach was associated with an improvement in response rates (31% vs. 10.5%, P < 0.001), progression‐free survival (5.9 months vs. 2.7 months, P < 0.001), overall survival (13.7 months vs. 8.9 months, P < 0.001), and led to fewer toxic deaths. These studies have encouraged many to consider genomics‐guided therapies in patients with advanced malignancies.\n\nMajor areas of investigation with molecular‐derived therapy include: (1) feasibility and timeliness of high‐throughput testing, (2) actionability of the targets identified, (3) and most importantly, effect on patient outcomes. Our results are discussed in these three contexts.\n\nFeasibility and timeliness of reporting\nOur results are comparable to others studies which reported a median time of 18–26 days from consent to reporting 8, 9, 20, 21. Of note, as this was a retrospective analysis, time from consent to dispatch of the specimens was not evaluable and this may have led to a shorter median time to reporting of 11 days in this study. Similarly, previous studies have reported feasibility of genomic analyses in 61–86% of the patients 9, 20, 21. In this study only patients who had specimens available for genomic profiling were analyzed and we could not evaluate the number of patients who could not undergo genomic testing due to inadequate specimens. Although molecular profiling could be performed in 97% of the specimens, approximately 30% of the reports were qualified. This could be due to poor specimen quality or sequencing failure, but the exact reasons could not be ascertained.\n\n“Actionability” of identified targets\nThe definition of actionability is not uniform and different terms such as “druggable”, “actionable”, “therapy matching”, “genomic guidance”, etc. have been used. Similarly, the impact of a genetic alteration and response to treatment may be different in different tumors, for example, BRAF V600E mutation predicts response to single‐agent vemurafenib in melanoma but not in colorectal cancer 22. Most of the studies have previously reported a targetable/actionable/druggable mutation in 30–49% of the patients 8, 9, 19, 20. In contrast to the study by Boland et al. (discussed above), KRAS mutations were not considered clinically actionable for therapy in this study due to (1) lack of effective agents that target RAS pathway and (2) most patients with metastatic colorectal cancer undergo expanded RAS analysis at our institute prior to Foundations testing 23. Although this study confirmed the presence of previously known mutations in GI tumors, one of the interesting findings was the presence of BRCA2 mutations in 25% of the tested pancreatic adenocarcinoma samples allowing for tailored therapy using platinum‐based or mitomycin‐based agents for these patients. They also support the investigational use of PARP inhibitors in available clinical trials at progression. These results are consistent with the recent reports which suggested a 17–24% incidence of BRCA2/PALB2 mutations in patients with pancreatic adenocarcinoma 24, 25. Additionally, based on the NGS results identifying the MLH1 mutation in one patient with cholangiocarcinoma, as well as other data supporting the incidence of a deficient mismatch repair (dMMR) phenotype in multiple GI cancers, we have routinely started screening all GI tumors for mismatch repair deficiency. Although the true incidence of dMMR in various GI tumors remains uncertain, we believe this is a prudent algorithm given the efficacy of PD‐1 inhibitors in tumors with mismatch repair deficiency 26. As a result, another patient with advanced pancreatic cancer not reported here was found to have an MLH1 gene mutation on our routine screening for MMR genes and treated with a PD1 inhibitor resulting in a partial response.\n\nEfforts for integration of genomic approaches in clinical practice are ongoing. At some institutions panel testing is undertaken for all patients. Other institutions utilize the FoundationsOne or similar platforms. Our own institution is in the process of creating a panel including BRCA and other DNA repair pathway genes. Rather than dictate a single platform we would recommend the platform that is available to the individual oncologist, which will differ whether they are located in the community or at academic institutions.\n\nPatient outcomes\nIt remains largely unknown as to what percentage of all patients eventually benefit from genomic‐guided therapy as only a small percentage of mutations are drivers and the vast majority are passenger mutations which confer no growth advantage 27. Additionally, clinical significance of many variants remains unknown at this time. No such variants were used to guide therapy in this study. Several randomized controlled trials are underway to assess the effectiveness of genomic‐guided therapy including IMPACT II (Initiative for Molecular Profiling and Advanced Cancer Therapy II, www.clincaltrials.gov NCT02152254), SHIVA (A Randomized Phase II Trial Comparing Therapy Based on Tumor Molecular Profiling Versus Conventional Therapy in Patients With Refractory Cancer, www.clincaltrials.gov NCT01771458), and NCI‐MPACT (National Cancer Institute—Molecular Profiling‐based Assignment of Clinical Trials, www.clincaltrials.gov NCT01827384)3. One of the major barriers to the receipt of genomic‐driven therapy is the rapid functional decline in these patients with advanced malignancies. Most of these clinical trials allow only patients with good functional status which may not be the case in the real world. Sohal et al. in their prospective study of precision oncology in solid tumors reported that 49 (26%) of 109 patients (109/223, 49% of total) who were recommended genomic‐guided therapy could not receive the therapy given rapid functional decline. In this study, 38% of the patients were recommended genomic‐guided therapy, but 25% (9/36) of these patients had rapid functional decline. This raises the question of the timing of genomic profiling with regards to the stage of disease. The median time from diagnosis to genomic profiling in this study was 20 months and was 18 months in the study by Sohal et al. Chantrill et al. in their report of pilot stage of IMPaCT trial identified 22 of 93 patients with potential for receipt of molecular‐guided therapy, but none of these patients were eligible given rapid decline in functional status 8. Earlier testing will allow more patients to have genomic‐guided therapy and possibly positively impact patient outcomes as well.\n\nThis study is unique as it focused on advanced GI malignancies and reported the clinical outcomes in patients who received genomic‐guided therapy. Von Hoff et al. in their pilot study reported that 18 (27%) of the 66 patients who received molecular profiling (MP)‐guided therapy demonstrated an improvement in their PFS, that is, PFS on MP‐guided therapy/PFS on most recent therapy >1.3 28. However, only 6 of the 18 (6/86, 7%) patients had GI malignancies. Definitions such as PFS on MP‐guided therapy/PFS on most recent therapy >1.3 may not assess clinical benefit as transparently as disease control at 3 months, as used in this study. Recently, a large single‐center prospective study by Wheler et al. was published wherein the authors reported their experience in 500 patients who underwent NGS using a similar platform as used in this study 29. Approximately 38% (188/500) of the patients received therapy of which 65% (122/500) received matched (genomic‐guided therapy) and 35% (66/188) received unmatched therapy. These authors reported a significant improvement in time to failure in patients who underwent matched therapy (median 2.8 months vs. 1.9 months, P = 0.001). Additionally, patients who underwent matched therapy also demonstrated a trend toward improved OS (median 9.2 months vs. 6.8 months, P = 0.087) and were more likely to derive clinical benefit (19% vs. 8%, respectively, P = 0.061). Similar to this study the most common reasons for nonreceipt of therapy were functional decline/death or hospice transfer. This study only focuses on GI malignancies, whereas in the Wheler et al. study, the majority of the patients had nongastrointestinal malignancies including ovarian (18%), breast (16%), sarcoma (13%), and renal cell cancers (7%).\n\nThe limitations of this study include its retrospective design, different tumor types, small sample size of each individual tumor type, and the limited variety of analyzed tumors resulting from inherent local referral patterns and patients' insurance willingness to bear the costs of the analysis. As only a single platform was utilized, underdetection of some targetable mutations in genes recently implicated in genomic instability, such as RPA1, XRCC4, and XRCC6, may have occurred 24, 25. As NGS platforms continue to evolve further actionable/targetable mutations will be analyzed. Additionally, given the small sample size distribution of tumor types in this study, these results may not match the tumors' epidemiologic distribution. Mutant allele frequencies (MAFs), which can provide insight into tumor heterogeneity or germline status, were not available for all patients in this study. Finally, given the possibility of uncovering germline mutations, all efforts should be made to determine if the source of mutations is germline. Genetic counseling should then be sought in patients found to have germline mutations.\n\nIn conclusion, current platform genomic profiling results can be obtained in most patients within 2 weeks, and up to one third of the patients may be candidates for genomic‐guided therapy. However, only a small percentage of patients are able to receive such therapies given that most patients had such determinations made late in the clinical course, when they are facing a rapid functional decline. Genomic profiling undertaken earlier in a patient's clinical course may afford an improved chance to undergo directed therapy or afford time to access clinical trials of new agents. In this study, despite the limitations of our testing paradigm, about 7% of the patients experienced clinical benefit from directed treatment encompassing multiple targetable pathways. These data support the utility of early mutational assessments and utilization of targeted therapies. As new agents that can exploit this mutational landscape find their way into clinical practice, the overall utility of this paradigm can only improve. Randomized controlled trials which are under way will shed more light on the subject.\n\nConflicts of Interest\nNone.\n\nSupporting information\n\nTable S1. Summary of previous treatments and genomic alterations among the 12 patients treated with genomic‐guided therapy.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nGarraway , L. A. \n, \nJ. \nVerweij \n, and \nK. V. \nBallman \n. 2013 \nPrecision oncology: an overview . J. Clin. Oncol. \n31 :1803 –1805 .23589545 \n2 \n\nSchilsky , R. 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Oncotarget \n6 :20099 –20110 .26015395 \n20 \n\nTran , B. \n, \nA. M. \nBrown \n, \nP. L. \nBedard \n, \nE. \nWinquist \n, \nG. D. \nGoss \n, \nS. J. \nHotte \n, et al. 2013 \nFeasibility of real time next generation sequencing of cancer genes linked to drug response: results from a clinical trial . Int. J. Cancer \n132 :1547 –1555 .22948899 \n21 \n\nLe Tourneau , C. \n, \nX. \nPaoletti \n, \nN. \nServant \n, \nI. \nBieche \n, \nD. \nGentien \n, \nT. \nRio Frio \n, et al. 2014 \nRandomised proof‐of‐concept phase II trial comparing targeted therapy based on tumour molecular profiling vs conventional therapy in patients with refractory cancer: results of the feasibility part of the SHIVA trial . Br. J. Cancer \n111 :17 –24 .24762958 \n22 \n\nKopetz , S. \n, \nJ. \nDesai \n, \nE. \nChan \n, \nJ. R. \nHecht \n, \nP. J. \nO'Dwyer \n, \nD. \nMaru \n, et al. 2015 \nPhase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF‐Mutated Colorectal Cancer . J. Clin. 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R. \nBartlett \n, \nH. \nKemberling \n, \nA. D. \nEyring \n, et al. 2015 \nPD‐1 Blockade in Tumors with Mismatch‐Repair Deficiency . N. Engl. J. Med. \n372 :2509 –2520 .26028255 \n27 \n\nVogelstein , B. \n, \nN. \nPapadopoulos \n, \nV. E. \nVelculescu \n, \nS. \nZhou \n, \nL. A. \nJr Diaz \n, and \nK. W. \nKinzler \n. 2013 \nCancer genome landscapes . Science \n339 :1546 –1558 .23539594 \n28 \n\nVon Hoff , D. D. \n, \nJ. J. \nJr\nStephenson \n, \nP. \nRosen \n, \nD. M. \nLoesch \n, \nM. J. \nBorad \n, \nS. \nAnthony \n, et al. 2010 \nPilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers . J. Clin. Oncol. \n28 :4877 –4883 .20921468 \n29 \n\nWheler , J. J. \n, \nF. \nJanku \n, \nA. \nNaing \n, \nY. \nLi \n, \nB. \nStephen \n, \nR. G. \nZinner \n, et al. 2016 \nCancer therapy directed by comprehensive genomic profiling: a single center study . Cancer Res. \n76 :3690 –3701 .27197177\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-7634", "issue": "6(1)", "journal": "Cancer medicine", "keywords": "Clinical benefit; gastrointestinal malignancies; genomic-guided therapy; genomics; precision medicine", "medline_ta": "Cancer Med", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D002945:Cisplatin; D005260:Female; D005472:Fluorouracil; D005770:Gastrointestinal Neoplasms; D023281:Genomics; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009944:Organoplatinum Compounds; D010180:Pancreatectomy; D057285:Precision Medicine; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D016896:Treatment Outcome", "nlm_unique_id": "101595310", "other_id": null, "pages": "195-206", "pmc": null, "pmid": "28028924", "pubdate": "2017-01", "publication_types": "D016428:Journal Article", "references": "24142049;24687035;23539594;20393554;24857061;19924296;24915778;25658984;24663044;27197177;23589545;24633422;28028924;26028255;27022117;24360397;25896973;25719666;20921468;26015395;16959974;24762958;26909576;26304871;26460303;22948899;18772890;26553780", "title": "Impact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies.", "title_normalized": "impact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies" }

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IMPACT OF GENOMIC PROFILING ON THE TREATMENT AND OUTCOMES OF PATIENTS WITH ADVANCED GASTROINTESTINAL MALIGNANCIES. CANCER MEDICINE. 2017;6(1):195-206", "literaturereference_normalized": "impact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170302", "receivedate": "20170302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13287742, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" } ]

{ "abstract": "To systematically describe the clinical and histopathological features of a case series of conjunctival carcinomatous lesions underlying as-and also masquerading-pyogenic granuloma.\n\n\n\nNine cases of conjunctival carcinomatous lesions underlying a pyogenic granuloma (which were clinically predominant) were retrospectively identified. Patients' records were analysed for demographic data, clinical appearance and the postoperative course. Formalin-fixed paraffin-embedded specimens were routinely processed and stained with H&E and periodic acid-Schiff. Immunohistochemical stains for cytokeratin were performed in selected cases.\n\n\n\nAll nine tumours were located in the conjunctiva (bulbar, tarsal, limbal conjunctiva) of patients between 44 and 80 years. The lesions exhibited clinical features of pyogenic granuloma which dominated the clinical appearance. Additional features comprised a papillomatous appearance of the adjacent conjunctiva, a more whitish aspect of the lesion and a history of squamous cell carcinoma (SCC) respectively surgery for other entities. Histopathological analysis revealed a carcinomatous lesion (conjunctival intraepithelial neoplasia or SCC) at the base of a classic pyogenic granuloma in all nine cases. Surgical removal (R0 resection) was performed. Three cases received adjuvant mitomycin C or interferon α2b treatment. Two lesions locally recurred within 2 years after initial presentation.\n\n\n\nCarcinomatous lesions may be accompanied by a pyogenic granuloma which may dominate the clinical pictures. As the tumour is usually located at the base of the lesion, a complete surgical excision followed by histopathological analysis is mandatory for each lesion appearing as conjunctival pyogenic granuloma.", "affiliations": "Division of Ophthalmic Pathology, Department of Ophthalmology, University Hospital Bonn, Bonn, Germany [email protected].;L.F. Montgomery Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Emory University, Atlanta, Georgia, USA.;Division of Ophthalmic Pathology, Department of Ophthalmology, University Hospital Bonn, Bonn, Germany.;Eye Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Division of Ophthalmic Pathology, Department of Ophthalmology, University Hospital Bonn, Bonn, Germany.;Eye Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.", "authors": "Herwig-Carl|Martina C|MC|0000-0002-5943-7675;Grossniklaus|Hans E|HE|;Müller|Philipp L|PL|;Atzrodt|Lisa|L|;Loeffler|Karin U|KU|;Auw-Haedrich|Claudia|C|", "chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077190:Interferon alpha-2; D016685:Mitomycin; D007633:Keratins", "country": "England", "delete": false, "doi": "10.1136/bjophthalmol-2018-312960", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-1161", "issue": "103(10)", "journal": "The British journal of ophthalmology", "keywords": "conjunctival intraepithelial neoplasia; histology; pyogenic granuloma; squamous cell carcinoma; tumour", "medline_ta": "Br J Ophthalmol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002278:Carcinoma in Situ; D002294:Carcinoma, Squamous Cell; D017024:Chemotherapy, Adjuvant; D003230:Conjunctival Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D017789:Granuloma, Pyogenic; D006801:Humans; D000077190:Interferon alpha-2; D007633:Keratins; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D012189:Retrospective Studies", "nlm_unique_id": "0421041", "other_id": null, "pages": "1469-1474", "pmc": null, "pmid": "30709809", "pubdate": "2019-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Pyogenic granuloma associated with conjunctival epithelial neoplasia: report of nine cases.", "title_normalized": "pyogenic granuloma associated with conjunctival epithelial neoplasia report of nine cases" }

[ { "companynumb": "US-009507513-2003USA010240", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "INTERFERON ALFA-2B" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "103132", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 MIO IE/ML 4 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT NEOPLASM OF CONJUNCTIVA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTRON A" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HERWIG C, GROSSNIKLAUS H, MULLER P, ATZRODT L, LOEFFLER K, AUW H, ET AL. PYOGENIC GRANULOMA ASSOCIATED WITH CONJUNCTIVAL EPITHELIAL NEOPLASIA: REPORT OF NINE CASES. THE BRITISH JOURNAL OF OPHTHALMOLOGY. 2019?103 (10):1469-74", "literaturereference_normalized": "pyogenic granuloma associated with conjunctival epithelial neoplasia report of nine cases", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200328", "receivedate": "20200328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17595312, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-2003USA010213", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "INTERFERON ALFA-2B" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "103132", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 MIO IE/ML 4 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT NEOPLASM OF CONJUNCTIVA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTRON A" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HERWIG C, GROSSNIKLAUS H, MULLER P, ATZRODT L, LOEFFLER K, AUW H, ET AL. PYOGENIC GRANULOMA ASSOCIATED WITH CONJUNCTIVAL EPITHELIAL NEOPLASIA: REPORT OF NINE CASES. THE BRITISH JOURNAL OF OPHTHALMOLOGY. 2019?103 (10):1469-74", "literaturereference_normalized": "pyogenic granuloma associated with conjunctival epithelial neoplasia report of nine cases", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200328", "receivedate": "20200328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17595313, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]

{ "abstract": "OBJECTIVE\nTo analyse the incidence and type of epidural steroid injection (ESI)-related adverse events, including procedure-related complications and drug-related systemic effects requiring hospitalisation or emergency room (ER) visits.\n\n\nMETHODS\nThis study included 52,935 ESI procedures performed in 22,059 patients in our department from March 2004 to February 2016. Of these, we retrospectively reviewed the cases of 1570 patients (1713 procedures) who were hospitalised or visited the ER within 1 month after ESI. ESI-related events were classified as procedure-related complications, drug-related systemic effects, or of uncertain relationship. Descriptive data are provided; no statistical analysis was performed.\n\n\nRESULTS\nThere were 244 ESI-related events in 235 patients (males:females = 102:133; mean age: 65.7 years; range: 20-93 years). The incidence of ESI-related events was 0.46% per procedure, including 14 procedure-related complications, 56 drug-related systemic effects, and 174 events of uncertain cause. Of the 52,935 patients, 6 (0.011%) experienced major complications (two spine haematomas and four infections), 1 patient died, and 1 experienced neurological sequelae.\n\n\nCONCLUSIONS\nAlthough major procedure-related complications and drug-related systemic effects of ESI requiring hospitalisation are very rare, infection and haematoma can occur, resulting in serious outcomes. Hence, ESI should be carefully considered in high-risk patients.\n\n\nCONCLUSIONS\n• The incidence of ESI-related events requiring hospitalisation was 0.46%. • The incidence of procedure-related complications was 0.026%. • The incidence of drug-related systemic effects was 0.11%. • The incidence of major complication of ESI was 0.011%. • The major complications were spine infection, haematoma, and sepsis.", "affiliations": "Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea.;Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea.;Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea.;Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea.;Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea.;Department of Radiology, Seoul National University Bundang Hospital, Gyeongi-do, 463-707, Korea. [email protected].", "authors": "Lee|Joon Woo|JW|;Lee|Eugene|E|;Lee|Guen Young|GY|;Kang|Yusuhn|Y|;Ahn|Joong Mo|JM|;Kang|Heung Sik|HS|http://orcid.org/0000-0002-7024-388X", "chemical_list": "D013256:Steroids", "country": "Germany", "delete": false, "doi": "10.1007/s00330-017-4977-7", "fulltext": null, "fulltext_license": null, "issn_linking": "0938-7994", "issue": "28(1)", "journal": "European radiology", "keywords": "Complications; Drug-related side effects and adverse reactions; Epidural; Injections; Spine; Steroids", "medline_ta": "Eur Radiol", "mesh_terms": "D059787:Acute Pain; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064420:Drug-Related Side Effects and Adverse Reactions; D004636:Emergency Service, Hospital; D005260:Female; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D007268:Injections, Epidural; D008297:Male; D008875:Middle Aged; D011843:Radiculopathy; D056910:Republic of Korea; D012189:Retrospective Studies; D013256:Steroids; D055815:Young Adult", "nlm_unique_id": "9114774", "other_id": null, "pages": "418-427", "pmc": null, "pmid": "28726118", "pubdate": "2018-01", "publication_types": "D016428:Journal Article", "references": "20616178;21699610;23765044;23159970;17296980;17340166;15749619;18850035;19863744;19404169;21790519;21392252;19543892;24850123;20870478;25903715;16799275;2218714;19369604;26065819;16904497;17114531;26761719;25806907;17940309;27183400;20033148;19165301;16858486;27228513;17853663;25694868;19769520;18675752;11452067;25200706;23756957", "title": "Epidural steroid injection-related events requiring hospitalisation or emergency room visits among 52,935 procedures performed at a single centre.", "title_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre" }

[ { "companynumb": "KR-FRESENIUS KABI-FK201800185", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diabetic gastroparesis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180109", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354868, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083862", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372718, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083882", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebellar infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372318, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800188", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180109", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354446, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083863", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "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": "OMNIPAQUE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372716, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083867", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372239, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800193", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180108", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354749, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083810", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diabetic gastroparesis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372809, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800189", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180108", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354442, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800187", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Duodenal ulcer", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180109", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354552, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800190", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180108", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354420, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800191", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebellar infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180108", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354375, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-FRESENIUS KABI-FK201800192", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lacunar infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE J,LEE E,LEE G,KANG Y,AHN J,KANG H. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180109", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14354835, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083875", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "2ML (10MG) WAS ADMINISTERED", "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": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372303, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "KR-MYLANLABS-2017M1083843", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "050", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10MG (2ML)", "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": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IOHEXOL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG IODINE PER ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIAGNOSTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMNIPAQUE" } ], "patientagegroup": null, "patientonsetage": "84", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEE JW, LEE E, LEE GY, KANG Y, AHN JM, KANG HS. EPIDURAL STEROID INJECTION-RELATED EVENTS REQUIRING HOSPITALISATION OR EMERGENCY ROOM VISITS AMONG 52,935 PROCEDURES PERFORMED AT A SINGLE CENTRE. EUR-RADIOL 2018?28(1):418-427.", "literaturereference_normalized": "epidural steroid injection related events requiring hospitalisation or emergency room visits among 52 935 procedures performed at a single centre", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372713, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "Antipsychotic medications, including risperidone, are widely used in the treatment of psychiatric disorders, including schizophrenia. While hyperthermia is an establish adverse effect of these medications, less is known about the rare occurrence of hypothermia. We present two patients who developed hypothermia, bradycardia and cardiac arrest in association with risperidone. We briefly review previously similarly reported cases.", "affiliations": "Internal Medicine, Wright Center for Graduate Medical Education, Scranton, Pennsylvania, USA [email protected].;Internal Medicine, Wright Center for Graduate Medical Education, Scranton, Pennsylvania, USA.;Internal Medicine, Wright Center for Graduate Medical Education, Scranton, Pennsylvania, USA.;Pulmonary and Critical Care Medicine, Geisinger Community Medical Center, Scranton, Pennsylvania, USA.", "authors": "Sharma|Nishant|N|http://orcid.org/0000-0001-5324-922X;Bhat|Sangeeta|S|;Ravi|Divya|D|;Ochieng|Pius|P|", "chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-234999", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "13(5)", "journal": "BMJ case reports", "keywords": "psychiatry (drugs and medicines); unwanted effects / adverse reactions", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D001919:Bradycardia; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007035:Hypothermia; D008297:Male; D018967:Risperidone; D012559:Schizophrenia", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32439747", "pubdate": "2020-05-20", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Severe hypothermia, bradycardia and cardiac arrest in association with risperidone.", "title_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone" }

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"activesubstancename": "FINASTERIDE" }, "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": "FINASTERIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LISINOPRIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TERAZOSIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TERAZOSIN" } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Sinus bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P.. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TERAZOSIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TERAZOSIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FINASTERIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076436", "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": "FINASTERIDE." } ], "patientagegroup": "6", "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus bradycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REPORTS. 2020?13(5):E234999. DOI: 10.1136/BCR?2020?234999.", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200910", "receivedate": "20200615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17894624, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-EMCURE PHARMACEUTICALS LTD-2020-EPL-000692", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "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": "WARFARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "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": "METOPROLOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "076228", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HAD BEEN ON FOR OVER 4 YEARS", "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": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REP. 2020?13(5):E234999", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200608", "receivedate": "20200608", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17869517, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-OXFORD PHARMACEUTICALS, LLC-2020OXF00074", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "078071", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P.. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REP.. 2020?13(5)", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200616", "receivedate": "20200616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17901187, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-TEVA-2020-US-1796926", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR OVER 4 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR OVER 4 YEARS", "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": "METOPROLOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR OVER 4 YEARS", "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": "RISPERIDONE." } ], "patientagegroup": "6", "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE.. DRUG AND THERAPEUTICS BULLETIN. 2021 JAN?59:13?15.", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210217", "receivedate": "20200707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17991076, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20210419" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0124085", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076879", "drugbatchnumb": "UNKNOWN", "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": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL SUCCINATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090617", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL SUCCINATE." } ], "patientagegroup": "6", "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus bradycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REPORTS. 2020?13(5):E234999. DOI: 10.1136/BCR?2020?234999.", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200910", "receivedate": "20200615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17894626, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-AJANTA PHARMA USA INC.-2085850", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "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": "METOPROLOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "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": "WARFARIN SODIUM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201003", "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": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REP.2020? 13(5).", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200615", "receivedate": "20200615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 17896152, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-PRINSTON PHARMACEUTICAL INC.-2020PRN00201", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "077493", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. BMJ CASE REP. 2020?13(5)", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200612", "receivedate": "20200612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17890520, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2020JUB00202", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "078828", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N, BHAT S, RAVI D, OCHIENG P.. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE.. BMJ CASE REP. 2020?13(5)", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200616", "receivedate": "20200616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17901085, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "US-TEVA-2020-US-1796930", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LISINOPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FINASTERIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FINASTERIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "077860", "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": "RISPERIDONE." } ], "patientagegroup": "6", "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHARMA N. SEVERE HYPOTHERMIA, BRADYCARDIA AND CARDIAC ARREST IN ASSOCIATION WITH RISPERIDONE. DRUG AND THERAPEUTICS BULLETIN. 2021 JAN?59:13?15.", "literaturereference_normalized": "severe hypothermia bradycardia and cardiac arrest in association with risperidone", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210712", "receivedate": "20200707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17991075, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20211014" } ]

{ "abstract": "BACKGROUND\nThe widespread availability of medication without prescription, so-called over the counter (OTC), and the rapid development of health consciousness of Poles is associated with broad access to medical information in the mass media. This causes patients to recognize their own disease, cancel doctor's appointments, and begin self-treatment. This time and money-saving behavior, often signaled by pain, usually leads to the treatment of symptoms alone, without seeking the cause of the disease.The aim of the study was to present life-threatening paracetamol poisoning, and the treatment of acute liver failure.\n\n\nMETHODS\nIn 2002-2014, 35 patients were hospitalized due to acute paracetamol poisoning: 17 female and 18 male patients aged between 17-59 (mean 32.3 years). Patients were treated in the surgical intensive care unit, where their parameters of liver and renal function were continuously monitored. If there was no improvement in the liver function, patients underwent albumin dialysis with the Prometheus system and were qualified for liver transplantation (LTx).\n\n\nRESULTS\n26 patients were treated pharmacologically and 7 out of 9 patients who underwent LTx were dialyzed. Overall, 11 patients had 26 albumin dialysis in total; 4 patients died - 1 post-transplant and 3 pre-transplant.\n\n\nCONCLUSIONS\nParacetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.", "affiliations": "Department of General, Transplant & Liver Surgery, Medical University of Warsaw, Poland.;Department of General, Transplant & Liver Surgery, Medical University of Warsaw, Poland.;Department of General, Transplant & Liver Surgery, Medical University of Warsaw, Poland.;Liver and Internal Medicine Unit of Department of General, Transplant & Liver Surgery, Medical University of Warsaw, Poland.;1. Centre of Postgraduate Medical Education, Warsaw Poland 2. Ministry of Health, Warsaw, Poland.;1. Polish Transplant Coordinating Center \"Poltransplant\", Warsaw, Poland 2. Department of Surgical and Transplant Nursing, Medical University of Warsaw, Poland.;Department of Pathology, Medical University of Warsaw, Poland.;Department of General, Transplant & Liver Surgery, Medical University of Warsaw, Poland.", "authors": "Wróblewski|Tadeusz|T|;Kobryń|Konrad|K|;Kozieł|Sławomir|S|;Ołdakowska-Jedynak|Urszula|U|;Pinkas|Jarosław|J|;Danielewicz|Roman|R|;Ziarkiewicz-Wróblewska|Bogna|B|;Krawczyk|Marek|M|", "chemical_list": "D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D000082:Acetaminophen", "country": "Poland", "delete": false, "doi": "10.5604/12321966.1185790", "fulltext": null, "fulltext_license": null, "issn_linking": "1232-1966", "issue": "22(4)", "journal": "Annals of agricultural and environmental medicine : AAEM", "keywords": null, "medline_ta": "Ann Agric Environ Med", "mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D005260:Female; D006760:Hospitalization; D006801:Humans; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D011044:Poland; D055815:Young Adult", "nlm_unique_id": "9500166", "other_id": null, "pages": "762-7667", "pmc": null, "pmid": "26706992", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": null, "title": "Acetaminophen (Paracetamol) induced acute liver failure - A social problem in an era of increasing tendency to self-treatment.", "title_normalized": "acetaminophen paracetamol induced acute liver failure a social problem in an era of increasing tendency to self treatment" }

[ { "companynumb": "PL-JNJFOC-20160101971", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALCOHOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALCOHOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematuria", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cirrhosis alcoholic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bladder tamponade", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma hepatic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WROBLEWSKI T, KOBRYN K, KOZIEL S, OLDAKOWSKA-JEDYNAK U, PINKAS J, DANIELEWICZ R, ET AL. ACETAMINOPHEN (PARACETAMOL) INDUCED ACUTE LIVER FAILURE - A SOCIAL PROBLEM IN AN ERA OF INCREASING TENDENCY TO SELF-TREATMENT. ANNALS OF AGRICULTURAL AND ENVIRONMENTAL MEDICINE 2015?22(4):762-767.", "literaturereference_normalized": "acetaminophen paracetamol induced acute liver failure a social problem in an era of increasing tendency to self treatment", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20160119", "receivedate": "20160119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11928883, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "Approximately 5% of all women in the world are HBsAg-positive. Chronic hepatitis B is a problem in women of reproductive age. This paper assessed 88 HBsAg-positive pregnant women, of whom 11 began treatment during pregnancy and five became pregnant while receiving treatment. The files of HBsAg-positive pregnant women were reviewed between January 2010 and December 2013-retrospectively. From these 88 pregnant women, 72 did not receive any treatment during their pregnancy, 11 began treatment during their pregnancy, and five became pregnant while receiving treatment. Nine of these 11 pregnant women were given tenofovir disoproxil fumarate and two of them lamivudine. Ten babies of the 11 mothers that began treatment during their pregnancy were healthy, but one was lost due to preterm birth. Of the five patients who became pregnant while receiving treatment, the treatments of four women were discontinued and they were monitored during their pregnancies because mild-moderate (less than stage 3) fibrosis was found in their liver biopsy results. It is important to screen all pregnant women for hepatitis B and to assess those found HBsAg-positive. It is possible to protect both the mother and baby using appropriate approaches.", "affiliations": null, "authors": "Kolgelier|S|S|;Sumer|S|S|;Demir|N A|NA|;Asci|Z|Z|;Demir|L S|LS|;Ozcimen|S|S|;Ural|O|O|", "chemical_list": "D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D019259:Lamivudine; D000068698:Tenofovir", "country": "China", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0390-6663", "issue": "43(6)", "journal": "Clinical and experimental obstetrics & gynecology", "keywords": null, "medline_ta": "Clin Exp Obstet Gynecol", "mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D005260:Female; D006514:Hepatitis B Surface Antigens; D019694:Hepatitis B, Chronic; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D019259:Lamivudine; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D047928:Premature Birth; D012189:Retrospective Studies; D000068698:Tenofovir; D055815:Young Adult", "nlm_unique_id": "7802110", "other_id": null, "pages": "866-870", "pmc": null, "pmid": "29944240", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": null, "title": "Monitoring and treatment results of 88 HBsAg-positive pregnant women.", "title_normalized": "monitoring and treatment results of 88 hbsag positive pregnant women" }

[ { "companynumb": "TR-MYLANLABS-2017M1014828", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "204002", "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": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KOLGELIER S, SUMER S, DEMIR NA, ASCI Z, DEMIR LS, OZCIMEN S, ET AL. MONITORING AND TREATMENT RESULTS OF 88 HBSAG-POSITIVE PREGNANT WOMEN. CLIN-EXP-OBSTET-GYNECOL 2016;43(6):866-870.", "literaturereference_normalized": "monitoring and treatment results of 88 hbsag positive pregnant women", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20170309", "receivedate": "20170309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13313878, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]

{ "abstract": "Chronic airway inflammation and infection drive morbidity and mortality among patients with cystic fibrosis (CF). While Haemophilus influenzae and Staphylococcus aureus predominate in children, the prevalence of Pseudomonas aeruginosa increases as patients age. Other bacteria, including species within the Burkholderia cepacia complex (Bcc), are also more prevalent among adults with CF. Species within the Bcc accelerate lung function decline and can trigger development of \"cepacia syndrome,\" both before and after lung transplantation. As a result, some centers advise against lung transplantation for Bcc-infected patients; however, little is known about the relative virulence of uncommon Bcc species. We describe a successful lung re-transplant in a patient with CF, chronic Burkholderia ambifaria airway infection, and cepacia syndrome.", "affiliations": "Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Glendale, AZ, United States.;Deparment of Pharmacy Services, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.;Division of Transplant Pulmonology, Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.;Division of Transplant Surgery, Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.;Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, United States.;Division of Transplant Pulmonology, Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.;Division of Transplant Pulmonology, Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States. Electronic address: [email protected].", "authors": "Goodlet|Kellie J|KJ|;Nailor|Michael D|MD|;Omar|Ashraf|A|;Huang|Jasmine L|JL|;LiPuma|John J|JJ|;Walia|Rajat|R|;Tokman|Sofya|S|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jcf.2018.08.011", "fulltext": null, "fulltext_license": null, "issn_linking": "1569-1993", "issue": "18(1)", "journal": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society", "keywords": "Burkholderia ambifaria; Burkholderia cepacia complex; cystic fibrosis; lung transplantation", "medline_ta": "J Cyst Fibros", "mesh_terms": "D000328:Adult; D016470:Bacteremia; D019117:Burkholderia; D019121:Burkholderia Infections; D003550:Cystic Fibrosis; D005260:Female; D006801:Humans; D008168:Lung; D016040:Lung Transplantation; D012086:Reoperation; D013577:Syndrome; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101128966", "other_id": null, "pages": "e1-e4", "pmc": null, "pmid": "30224331", "pubdate": "2019-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful Lung Re-transplant in a Patient with Cepacia Syndrome due to Burkholderia ambifaria.", "title_normalized": "successful lung re transplant in a patient with cepacia syndrome due to burkholderia ambifaria" }

[ { "companynumb": "US-BAYER-2019-028597", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019537", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "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, "medicinalproduct": "CIPROFLOXACIN MONOHYDROCHLORIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOCYCLINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "AMIKACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "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": "MINOCYCLINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTAZIDIME" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTAZIDIME." } ], "patientagegroup": "5", "patientonsetage": "41", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "GOODLET KJ, NAILOR MD, OMAR A, HUANG JL, LIPUMA JJ, WALIA R, TOKMAN S. SUCCESSFUL LUNG RE-TRANSPLANT IN A PATIENT WITH CEPACIA SYNDROME DUE TO BURKHOLDERIA AMBIFARIA. JOURNAL OF CYSTIC FIBROSIS (2019). 2019?18:1:(E1-E4)", "literaturereference_normalized": "successful lung re transplant in a patient with cepacia syndrome due to burkholderia ambifaria", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190211", "receivedate": "20190211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15948145, "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-PFIZER INC-2019060552", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKHOLDERIA CEPACIA COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKHOLDERIA CEPACIA COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOCYCLINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": "1", "drugadministrationroute": "055", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKHOLDERIA CEPACIA COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTAZIDIME" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "062662", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BURKHOLDERIA CEPACIA COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTAZIDIME." } ], "patientagegroup": null, "patientonsetage": "41", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GOODLET, K.. SUCCESSFUL LUNG RE-TRANSPLANT IN A PATIENT WITH CEPACIA SYNDROME DUE TO BURKHOLDERIA AMBIFARIA. JOURNAL OF CYSTIC FIBROSIS. 2019?18 (1):E1-E4", "literaturereference_normalized": "successful lung re transplant in a patient with cepacia syndrome due to burkholderia ambifaria", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190219", "receivedate": "20190213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15956595, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]

{ "abstract": "A 54-year-old man with acute myeloid leukemia (AML) underwent allogeneic bone marrow transplantation from a human leukocyte antigen-matched unrelated donor in nonremission status. Bone marrow aspiration performed on day 14 showed that the patient had achieved complete remission; however, he relapsed on day 28. The patient developed a wet cough, and chest computed tomography performed on day 27 revealed pneumonia. Because pneumonia developed along with the leukemic relapse, we suspected that it was due to pulmonary leukemic infiltration (PLI). Giemsa-stained sputum showed some blast cells and fluorescence in situ hybridization indicated that the patient had monosomy 7, which was also detected in bone marrow blasts. Though we prescribed hydroxycarbamide and decreased tacrolimus rapidly, AML progressed and led to the patient's death on day 45. Histopathological findings of the autopsy performed the next day showed diffuse alveolar damage in both lungs. The blast cells were packed in blood vessels of alveolar septa and were also seen in alveoli. PLI was diagnosed pathologically. In conclusion, our case demonstrates that Giemsa stain of sputum is useful in quick diagnosis of PLI without invasive examination.", "affiliations": "Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Division of Laboratory, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Pathology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.;Department of Pathology, Japanese Red Cross Nagoya First Hospital.;Department of Hematology, Japanese Red Cross Nagoya First Hospital.", "authors": "Osaki|Masahide|M|;Lee|Yoonha|Y|;Osamura|Yoko|Y|;Ichiki|Tomoe|T|;Okabe|Motohito|M|;Kawaguchi|Yuka|Y|;Obiki|Marie|M|;Ito|Ai|A|;Goto|Miyo|M|;Araie|Hiroaki|H|;Goto|Tatsunori|T|;Morishita|Takanobu|T|;Ozawa|Yukiyasu|Y|;Ito|Masafumi|M|;Miyamura|Koichi|K|", "chemical_list": "D001399:Azure Stains", "country": "Japan", "delete": false, "doi": "10.11406/rinketsu.61.257", "fulltext": null, "fulltext_license": null, "issn_linking": "0485-1439", "issue": "61(3)", "journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology", "keywords": "Acute myeloid leukemia; Pulmonary complication; Pulmonary leukemic infiltration", "medline_ta": "Rinsho Ketsueki", "mesh_terms": "D001399:Azure Stains; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute; D017254:Leukemic Infiltration; D008297:Male; D008875:Middle Aged; D013183:Sputum", "nlm_unique_id": "2984782R", "other_id": null, "pages": "257-261", "pmc": null, "pmid": "32224587", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Leukemic pulmonary infiltration diagnosed by sputum Giemsa-staining.", "title_normalized": "leukemic pulmonary infiltration diagnosed by sputum giemsa staining" }

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LEUKEMIC PULMONARY INFILTRATION DIAGNOSED BY SPUTUM GIEMSA-STAINING. RINSHO KETSUEKI. 2020?61(3):257-261.", "literaturereference_normalized": "leukemic pulmonary infiltration diagnosed by sputum giemsa staining", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200415", "receivedate": "20200415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17670189, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "JP-PBT-000280", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROXYUREA" }, "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": "HYDROXYCARBAMIDE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE REDUCED", "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": "TACROLIMUS." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "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": "TACROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neoplasm recurrence", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neoplasm progression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Leukaemic infiltration pulmonary", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "OSAKI M, LEE Y, OSAMURA Y, ICHIKI T, OKABE M, KAWAGUCHI Y. ET AL. LEUKEMIC PULMONARY INFILTRATION DIAGNOSED BY SPUTUM GIEMSA-STAINING. RINSHO KETSUEKI. 2020?61(3):257-261. DOI: 10.11406/RINKETSU.61.257", "literaturereference_normalized": "leukemic pulmonary infiltration diagnosed by sputum giemsa staining", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20201011", "receivedate": "20200421", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17688023, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" } ]

{ "abstract": "It has been well known that mesalazine can cause the interstitial lung disease, such as Bronchiolitis obliterans with organizing pneumonia (BOOP), Non-Specific Interstitial Pneumonia (NSIP), or eosinophilic pneumonia. 5-Aminosalicylic acid (5-ASA), mesalazine, and sulfasalazine are important drugs for treating inflammatory bowel disease. Topical products of these limited systemic absorption and have less frequent side effects, therefore suppository form of these drugs have been used more than systemic drug. Most cases of measalzine-induced lung toxicity develop from systemic use of the drug. A 30-year-old woman had an interstitial lung disease after using mesalazine suppository because of ulcerative colitis. The lung biopsy demonstrated eosinophilic pneumonia combined with BOOP. She was recovered after stopping of mesalazine suppository and treatment with systemic steroid.", "affiliations": "Division of Respiratory and Allergy, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 420-767, Korea.", "authors": "Kim|Jung Hyun|JH|;Lee|June-Hyuk|JH|;Koh|Eun-Suk|ES|;Park|Sung Woo|SW|;Jang|An-Soo|AS|;Kim|Dojin|D|;Park|Choon-Sik|CS|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.5415/apallergy.2013.3.2.136", "fulltext": "\n==== Front\nAsia Pac AllergyAsia Pac AllergyAPAAsia Pacific Allergy2233-82762233-8268Asia Pacific Association of Allergy, Asthma and Clinical Immunology 10.5415/apallergy.2013.3.2.136Case ReportAcute eosinophilic pneumonia related to a mesalazine suppository Kim Jung Hyun 1Lee June-Hyuk 1Koh Eun-Suk 2Park Sung woo 1Jang An-Soo 1Kim Dojin 1Park Choon-Sik 11 Division of Respiratory and Allergy, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 420-767, Korea.2 Department of Pathology, Soonchunhyang University Bucheon Hospital, Bucheon 420-767, Korea.\nCorrespondence: June-Hyuk Lee. Division of Respiratory and Allergy, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, 170, jomaru-ro, Wonmi-gu, Bucheon 420-767, Korea. Tel: +82-32-621-5154, Fax: +82-32-621-6950, [email protected] 2013 26 4 2013 3 2 136 139 25 7 2012 24 2 2013 Copyright © 2013. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.2013This 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.It has been well known that mesalazine can cause the interstitial lung disease, such as Bronchiolitis obliterans with organizing pneumonia (BOOP), Non-Specific Interstitial Pneumonia (NSIP), or eosinophilic pneumonia. 5-Aminosalicylic acid (5-ASA), mesalazine, and sulfasalazine are important drugs for treating inflammatory bowel disease. Topical products of these limited systemic absorption and have less frequent side effects, therefore suppository form of these drugs have been used more than systemic drug. Most cases of measalzine-induced lung toxicity develop from systemic use of the drug. A 30-year-old woman had an interstitial lung disease after using mesalazine suppository because of ulcerative colitis. The lung biopsy demonstrated eosinophilic pneumonia combined with BOOP. She was recovered after stopping of mesalazine suppository and treatment with systemic steroid.\n\nEosinophilic pneumoniaBronchiolitis obliterans with organizing pneumoniaMesalazineSuppository\n==== Body\nINTRODUCTION\nMesalazine and sulfasalazine are important drugs for treating inflammatory bowel disease (IBD). Adverse effects of mesalazine include nausea, vomiting, diarrhea, rash, fever, and hepatic dysfunction. The incidence rate of adverse effects is 3%, but most cases are not serious [1-3]. There have been many reports of interstitial lung disease (ILD) induced by sulfasalazine or mesalazine for treating IBD [4, 5]. Sulfasalazine and mesalazine can cause problems in the lung, such as Bronchiolitis obliterans with organizing pneumonia (BOOP), Non-Specific Interstitial Pneumonia (NSIP), or eosinophilic pneumonia, although it has been known that there are associations between IBD and lung involvement [6]. Most cases of mesalazine or sulfasalazine-induced lung toxicity develop from systemic use of the drugs. There were limited reports that lung toxicity associated with using of suppository form of mesalazine. We report a patient with eosiophilc pneumonia combined with BOOP that developed after using mesalazine suppository.\n\nCASE REPORT\nA 30-year-old woman presented with cough that was aggravated at night for 10 days. She had ulcerative colitis and had undergone a left hemi-colectomy with a colostomy 7 weeks ago. She had received a mesalazine suppository (1 g/day) for 19 days after the operation. At the time of presentation, the patient complained of fatigue, general weakness, myalgia, cough, and a small amount of non-purulent sputum. A chest X-ray and high resolution computed tomography showed peripheral patchy consolidations with interlobular septal thickening in both lungs. Blood eosinophils were 24.5%, level of total IgE was 169 KU/L and specific IgE for dust mites were 3+ in UniCAP system. Total cell count was 31.5 × 105 cell/mL with 73.2% macrophages, 19.6% neutrophils, 1.6% eosinophils, 0% lymphocytes in bronchoalveolar lavage fluid. Tests for nine respiratory associated viruses (adenovirus; Rous sarcoma virus; rhinovirus; metapneumovirus; seasonal influenza A and B; parainfluenza virus 1, 2, and 3; and novel H1N1 virus) were all negative by real-time PCR. Test results for antinuclear antibodies, rheumatoid factor, anti-ds DNA antibody, and antineutrophil cytoplasmic antibody were negative. The lung biopsy demonstrated that a patchy interstitial and intra-alveolar histiocytic infiltration was admixed with many eosinophils and some neutrophils and foci of organizing fibrosis, suggestive of eosinophilic pneumonia and BOOP (Fig. 1). The mesalazine suppository was stopped. She was treated with 500 mg methylprednisolone intravenously for 3 days followed by 30 mg prednisolone orally. She recovered completely.\n\nDISCUSSION\nSulfasalazine or mesalazine for treating IBD has been known to be associated with development of ILD [4, 5]. This issue is open to dispute. Because these drugs can cause problems in the lung, such as BOOP, NSIP, or eosinophilic pneumonia, some ILDs are similar to those seen in patients with IBD unexposed to drugs [6]. Lung involvement with IBD as a part of the extra-intestinal manifestations of IBD is not common, and the incidence rate is only 0.4% [7]. In this case, no lesion was found in the mid and lower lung areas on an abdominal computed tomography scan that was performed at the time of IBD evaluation, before the operation, although the whole lung condition was not shown.\n\nThe incidence of mesalazine-associated lung disease is unknown but appears to be low. A study of 1,700 mesalazine treated patients had a 3%-20% incidence of adverse effects and did not include any patients with pulmonary complications [2, 3].\n\nWhen the drug was administrated orally, the mean age of sulfasalazine-induced lung toxicity patients was 48.3 years. Dose-dependent lung toxicity was not defined. The daily dose of sulfasalazine ranged from 1 to 8 g, with a mean of 3 g. The average duration of exposure to sulfasalazine was 17.8 months [1].\n\nMost cases of mesalazine or sulfasalazine-induced lung toxicity developed from systemic use of the drugs. In this case, mesalazine was used as a suppository and the patient had never been exposed to mesalazine or other 5-Aminosalicylic acid (5-ASA) before. The dose of mesalazine suppository was 1 g/day, and the duration of use was only 19 days. The dosage and duration are thought to be smaller and shorter for inducing lung toxicity than when the drugs are used systemically. It is also uncertain whether the lung lesions in this patient were side effects of the drug or hypersensitivity reactions.\n\nThe mechanisms of pharmacologic effect of mesalazine has been thought to block the production of interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) and inhibit nuclear factor-κB (NF-κB) activation. The pathogenesis of mesalazine-induced lung injury is unknown, but four mechanisms are considered as a causes of drug induced lung injury; 1) oxidant injury by a drug, such as nitrofurantoin ingestion; 2) direct cytotoxic effect on alveolar capillary endothelial cells; 3) injury mediated by deposition of phospholipids within the cell; and 4) immune-mediated injury causing clinical symptoms of systemic lupus erythematosus. Currently, it is postulated that mesalazine causes immune-mediated alveolitis as evidenced by lymphocyte stimulation [2, 5, 8].\n\nIt has not been known the incidence rate of hypersensitivity reaction after using 5-ASA suppository form including mesalazine and sulfasalazine. We failed to find a case concerning the side effects or hypersensitivity reactions in the lung after using a mesalazine suppository. Only three cases are available that reported side effects after using topical 5-ASA [9-11]. Two cases were the development of pancreatitis caused by 5-ASA enema [9] or suppository [10] and the other was a case of fever and skin rash by 5-ASA enema [10] (Table 1). The cases of pancreatitis were thought be associated with form of administration. The best indicator of mesalazine's release and subsequent action in the bowel is unknown. Administrating mesalazine as an enema or suppository, effectively bypassing the threat of small bowel absorption [12]. Mesalazine has a lower absorption rate after rectal administration compared to oral administration (10% vs. 35%, respectively) [13, 14]. Because of this, the incidence of systemic side effect of the administration of suppository mesalazine is lower than other form of intake. The common side effects are dizziness (3%), rectal pain (2%), fever, rash, acne, and colitis (1% each) [15].\n\nWe didn't try to administration of mesalazine to the patient for confirm, because the condition of patient was serious at time of diagnosis. Suppository has been thought to be safer than systemic administration, even some adverse effects reported. This is a first report that a patient who experienced lung involvement to mesalazine suppository.\n\nFig. 1 (A) Many chronic inflammatory cells (predominantly macrophages) and some aggregation of eosinophils are seen. (B) Interstitial thickenings with chronic inflammatory cells infiltration and intraluminal young fibroblastic polyps, that are consistent with Bronchiolitis obliterans with organizing pneumonia, are also seen.\n\nTable 1 Cases reported to show side effects associated with topical 5-ASA administration\n\n5-ASA, 5-Aminosalicylic acid.\n==== Refs\n1 Parry SD Barbatzas C Peel ET Barton JR Sulphasalazine and lung toxicity Eur Respir J 2002 19 756 764 11999006 \n2 Foster RA Zander DS Mergo PJ Valentine JF Mesalamine-related lung disease: clinical, radiographic, and pathologic manifestations Inflamm Bowel Dis 2003 9 308 315 14555914 \n3 Brimblecombe R Mesalazine: a global safety evaluation Scand J Gastroenterol Suppl 1990 172 66 1972297 \n4 Salerno SM Ormseth EJ Roth BJ Meyer CA Christensen ED Dillard TA Sulfasalazine pulmonary toxicity in ulcerative colitis mimicking clinical features of Wegener's granulomatosis Chest 1996 110 556 559 8697866 \n5 Tanigawa K Sugiyama K Matsuyama H Nakao H Kohno K Komuro Y Iwanaga Y Eguchi K Kitaichi M Takagi H Mesalazine-induced eosinophilic pneumonia Respiration 1999 66 69 72 9973695 \n6 Camus P Colby TV The lung in inflammatory bowel disease Eur Respir J 2000 15 5 10 10678613 \n7 Carter MJ Lobo AJ Travis SP IBD Section, British Society of Gastroenterology Guidelines for the management of inflammatory bowel disease in adults Gut 2004 53 Suppl 5 V1 V16 15306569 \n8 Sviri S Gafanovich I Kramer MR Tsvang E Ben-Chetrit E Mesalamine-induced hypersensitivity pneumonitis. A case report and review of the literature J Clin Gastroenterol 1997 24 34 36 9013348 \n9 Isaacs KL Murphy D Pancreatitis after rectal administration of 5-aminosalicylic acid J Clin Gastroenterol 1990 12 198 199 1969872 \n10 Kim KH Kim TN Jang BI A case of acute pancreatitis caused by 5-aminosalicylic acid suppositories in a patient with ulcerative colitis Korean J Gastroenterol 2007 50 379 383 18159175 \n11 Borum ML Ginsberg A Hypersensitivity to 5-ASA suppositories Dig Dis Sci 1997 42 1076 1078 9149065 \n12 Qureshi AI Cohen RD Mesalamine delivery systems: do they really make much difference? Adv Drug Deliv Rev 2005 57 281 302 15555743 \n13 Aumais G Lefebvre M Tremblay C Bitton A Martin F Giard A Madi M Spénard J Rectal tissue, plasma and urine concentrations of mesalazine after single and multiple administrations of 500 mg suppositories to healthy volunteers and ulcerative proctitis patients Aliment Pharmacol Ther 2003 17 93 97 12492737 \n14 Williams CN Haber G Aquino JA Double-blind, placebo-controlled evaluation of 5-ASA suppositories in active distal proctitis and measurement of extent of spread using 99mTc-labeled 5-ASA suppositories Dig Dis Sci 1987 32 71S 75S 3319461 \n15 Physicians' desk reference 2004 58th ed Montvale, NJ Thomson PDR 795 796\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2233-8276", "issue": "3(2)", "journal": "Asia Pacific allergy", "keywords": "Bronchiolitis obliterans with organizing pneumonia; Eosinophilic pneumonia; Mesalazine; Suppository", "medline_ta": "Asia Pac Allergy", "mesh_terms": null, "nlm_unique_id": "101561954", "other_id": null, "pages": "136-9", "pmc": null, "pmid": "23667838", "pubdate": "2013-04", "publication_types": "D002363:Case Reports", "references": "9013348;11999006;18159175;9149065;15555743;12492737;15306569;8697866;1969872;3319461;14555914;9973695;1972297;10678613", "title": "Acute eosinophilic pneumonia related to a mesalazine suppository.", "title_normalized": "acute eosinophilic pneumonia related to a mesalazine suppository" }

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{ "abstract": "Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT.\n\n\n\nScrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3).\n\n\n\nMedian observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation.\n\n\n\nLong-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.", "affiliations": "Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.;Swabian Children's Cancer Center, University Children's Hospital, University Hospital Augsburg, Augsburg, Germany.;Swabian Children's Cancer Center, University Children's Hospital, University Hospital Augsburg, Augsburg, Germany.;Institute of Neuropathology, University Hospital Münster, Münster, Germany.;West German Proton Therapy Center Essen/Clinic for Particle Therapy, Essen University Hospital, Essen, Germany.;Institute of Diagnostic and Interventional Neuroradiology, University Hospital Wuerzburg, Wuerzburg, Germany.;Department of Pediatrics, Kepler University Hospital and School of Medicine, Johannes Kepler University, Linz, Austria.;PSL Research University, Institut Curie, Pediatric Care and Research Center, Paris, France.;Gustave Roussy, Grand Paris Cancer Campus, Department of Childhood and Adolescent Oncology, Villejuif, France.;S.C. Pediatria, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Oncology Department at Hospital Sant Joan de Deu, Barcelona Children's Hospital, Barcelona, Spain.;Pediatric Oncology Unit, University Hospital, Strasbourg, France.;Department of Pediatric Oncology, University Hospital, Besançon, France.;Institute for Medical Statistics, Medical University of Graz, Graz, Austria.;Division of Neuropathology, Department of Pathology and Neuropathology, Kepler University Hospital and School of Medicine, Johannes Kepler University, Linz, Austria.;Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.;Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.;Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany.;Laboratory of Genetics, Pathology Unit, S. Anna General Hospital, Como, Italy.;University Hospital of Nancy, Pediatric Hematology and Oncology, Nancy, France.;Swabian Children's Cancer Center, University Children's Hospital, University Hospital Augsburg, Augsburg, Germany.", "authors": "Benesch|Martin|M|0000-0001-7827-4130;Nemes|Karolina|K|0000-0003-0270-5875;Neumayer|Petra|P|;Hasselblatt|Martin|M|;Timmermann|Beate|B|;Bison|Brigitte|B|;Ebetsberger-Dachs|Georg|G|;Bourdeaut|Franck|F|;Dufour|Christelle|C|0000-0001-5993-8077;Biassoni|Veronica|V|;Morales La Madrid|Andrés|A|;Entz-Werle|Natacha|N|;Laithier|Véronique|V|;Quehenberger|Franz|F|;Weis|Serge|S|;Sumerauer|David|D|;Siebert|Reiner|R|;Bens|Susanne|S|;Schneppenheim|Reinhard|R|;Kool|Marcel|M|;Modena|Piergiorgio|P|0000-0002-2339-4300;Fouyssac|Fanny|F|;C Frühwald|Michael|M|0000-0002-8237-1854", "chemical_list": "D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases", "country": "United States", "delete": false, "doi": "10.1002/pbc.28022", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "67(1)", "journal": "Pediatric blood & cancer", "keywords": "brain tumors; neuro-oncology; pediatric oncology; teratoid/rhabdoid tumors", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D014408:Biomarkers, Tumor; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D004265:DNA Helicases; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D009687:Nuclear Proteins; D011379:Prognosis; D012189:Retrospective Studies; D018335:Rhabdoid Tumor; D000071796:SMARCB1 Protein; D013120:Spinal Cord Neoplasms; D015996:Survival Rate; D013724:Teratoma; D014157:Transcription Factors", "nlm_unique_id": "101186624", "other_id": null, "pages": "e28022", "pmc": null, "pmid": "31571386", "pubdate": "2020-01", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Spinal cord atypical teratoid/rhabdoid tumors in children: Clinical, genetic, and outcome characteristics in a representative European cohort.", "title_normalized": "spinal cord atypical teratoid rhabdoid tumors in children clinical genetic and outcome characteristics in a representative european cohort" }

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SPINAL CORD ATYPICAL TERATOID/RHABDOID TUMORS IN CHILDREN: CLINICAL, GENETIC, AND OUTCOME CHARACTERISTICS IN A REPRESENTATIVE EUROPEAN COHORT. 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DAYS 1, 8, AND 15", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 UG/M2/DAY; DAYS 1 AND 2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "010", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BENESCH M, NEMES K, NEUMAYER P, HASSELBLATT M, TIMMERMANN B, BISON B, ET AL.. SPINAL CORD ATYPICAL TERATOID/RHABDOID TUMORS IN CHILDREN: CLINICAL, GENETIC, AND OUTCOME CHARACTERISTICS IN A REPRESENTATIVE EUROPEAN COHORT.. PEDIATR. BLOOD CANCER.. 2020?67 (1):E28022", "literaturereference_normalized": "spinal cord atypical teratoid rhabdoid tumors in children clinical genetic and outcome characteristics in a representative european cohort", "qualification": "1", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20200302", "receivedate": "20200302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17485070, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "AT-PFIZER INC-2020040814", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "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": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "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": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage intracranial", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BENESCH, M.. SPINAL CORD ATYPICAL TERATOID/RHABDOID TUMORS IN CHILDREN: CLINICAL, GENETIC, AND OUTCOME CHARACTERISTICS IN A REPRESENTATIVE EUROPEAN COHORT.. PEDIATR BLOOD CANCER. 2020?JAN:1-8", "literaturereference_normalized": "spinal cord atypical teratoid rhabdoid tumors in children clinical genetic and outcome characteristics in a representative european cohort", "qualification": "1", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20200212", "receivedate": "20200203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17363255, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "DE-MYLANLABS-2020M1018650", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL TERATOID/RHABDOID TUMOUR OF CNS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091062", "drugbatchnumb": null, "drugcharacterization": "1", 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BENESCH M, NEMES K, NEUMAYER P, HASSELBLATT M, TIMMERMANN B, BISON B, ET AL.. SPINAL CORD ATYPICAL TERATOID/RHABDOID TUMORS IN CHILDREN: CLINICAL, GENETIC, AND OUTCOME CHARACTERISTICS IN A REPRESENTATIVE EUROPEAN COHORT.. PEDIATR-BLOOD-CANCER. 2020?67(1):E28022", "literaturereference_normalized": "spinal cord atypical teratoid rhabdoid tumors in children clinical genetic and outcome characteristics in a representative european cohort", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200220", "receivedate": "20200220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17441533, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]

{ "abstract": "In the European Association for Palliative Care recommendations for cancer pain management, there was no consensus regarding the indications, titration, or monitoring of methadone.\n\n\n\nThis national, randomized, multicenter trial aimed to compare two methadone titration methods (stop-and-go vs. progressive) in patients with cancer-related pain who were inadequately relieved by or intolerant to Level 3 opioids.\n\n\n\nThe primary end point was the rate of success/failure at Day 4, defined as pain relief (reduction of at least two points on the visual scale and a pain score <5 for two consecutive days) and no overdose (Rudkin scale ≥3 and respiratory rate <8/minute). The patients were followed for two months after enrollment.\n\n\n\nThe cancer-related pain characteristics of the 146 patients were as follows: 16% were nociceptive, 85% experienced breakthrough pain, and 84% had mixed types of pain. The reasons for switching to methadone were a lack of efficacy that was either isolated (56%) or associated with intolerance (38%). Adequate pain relief was obtained in 80% of the patients (median of three days in both groups [P = 0.12]) and lasted until D56. The rate of success/failure was approximately 40% at Day 4 in both groups, with overdoses in 13% of the patients throughout the study. The two methods were considered equally easy to perform by nearly 60% of the clinicians.\n\n\n\nMethadone is an effective and sustainable second-line alternative opioid for the treatment of cancer-related pain. The methods of titration are comparable in terms of efficacy, safety, and ease of use.", "affiliations": "Polyclinique de l'ormeau, Tarbes, France. Electronic address: [email protected].;Assistance Publique-Hôpitaux de Paris, Paris, France.;Laboratoires Bouchara-Recordati, Puteaux, France.;Centre Oscar Lambret, Lille, France.;Centre Léon Bérard, Lyon, France.;CHU Nord, Amiens, France.;CHU L'Archet2, Nice, France.;CHI Alpes du Sud, Gap, France.;CH Lyon Sud, Pierre Bénite, France.", "authors": "Poulain|Philippe|P|;Berleur|Marie-Pierre|MP|;Lefki|Shimsi|S|;Lefebvre|Danièle|D|;Chvetzoff|Gisèle|G|;Serra|Eric|E|;Tremellat|Fibra|F|;Derniaux|Alain|A|;Filbet|Marilène|M|;|||", "chemical_list": "D000701:Analgesics, Opioid; D008691:Methadone", "country": "United States", "delete": false, "doi": "10.1016/j.jpainsymman.2016.05.022", "fulltext": null, "fulltext_license": null, "issn_linking": "0885-3924", "issue": "52(5)", "journal": "Journal of pain and symptom management", "keywords": "Cancer pain; methadone; opioid", "medline_ta": "J Pain Symptom Manage", "mesh_terms": "D000701:Analgesics, Opioid; D059390:Breakthrough Pain; D000072716:Cancer Pain; D062787:Drug Overdose; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008691:Methadone; D008875:Middle Aged; D010147:Pain Measurement; D019233:Retreatment; D016896:Treatment Outcome", "nlm_unique_id": "8605836", "other_id": null, "pages": "626-636.e1", "pmc": null, "pmid": "27693901", "pubdate": "2016-11", "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": "Efficacy and Safety of Two Methadone Titration Methods for the Treatment of Cancer-Related Pain: The EQUIMETH2 Trial (Methadone for Cancer-Related Pain).", "title_normalized": "efficacy and safety of two methadone titration methods for the treatment of cancer related pain the equimeth2 trial methadone for cancer related pain" }

[ { "companynumb": "FR-JNJFOC-20161218763", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021217", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OROS (ORAL OSMOTIC) THERAPEUTIC SYSTEM TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANCER PAIN", "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": "OXYCODONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANCER PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUFENTANIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "000000", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANCER PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUFENTANIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019813", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANCER PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CANCER PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adverse event", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "P P, BERLEUR M, LEFKI S, LEFEBVRE D, CHVETZOFF G, SERRA E, ET AL. EFFICACY AND SAFETY OF TWO METHADONE TITRATION METHODS FOR THE TREATMENT OF CANCER-RELATED PAIN: THE EQUIMETH2 TRIAL (METHADONE FOR CANCER-RELATED PAIN). JOURNAL OF PAIN AND SYMPTOM MANAGEMENT 01-NOV-2016;52/5:626-636.", "literaturereference_normalized": "efficacy and safety of two methadone titration methods for the treatment of cancer related pain the equimeth2 trial methadone for cancer related pain", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20161228", "receivedate": "20161228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13068757, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "Hyperthermia, which is a noninvasive treatment that causes tumor cells to become heated and that works in synergy with anticancer drugs and radiation therapy, is emerging as a promising treatment for patients with cancer. The purpose of this study is to report the efficacy of hyperthermia combined with chemotherapy (gemcitabine/cisplatin) for the treatment of a patient with unresectable cholangiocarcinoma. A 54-year-old man was diagnosed as hilar cholangiocarcinoma (Klatskin tumor) and was administered neoadjuvant and preoperative radiation with chemotherapy. However, because the treatment with radiation and chemotherapy was not successful, he decided to undergo hyperthermia combined with chemotherapy as a second treatment option. He was suffering from fatigue, dyspepsia, epigastralgia, and jaundice. Hyperthermia combined with chemotherapy was administered 32 times over a period of 4 months. The patient experienced no critical complications, and the patient's condition improved, with the carbohydrate antigen 19-9 (CA 19-9) and the total bilirubin levels being relatively lowered. In addition, the computed tomography scan showed that the cholangiocarcinoma had not progressed. In conclusion, this case report suggests radiofrequency hyperthermia combined with chemotherapy may be a promising treatment option for patients with unresectable cholangiocarcinoma.", "affiliations": "1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea.;1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea.;1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea.;2 Jeonju Korean Medicine Hospital, Wonkwang University, Jeonju, Korea.;1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea.;3 Dunsan Korean Medicine Hospital, Daejeon University, Daejeon, Korea.", "authors": "Ryu|Juyoung|J|;Lee|Kangwook|K|;Joe|Changmug|C|;Joo|JongCheon|J|;Lee|Namhun|N|;Yoo|Hwa-Seung|HS|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/1534735417722225", "fulltext": "\n==== Front\nIntegr Cancer TherIntegr Cancer TherICTspictIntegrative Cancer Therapies1534-73541552-695XSAGE Publications Sage CA: Los Angeles, CA 2874508410.1177/153473541772222510.1177_1534735417722225Case StudiesPatient With Unresectable Cholangiocarcinoma Treated With Radiofrequency Hyperthermia in Combination With Chemotherapy: A Case Report Ryu Juyoung MS, KMD1Lee Kangwook BS, KMD1Joe Changmug PhD, MD1Joo JongCheon PhD, KMD2Lee Namhun PhD, KMD1*Yoo Hwa-Seung PhD, KMD3*1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea2 Jeonju Korean Medicine Hospital, Wonkwang University, Jeonju, Korea3 Dunsan Korean Medicine Hospital, Daejeon University, Daejeon, KoreaNamhun Lee, Department of Clinical Oncology, Cheonan Korean Medical Hospital, Korean Medical College, Daejeon University, 4, Notaesan-ro, Seobuk-gu, Cheonan-si, Chungcheongnam-do 31099, Korea. Email: [email protected] Yoo. East West Cancer Center, Dunsan Korean Medicine Hospital, Korean Medical College, Daejeon University, 75, Daedeok-daero 176 beon-gil, Seo-gu, Daejeon, 35235, Korea. E-mail: [email protected]* These authors contributed equally to this work.\n\n26 7 2017 6 2018 17 2 558 561 6 3 2017 1 6 2017 18 6 2017 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Hyperthermia, which is a noninvasive treatment that causes tumor cells to become heated and that works in synergy with anticancer drugs and radiation therapy, is emerging as a promising treatment for patients with cancer. The purpose of this study is to report the efficacy of hyperthermia combined with chemotherapy (gemcitabine/cisplatin) for the treatment of a patient with unresectable cholangiocarcinoma. A 54-year-old man was diagnosed as hilar cholangiocarcinoma (Klatskin tumor) and was administered neoadjuvant and preoperative radiation with chemotherapy. However, because the treatment with radiation and chemotherapy was not successful, he decided to undergo hyperthermia combined with chemotherapy as a second treatment option. He was suffering from fatigue, dyspepsia, epigastralgia, and jaundice. Hyperthermia combined with chemotherapy was administered 32 times over a period of 4 months. The patient experienced no critical complications, and the patient’s condition improved, with the carbohydrate antigen 19-9 (CA 19-9) and the total bilirubin levels being relatively lowered. In addition, the computed tomography scan showed that the cholangiocarcinoma had not progressed. In conclusion, this case report suggests radiofrequency hyperthermia combined with chemotherapy may be a promising treatment option for patients with unresectable cholangiocarcinoma.\n\nchemotherapycholangiocarcinomahyperthermiaKlatskin tumorradiofrequency\n==== Body\nIntroduction\nCholangiocarcinoma (CCA) is rare malignancy that can occur anywhere along the intrahepatic or the extrahepatic biliary tree. Cholangiocarcinoma can be classified as intrahepatic, perihilar, or distal.1 Hilar CCAs and perihilar CCAs are associated with poor prognosis. Of the 3000 cases seen annually in the United States, less than one-half of the tumors are resectable. Patients typically present with abdominal pain, pruritus, weight loss, and jaundice. Computed tomography (CT), magnetic resonance imaging, and ultrasound are used to diagnose cancer and to characterize biliary lesions. Treatment consists of surgery, radiation therapy, chemotherapy and photodynamic therapy. Standard therapy consists of surgical margin-negative resection with extrahepatic bile duct resection, hepatectomy, and en-bloc lymphadenectomy.2 Complete resection of a hilar cholangiocarcinoma is the most effective and only potentially curative therapy, and it is now clear that concomitant hepatic resection is required in most cases.3 However, complete resection is sometimes difficult because of local extensions, which occur perineurally via lymphatic channels, subepithelial spread in the duct wall, and direct invasion of adjacent hepatic arteries or portal veins.4 Nonresected extrahepatic bile duct carcinoma has a dismal prognosis, with a life expectancy of about 6 month to 1 year.5\n\nIn oncology, the term hyperthermia refers to the treatment of malignant diseases by administering heat and generating electromagnetic induction. Hyperthermia is usually applied as an adjunct to an already established treatment modality (radiotherapy and chemotherapy), and the goal is to kill tumor cells6 and influence the increase in tumor immunogenicity.7 The present study reports the case of a patient with unresectable hilar cholangiocarcinoma who received concurrent hyperthermia and chemotherapy.\n\nCase Report\nThis case study was approved by the institutional review board of Cheonan Korean Medicine Hospital of Daejeon University (authorization number: DJUMC-P-2017-02).\n\nA-54-year-old man was diagnosed with hilar cholangiocarcinoma (Klatskin tumor) and underwent percutaneous transhepatic biliary drainage at Seoul National University Hospital in June 2016. He was administered neoadjuvant and preoperative 28 days of radiation with 2 cycles of chemotherapy from July to August to be able to perform surgery. The patient was administered cisplatin 25mg plus gemcitabine 1000 mg on the first and eighth days of a 21-day cycle for 6 weeks. Unfortunately, the tumor did not respond to radiation with chemotherapy and the patient was diagnosed as being unresectable. In July 2016, the patient, presenting with fatigue, dyspepsia, epigastralgia, and jaundice, visited Cheonan Korean Medicine Hospital of Daejeon University (Cheonan, Republic of Korea) to seek a second treatment option. At the time of the patient’s visit, his Eastern Cooperative Oncology Group (ECOG)8 grade scored 3 points. As a second line therapy, hyperthermia combined with chemotherapy (gemcitabine/cisplatin) was administered a total of 32 times from September to December 2016.\n\nRadiofrequency (RF) hyperthermia was carried out using the REMISSION 1°C device (AdipoLABs Company, Seoul, Korea). Two 12-cm-diameter electrodes were applied in opposition to each other, and 0.46-MHz RF wave was applied. We administered heat to the patient for 70 minutes and measured the surface temperature (39°C to 41°C) continuously. The applied power was gradually increased from 50 to 100 W, depending on the tolerance of the patient.\n\nRF hyperthermia was administered 32 times without the patient exhibiting any critical complications. The carbohydrate antigen 19-9 (CA 19-9) and the total bilirubin levels decreased during treatment (Figures 1 and 2). The patient’s ECOG8 grade had improved from 3 to 2 points. The several symptoms of fatigue, dyspepsia, epigastralgia, and jaundice were reduced. Judging from National Cancer Institute–Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0,9 fatigue was improved from grade 3 to 1 and dyspepsia was improved from grade 2 to 1. The size of tumor during concurrent hyperthermia and chemotherapy was measured by using CT scans; no progression was noted (Figure 3). Thus, we verified stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.10\n\nFigure 1. Change in the carbohydrate antigen 19-9 (CA 19-9) level with time. After neoadjuvant and preoperative radiation with chemotherapy, the CA 19-9 level was significantly lower than it was at the time of initial evaluation, but then started to increase. Hyperthermia combined with chemotherapy decreased the level of CA19-9 again from 328 to 212.6.\n\nFigure 2. Change in the serum total bilirubin level with time. The serum bilirubin level was significantly lower after percutaneous transhepatic biliary drainage, and that low value remained relatively the same throughout the hyperthermia combined with chemotherapy treatment.\n\nFigure 3. Computed tomography (CT) scan images. The size of tumor during concurrent hyperthermia and chemotherapy was measured by using CT scans in September (A), November (B), and December (C) 2016. No tumor progression was noted.\n\nDiscussion\nCCA may arise anywhere within the biliary tree, but tumors involving the biliary confluence (hilar CCAs) are the most common.11 CCA accounts for 3% of all gastrointestinal tumors. Over the past 3 decades, the overall incidence of CCAs appears to have increased.12 The percentage of patients who survive 5 years after diagnosis has not increased during this time period, remaining at 10%.13 In several studies published over the past three decades, the proportion of patients with hilar tumors has remained fairly constant at 40% to 60%, with the remaining tumors arising from intrahepatic biliary radicles or the distal bile duct.11 Even though resection is well established as the conventional treatment, early transitions can occur, and at the time of discovery, surgery to remove the tumor is performed in one-third, or fewer, of the cases.12 The majority of patients with unresectable bile duct cancer die within 12 months of diagnosis, often from hepatic failure or infectious complications secondary to biliary obstruction. The prognosis has been considered to be worse for lesions involving the biliary confluence than for distal lesions.11\n\nHyperthermia is the process of raising the body temperature, either locally or globally, for medicinal purposes. Hyperthermia can kill or weaken tumor cells without affecting normal cells. Tumor cells, with disorganized and compact vascular structures, have difficulty dissipating heat. Hyperthermia may, therefore, let cancerous cells undergo apoptosis in direct response to applied heat while healthy tissues can more easily maintain normal temperature. Even if the cancerous cells do not die outright, they may become more susceptible to ionizing radiation therapy or to certain chemotherapy drugs, which may allow such therapy to be given in smaller doses.6 Hyperthermia generates electromagnetic induction, selectively deposits energy on the cell membrane, and induces apoptosis more efficiently.14,15 Also, hyperthermia can cause the generation of circumstantial antitumor immunity, influence the increase in tumor immunogenicity due to hydrostatic pressure and lead to immunogenic cell death.7\n\nHyperthermia is rarely used as a single cancer treatment modality and is usually added to radiation therapy, chemotherapy, or radiochemotherapy, and recently to gene and immunotherapy. Many studies on hyperthermia are being conducted continuously in the field of oncology.16-18 As to CCA, a case series of 8 patients on regional hyperthermia with 8 MHz frequency in combination with chemoradiation therapy was reported to be a promising treatment, increasing both local control and long-term survival.19 The higher the frequency, the greater the attenuation and the lower is the penetration.20 The REMISSION 1°C device has a frequency of 0.46 MHz, the lowest frequency ever reported. A case study reported good result on a patient suffering from recurred hepatocellular carcinoma, in which the REMISSION 1°C device was combined with sorafenib.21 In this case study, the hyperthermia treatment was done using the REMISSION 1°C device and was combined with chemotherapy (gemcitabine/cisplatin).\n\nThe present case report shows the efficacy of combined RF hyperthermia and chemotherapy for the treatment of patient with unresectable extrahepatic bile duct carcinoma. After the treatment, the CA 19-9 and the total bilirubin levels have been lowered. The patient’s symptoms, fatigue, dyspepsia, epigastralgia, and jaundice, were alleviated because of the combined treatment. Judging from NCI-CTCAE version 4.0,9 fatigue was improved from grade 3 to 1 and dyspepsia was improved from grade 2 to 1. In addition, the patient experienced no critical complications during treatment, and he remained in fine condition. The general toxicity observed in gemicitabin/cisplatin combination is febrile neutropenia, bleeding, anorexia, nausea, fatigue, and reduced white blood cell count, and so forth.22 Judging from NCI-CTCAE version 4.0,9 severe toxicity was not observed. The patient did not suffer from febrile neutropenia or bleeding. White blood cell count maintained a normal range. Anorexia, nausea, and fatigue were improved. And the patient’s ECOG8 grade had improved from 3 to 2 points. Although the results of the CT scans of the patient showed no improvement, neither did they indicate any progression of the disease, according to RECIST version 1.1.10\n\nTo assure the quality for clinical studies in regional deep hyperthermia, the temperature in the target volume and in the area surrounding the target volume must be recorded.23 The REMISSION 1°C device used in this study did not allow that to be done, which is a limitation of this case study.\n\nBased on these results, hyperthermia is thought to have contributed, at least in part, to the patient’s remaining in fine condition and to the reduced toxic effect of chemotherapy. The present case report suggests that RF hyperthermia combined with chemotherapy may be a treatment option for patient with unresectable cholangiocarcinoma.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by a grant from Deajeon University’s Industry-Academic Cooperation Foundation of AdipoLABs Co. (2016).\n==== Refs\nReferences\n1 \nNakeeb A Pitt HA Sohn TA et al \nCholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors . Ann Surg . 1996 ;224 :463 -475 .8857851 \n2 \nSoares KC Kamel I Cosgrove DP Herman JM Pawlik TM \nHilar cholangiocarcinoma: diagnosis, treatment options, and management . Hepatobiliary Surg Nutr . 2014 ;3 :18 -34 .24696835 \n3 \nSchule S Altendorf-Hofmann AK Knösel T Uteß F Settmacher U \nDiagnostic procedures and results in surgical therapy for cholangiocarcinoma [in German] . Zentralbl Chir . 2014 ;139 (suppl 2 ):e25 -e34 .22274918 \n4 \nSakamoto E Nimura Y Hayakawa N et al \nThe pattern of infiltration at the proximal border of hilar bile duct carcinoma: a histologic analysis of 62 resected cases . Ann Surg . 1998 ;227 :405 -411 .9527064 \n5 \nRadtke A Königsrainer A \nSurgical therapy of cholangiocarcinoma . Visc Med . 2016 ;32 :422 -426 .28229077 \n6 \nHegyi G Szigeti GP Szász A \nHyperthermia versus oncothermia: cellular effects in complementary cancer therapy . Evid Based Complement Alternat Med . 2013 ;2013 :672873 .23662149 \n7 \nGarg AD Galluzzi L Apetoh L et al \nMolecular and translational classifications of DAMPs in immunogenic cell death . Front Immunol . 2015 ;6 :588 .26635802 \n8 \nOken MM Creech RH Tormey DC et al \nToxicity and response criteria of the Eastern Cooperative Oncology Group . Am J Clin Oncol . 1982 ;5 :649 -656 .7165009 \n9 \nNational Cancer Institute . Common Terminology Criteria for Adverse Events (CTCAE) v.4 data files . http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed July 10, 2017 .\n10 \nEisenhauer EA Therasse P Bogaerts J et al \nNew response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer . 2009 ;45 :228 -247 .19097774 \n11 \nJarnagin W Winston C \nHilar cholangiocarcinoma: diagnosis and staging . HPB (Oxford) . 2005 ;7 :244 -251 .18333200 \n12 \nKhan SA Davidson BR Goldin RD et al \nGuidelines for the diagnosis and treatment of cholangiocarcinoma: an update . Gut . 2012 ;61 :1657 -1669 .22895392 \n13 \nEverhart JE Ruhl CE \nBurden of digestive diseases in the United States part III: liver, biliary tract, and pancreas . Gastroenterology . 2009 ;136 :1134 -1144 .19245868 \n14 \nAndocs G Rehman MU Zhao QL Tabuchi Y Kanamori M Kondo T \nComparison of biological effects of modulated electro-hyperthermia and conventional heat treatment in human lymphoma U937 cells . Cell Death Discov . 2016 ;2 :16039 .27551529 \n15 \nYang KL Huang CC Chi MS et al \nIn vitro comparison of conventional hyperthermia and modulated electro-hyperthermia . Oncotarget . 2016 ;7 :84082 -84092 .27556507 \n16 \nDesiderio J Chao J Melstrom L et al \nThe 30-year experience—a meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer . Eur J Cancer . 2017 ;79 :1 -14 .28456089 \n17 \nBakrin N Classe JM Pomel C Gouy S Chene G Glehen O \nHyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer . J Visc Surg . 2014 ;151 :347 -353 .25168575 \n18 \nToraya-Brown S Fiering S \nLocal tumour hyperthermia as immunotherapy for metastatic cancer . Int J Hyperthermia . 2014 ;30 :531 -539 .25430985 \n19 \nKamisawa T Tu Y Egawa N et al \nThermo-chemo-radiotherapy for advanced bile duct carcinoma . World J Gastroenterol . 2005 ;11 :4206 -4209 .16015690 \n20 \nSadick NS Makino Y \nSelective electro-thermolysis in aesthetic medicine: a review . Lasers Surg Med . 2004 ;34 :91 -97 .15004818 \n21 \nKim JH Lee JH Joo JC Lee JB Cho CK Yoo HS \nA case report of recurred hepatocellular carcinoma patient treated with radio-frequency hyperthermia in conjunction with sorafenib . J Korean Tradit Oncol . 2016 ;21 :63 -74 .\n22 \nOkusaka T Nakachi K Fukutomi A et al \nGemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan . Br J Cancer . 2010 ;103 :469 -474 .20628385 \n23 \nBruggmoser G Bauchowitz S Canters R et al \nQuality assurance for clinical studies in regional deep hyperthermia . Strahlenther Onkol . 2011 ;187 :605 -610 .21932026\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1534-7354", "issue": "17(2)", "journal": "Integrative cancer therapies", "keywords": "Klatskin tumor; chemotherapy; cholangiocarcinoma; hyperthermia; radiofrequency", "medline_ta": "Integr Cancer Ther", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001650:Bile Duct Neoplasms; D018281:Cholangiocarcinoma; D003131:Combined Modality Therapy; D005334:Fever; D006801:Humans; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "101128834", "other_id": null, "pages": "558-561", "pmc": null, "pmid": "28745084", "pubdate": "2018-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "15004818;8857851;25168575;28456089;20628385;26635802;18333200;16015690;7165009;24696835;19245868;19097774;22895392;28229077;27556507;22274918;27551529;23662149;21932026;25430985;9527064", "title": "Patient With Unresectable Cholangiocarcinoma Treated With Radiofrequency Hyperthermia in Combination With Chemotherapy: A Case Report.", "title_normalized": "patient with unresectable cholangiocarcinoma treated with radiofrequency hyperthermia in combination with chemotherapy a case report" }

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PATIENT WITH UNRESECTABLE CHOLANGIOCARCINOMA TREATED WITH RADIOFREQUENCY HYPERTHERMIA IN COMBINATION WITH CHEMOTHERAPY: A CASE REPORT. 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PATIENT WITH UNRESECTABLE CHOLANGIOCARCINOMA TREATED WITH RADIOFREQUENCY HYPERTHERMIA IN COMBINATION WITH CHEMOTHERAPY: A CASE REPORT.. INTEGR-CANCER-THER. 2018?17(2):558-561.", "literaturereference_normalized": "patient with unresectable cholangiocarcinoma treated with radiofrequency hyperthermia in combination with chemotherapy a case report", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180608", "receivedate": "20180608", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14991550, "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": "Blockade of the cyclin-dependent kinase 4 and 6 pathway has been shown to be effective in the treatment of hormone receptor-positive advanced breast cancer (ABC). We report the interim results of DAWNA-1 ( NCT03927456 ), a double-blind, randomized, phase 3 trial of dalpiciclib (a new cyclin-dependent kinase 4 and 6 inhibitor) plus fulvestrant in hormone receptor-positive, HER2-negative ABC with disease progression after endocrine therapy. A total of 361 patients were randomized 2:1 to receive dalpiciclib plus fulvestrant or placebo plus fulvestrant. The study met the primary end point, showing significantly prolonged investigator-assessed progression-free survival with dalpiciclib plus fulvestrant versus placebo plus fulvestrant (median = 15.7, 95% confidence interval (CI) = 11.1-not reached versus 7.2, 95% CI = 5.6-9.2 months; hazard ratio = 0.42, 95% CI = 0.31-0.58; one-sided P < 0.0001 (boundary was P ≤ 0.008)). The most common grade 3 or 4 adverse events with dalpiciclib plus fulvestrant were neutropenia (84.2%) and leukopenia (62.1%). The incidence of serious adverse events was 5.8% with dalpiciclib plus fulvestrant versus 6.7% with placebo plus fulvestrant. Our findings support dalpiciclib plus fulvestrant as a new treatment option for pretreated hormone receptor-positive, HER2-negative ABC.", "affiliations": "Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].;Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.;Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, Fudan University Cancer Hospital, Shanghai, China.;Department of Medical Oncology, The First Hospital of Jilin University, Changchun, China.;Department of Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.;Department of Medical Oncology, Cancer Hospital of China Medical University/Liaoning Cancer Hospital, Shenyang, China.;Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China.;Department of Breast Oncology, Hubei Cancer Hospital, Wuhan, China.;Department of Medical Oncology, Hunan Cancer Hospital, Changsha, China.;Department of Head and Neck Cancer, West China Hospital, Sichuan University, Chengdu, China.;Department of Breast Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.;Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.;Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, China.;Department of Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences/Zhejiang Cancer Hospital, Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, China.;Department of Oncology, Jiangsu Province Hospital, Nanjing, China.;Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.;Department of Medical Oncology/Chemotherapy, Anhui Provincial Hospital, Hefei, China.;Breast Cancer Center, Shandong Cancer Hospital, Jinan, China.;Department of Breast, Bone & Soft Tissue Oncology, Guangxi Medical University Cancer Hospital, Nanning, China.;Department of Breast Disease, Henan Breast Cancer Center/The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.;Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.;Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.;Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.;Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.", "authors": "Xu|Binghe|B|http://orcid.org/0000-0003-4195-337X;Zhang|Qingyuan|Q|;Zhang|Pin|P|;Hu|Xichun|X|;Li|Wei|W|;Tong|Zhongsheng|Z|;Sun|Tao|T|;Teng|Yuee|Y|;Wu|Xinhong|X|;Ouyang|Quchang|Q|;Yan|Xi|X|;Cheng|Jing|J|;Liu|Qiang|Q|;Feng|Jifeng|J|;Wang|Xiaojia|X|;Yin|Yongmei|Y|;Shi|Yanxia|Y|;Pan|Yueyin|Y|;Wang|Yongsheng|Y|;Xie|Weimin|W|;Yan|Min|M|;Liu|Yunjiang|Y|;Yan|Ping|P|;Wu|Fei|F|;Zhu|Xiaoyu|X|;Zou|Jianjun|J|;|||", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1038/s41591-021-01562-9", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-8956", "issue": "27(11)", "journal": "Nature medicine", "keywords": null, "medline_ta": "Nat Med", "mesh_terms": null, "nlm_unique_id": "9502015", "other_id": null, "pages": "1904-1909", "pmc": null, "pmid": "34737452", "pubdate": "2021-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial.", "title_normalized": "dalpiciclib or placebo plus fulvestrant in hormone receptor positive and her2 negative advanced breast cancer a randomized phase 3 trial" }

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{ "abstract": "OBJECTIVE\nMycophenolate mofetil (MMF) is mainly used in conjunction with calcineurin inhibitors as an additional immunosuppressive for renal sparing after liver transplantation. However, few reports about MMF use in infants after living donor liver transplantation (LDLT) are available. The purpose of this study was to examine the efficacy and safety of MMF in infants.\n\n\nMETHODS\nThis study enrolled infants younger than 1 year of age who received LDLT at our institution. Patients received oral MMF twice daily. The initial dose was 40 to 50 mg/kg/d, which was increased to a target mycophenolic acid (MPA) trough level of 2 mg/L. Body weight, height, MMF dose, MPA trough level, acute cellular rejection (ACR) episodes, pathologic findings, and adverse effects were analyzed. Allograft fibrosis was graded using the Meta-analysis of Histological Data in Viral Hepatitis score.\n\n\nRESULTS\nPatients received MMF for refractory ACR (n = 2), fulminant hepatitis (n = 2), and pre-existing antibodies (n = 1). Original diseases were biliary atresia (n = 3) and fulminant hepatitis (n = 2). Mean age at transplant was 8 months (range 3-10 months). The last available mean trough level was 2.7 mg/L. The mean dose was 66 mg/kg/d or 1429 mg/m2/d at the time of the last available through level. The regression line for MMF dose and MPA trough level was y = 1.8 × 10-3x. The correlation coefficient was 0.65. All allografts showed F1 to F2 fibrosis. Two patients discontinued MMF because of infection and bone marrow suppression, respectively. Two patients converted to everolimus. One patient continued on MMF.\n\n\nCONCLUSIONS\nAfter LDLT, infants require a higher MMF dose than older patients based on trough levels, but allograft fibrosis can progress.", "affiliations": "Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. Electronic address: [email protected].;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.", "authors": "Ueno|Takehisa|T|;Kodama|Tasuku|T|;Noguchi|Yuki|Y|;Deguchi|Koichi|K|;Nomura|Motonari|M|;Saka|Ryuta|R|;Watanabe|Miho|M|;Tazuke|Yuko|Y|;Bessho|Kazuhiko|K|;Okuyama|Hiroomi|H|", "chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid", "country": "United States", "delete": false, "doi": "10.1016/j.transproceed.2020.01.160", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1345", "issue": "52(6)", "journal": "Transplantation proceedings", "keywords": null, "medline_ta": "Transplant Proc", "mesh_terms": "D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D009173:Mycophenolic Acid; D013997:Time Factors", "nlm_unique_id": "0243532", "other_id": null, "pages": "1855-1857", "pmc": null, "pmid": "32571709", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": null, "title": "Serum Trough Concentration and Effects of Mycophenolate Mofetil Based on Pathologic Findings in Infants After Liver Transplantation.", "title_normalized": "serum trough concentration and effects of mycophenolate mofetil based on pathologic findings in infants after liver transplantation" }

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SERUM TROUGH CONCENTRATION AND EFFECTS OF MYCOPHENOLATE MOFETIL BASED ON PATHOLOGIC FINDINGS IN INFANTS AFTER LIVER TRANSPLANTATION. TRANSPLANT PROC. 2020 JUN 19:S0041?1345(19)31830?5.", "literaturereference_normalized": "serum trough concentration and effects of mycophenolate mofetil based on pathologic findings in infants after liver transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200902", "receivedate": "20200902", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18222324, "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-TEVA-2020-JP-1829559", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TAPERED FROM TACROLIMUS BASED IMMUNOSUPPRESSION ACCORDING TO OUR PROTOCOL", "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": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SEE NARRATIVE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "UENO T, KODAMA T, NOGUCHI Y, DEGUCHI K, NOMURA M, SAKA R, ET AL. SERUM TROUGH CONCENTRATION AND EFFECTS OF MYCOPHENOLATE MOFETIL BASED ON PATHOLOGIC FINDINGS IN INFANTS AFTER LIVER TRANSPLANTATION. TRANSPLANT?PROC 2020?52(6):1855?1857.", "literaturereference_normalized": "serum trough concentration and effects of mycophenolate mofetil based on pathologic findings in infants after liver transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200929", "receivedate": "20200929", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18321391, "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\nThere is a significant prevalence of new onset neuropsychiatric symptoms (NPS), some severe and persistent, in patients with coronavirus disease 2019 (COVID-19).\n\n\nOBJECTIVE\nThis study reports on the use of electroconvulsive therapy (ECT) to treat NPS associated with COVID-19.\n\n\nMETHODS\nA review of the literature pertaining to the use of ECT in patients with COVID-19 and NPS was performed through PubMed, PsycINFO, and MEDLINE. Search terms included \"Electroconvulsive Therapy\" and \"ECT,\" combined with \"COVID-19\" and \"Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2).\" In addition, we present a case in which ECT was used to achieve complete remission in a patient who developed new onset, treatment-resistant depression, psychosis, and catatonia, associated with COVID-19.\n\n\nRESULTS\nA total of 67 articles were reviewed with 3 selected for inclusion. These articles detailed 3 case reports of patients with new onset NPS (mania, psychosis and suicidality, and catatonia) that developed in the context of active COVID-19 and were treated successfully with ECT.\n\n\nCONCLUSIONS\nECT, a broad-spectrum treatment that has been found to be effective in various NPS (independent of etiology), is shown in our case report and others, to be safe and effective for NPS associated with COVID-19. Although we identified only 3 other cases in the literature, we believe that the probable antiinflammatory mechanism of ECT, its safety and tolerability, and the faster time to symptom remission support the need for more research and increased clinician awareness about this life-saving procedure.", "affiliations": "The Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX. Electronic address: [email protected].;The Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.;The Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.;The Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.", "authors": "Austgen|Gabriela|G|;Meyers|Matthew S|MS|;Gordon|Mollie|M|;Livingston|Robin|R|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jaclp.2021.07.010", "fulltext": null, "fulltext_license": null, "issn_linking": "2667-2960", "issue": null, "journal": "Journal of the Academy of Consultation-Liaison Psychiatry", "keywords": "COVID-19; catatonia; electroconvulsive therapy; neuropsychiatric; psychiatric; psychosis", "medline_ta": "J Acad Consult Liaison Psychiatry", "mesh_terms": null, "nlm_unique_id": "101775059", "other_id": null, "pages": null, "pmc": null, "pmid": "34358726", "pubdate": "2021-08-04", "publication_types": "D016428:Journal Article; D016454:Review", "references": "32433118;26844966;33315969;21030090;33223217;32298803;32593479;31764451;27574610;29697715;33268001;31861926;31196793;15486852;32593341;33992595;33376990;32437679;32791211;32345550;33220366;19491313;29776679;29287239;28783929;32422545;32561222;32740329;33015547", "title": "The Use of Electroconvulsive Therapy in Neuropsychiatric Complications of Coronavirus Disease 2019: A Systematic Literature Review and Case Report.", "title_normalized": "the use of electroconvulsive therapy in neuropsychiatric complications of coronavirus disease 2019 a systematic literature review and case report" }

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{ "abstract": "Progressive outer retinal necrosis is a necrotizing herpetic retinopathy usually seen in immunocompromised patients. The authors describe two patients with this disease who initially had findings suggestive of an optic neuropathy. Vision declined after treatment with methylprednisolone, after which fundus examination became consistent with progressive outer retinal necrosis. These cases underscore the importance of careful examination of the retinal periphery before management of any presumed optic neuropathy with steroids.", "affiliations": "Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA.", "authors": "Nakamoto|B K|BK|;Dorotheo|E U|EU|;Biousse|V|V|;Tang|R A|RA|;Schiffman|J S|JS|;Newman|N J|NJ|", "chemical_list": "D000998:Antiviral Agents; D017245:Foscarnet; D011241:Prednisone; D000212:Acyclovir; D008775:Methylprednisolone", "country": "United States", "delete": false, "doi": "10.1212/01.wnl.0000147263.89255.b8", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-3878", "issue": "63(12)", "journal": "Neurology", "keywords": null, "medline_ta": "Neurology", "mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000212:Acyclovir; D000328:Adult; D000998:Antiviral Agents; D003586:Cytomegalovirus Infections; D017726:Cytomegalovirus Retinitis; D003951:Diagnostic Errors; D004172:Diplopia; D018450:Disease Progression; D018792:Encephalitis, Viral; D005260:Female; D017245:Foscarnet; D006562:Herpes Zoster; D006801:Humans; D008279:Magnetic Resonance Imaging; D008775:Methylprednisolone; D008875:Middle Aged; D009336:Necrosis; D009902:Optic Neuritis; D010291:Paresis; D011241:Prednisone; D012160:Retina", "nlm_unique_id": "0401060", "other_id": null, "pages": "2423-5", "pmc": null, "pmid": "15623719", "pubdate": "2004-12-28", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.; D016454:Review", "references": null, "title": "Progressive outer retinal necrosis presenting with isolated optic neuropathy.", "title_normalized": "progressive outer retinal necrosis presenting with isolated optic neuropathy" }

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PROGRESSIVE OUTER RETINAL NECROSIS PRESENTING WITH ISOLATED OPTIC NEUROPATHY. NEUROLOGY. 2004?63(12):2423-5.", "literaturereference_normalized": "progressive outer retinal necrosis presenting with isolated optic neuropathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160119", "receivedate": "20160119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11926568, "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": "US-ACTAVIS-2016-00670", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTABLE SUSPENSION", "drugdosagetext": "1 G, DAILY( 2 COURSES OF 3 DAYS EACH)", "drugenddate": null, "drugenddateformat": null, "drugindication": "OPTIC NEUROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE ACETATE (WATSON LABORATORIES)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "080356", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "70 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "OPTIC NEUROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE (WATSON LABORATORIES)" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Necrotising herpetic retinopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NAKAMOTO BK, DOROTHEO EU, BIOUSSE V, TANG RA, SCHIFFMAN JS, NEWMAN NJ. PROGRESSIVE OUTER RETINAL NECROSIS PRESENTING WITH ISOLATED OPTIC NEUROPATHY. NEUROLOGY. 2004?63(12):2423-5.", "literaturereference_normalized": "progressive outer retinal necrosis presenting with isolated optic neuropathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160119", "receivedate": "20160119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11926586, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "Since the introduction of targeted therapies, prognosis in human epidermal growth factor receptor (HER) 2-positive metastatic breast cancer (MBC) has radically changed. The addition of Pertuzumab to Trastuzumab and standard chemotherapy has further increased patients' overall survival (OS). However, there is no agreement regarding the optimal duration of trastuzumab therapy in selected patients achieving long-term complete remission. In addition, no potential factors of long-term benefit have been identified yet. In the present study, we report the case of a MBC woman who was successfully treated with trastuzumab for over 10 years. At the time of diagnosis (February 2005), she revealed lung, nodal and bone metastases. Therefore, a first-line chemotherapy with Epirubicine and Docetaxel was administered for 6 cycles and then the patient started Trastuzumab plus hormonal therapy until reaching a sensible reduction of mammary lump and disappearance of distant metastases. Following a multidisciplinary evaluation, in November 2006, the patient underwent radical mastectomy and axillary dissection, achieving a complete remission. She continued Trastuzumab until September 2015 (for a total of 156 cycles) when a pleural diffusion was demonstrated. Long-term survival during anti-HER2 treatment remains a rare and optimal situation. Currently, no data exist to support trastuzumab interruption in this setting and collaborative efforts to better analyze the characteristics of long-responder patients are needed. Data regarding prognostic factors in this setting are relatively confusing. Our review reveals that hormonal receptor (HR)-positive disease is associated with a better prognosis, whereas the role of visceral spread differs by single or dual target anti HER2-inhibition. The introduction of Pertuzumab is raising concerns in terms of toxicity and its cost effectiveness. While waiting for novel molecular data and randomized trials, available evidence advocates continuous use of anti-HER2 therapies until disease progression or development of side effects.", "affiliations": "Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.;Medical Oncology, Marche Polytechnic University, University Hospital Ospedali Riuniti Ancona, I-60126 Ancona, Italy.", "authors": "Cantini|Luca|L|;Pistelli|Mirco|M|;Savini|Agnese|A|;Bastianelli|Lucia|L|;Della Mora|Arianna|A|;Merloni|Filippo|F|;Burattini|Michela|M|;Berardi|Rossana|R|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3892/mco.2017.1495", "fulltext": null, "fulltext_license": null, "issn_linking": "2049-9450", "issue": "8(1)", "journal": "Molecular and clinical oncology", "keywords": "HER2; breast cancer; long-term survival; maintenance; pertuzumab; trastuzumab", "medline_ta": "Mol Clin Oncol", "mesh_terms": null, "nlm_unique_id": "101613422", "other_id": null, "pages": "147-152", "pmc": null, "pmid": "29387408", "pubdate": "2018-01", "publication_types": "D016428:Journal Article", "references": "24743708;18038883;27964843;23072512;26456898;25511015;24368024;23602601;27522517;25378932;22149875;24104881;23676508;22767587;17074677;11248153;22997442;24799465;26040825;21143954;26875184;25371387;25693012;28327998", "title": "Long-responders to anti-HER2 therapies: A case report and review of the literature.", "title_normalized": "long responders to anti her2 therapies a case report and review of the literature" }

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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/KG, EVERY 3 WEEKS, GLOBALLY 156 CYCLES FOR MORE THAN 10 YEARS", "drugenddate": "201509", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADO-TRASTUZUMAB EMTANSINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TDM-1" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG/KG FIRST DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200606", "drugstartdateformat": "610", "drugstructuredosagenumb": "8", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug effect incomplete", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CANTINI L, PISTELLI M, SAVINI A, BASTIANELLI L, MORA AD, MERLONI F, ET AL. LONG-RESPONDERS TO ANTI-HER2 THERAPIES: A CASE REPORT AND REVIEW OF THE LITERATURE. MOL-CLIN-ONCOL. 2018?8:147-152", "literaturereference_normalized": "long responders to anti her2 therapies a case report and review of the literature", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180206", "receivedate": "20180120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14414313, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "Patients with advanced and/or metastatic solid tumors have limited treatment options. Mutations that serve as biomarkers of carcinogenesis can be found in cell-free DNA of patients' plasma. Analysis of circulating tumor DNA (ctDNA) was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is not technically feasible or it is associated with high risk for complications. The role of ctDNA in precision oncology is promising but its clinical significance across tumor types remains to be validated. We report a case series of three heavily pretreated patients with advanced solid tumors who received matched targeted therapy based on ctDNA analysis and/or tumor molecular profiling.\nThree patients with advanced, metastatic cancer and the following characteristics are presented: a 71-year-old woman with ovarian cancer and BRCA2 mutation identified in ctDNA and tumor tissue was treated with a PARP inhibitor and achieved partial response by RECIST (Response Evaluation Criteria in Solid Tumors) for 22.6+ months; a 40-year-old woman with adenoid cystic carcinoma of the parotid gland was treated with a MEK/RAF pathway inhibitor on the basis of RAF1 amplification on ctDNA analysis and had stable disease for 20.2 months; and a 56-year-old woman with breast cancer and a BRCA1 mutation identified by ctDNA analysis was treated with a PARP inhibitor and achieved stable disease for 9.1 months. All three patients are alive at the time of this report.\nThese results suggest that ctDNA analysis can contribute to selection of targeted therapy in patients with advanced, metastatic cancer. Prospective clinical trials to evaluate and optimize ctDNA biomarkers, as well as the integration of novel and/or alternative targeted therapies, are warranted to fully assess the role of ctDNA analysis in cancer therapy.\nwww.clinicaltrials.gov (NCT02152254). Registered May 28, 2014. https://www.clinicaltrials.gov/ct2/show/NCT02152254. MD Anderson protocol # PA12-1161 (approval ID IRB1 FWA00000121) and # PA11-0377 (approval ID IRB4 FWA00005015).", "affiliations": "Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Abdominal Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030, USA.", "authors": "Naqvi|Mohammad Faraz|MF|;Vo|Henry Hiep|HH|;Vining|David|D|;Tsimberidou|Apostolia-Maria|AM|https://orcid.org/0000-0003-2713-233X", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/17588359211001538", "fulltext": "\n==== Front\nTher Adv Med Oncol\nTher Adv Med Oncol\nTAM\nsptam\nTherapeutic Advances in Medical Oncology\n1758-8340\n1758-8359\nSAGE Publications Sage UK: London, England\n\n10.1177/17588359211001538\n10.1177_17588359211001538\nCase Series\nProlonged response to treatment based on cell-free DNA analysis and molecular profiling in three patients with metastatic cancer: a case series\nNaqvi Mohammad Faraz *Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\n\nVo Henry Hiep *Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\n\nVining David Department of Abdominal Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\n\nhttps://orcid.org/0000-0003-2713-233X\nTsimberidou Apostolia-Maria Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030, USA\n\[email protected]\n* These authors contributed equally to this work.\n\n24 3 2021\n2021\n13 1758835921100153819 1 2021\n10 2 2021\n© The Author(s), 2021\n2021\nSAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nBackground:\n\nPatients with advanced and/or metastatic solid tumors have limited treatment options. Mutations that serve as biomarkers of carcinogenesis can be found in cell-free DNA of patients’ plasma. Analysis of circulating tumor DNA (ctDNA) was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is not technically feasible or it is associated with high risk for complications. The role of ctDNA in precision oncology is promising but its clinical significance across tumor types remains to be validated. We report a case series of three heavily pretreated patients with advanced solid tumors who received matched targeted therapy based on ctDNA analysis and/or tumor molecular profiling.\n\nCase presentation:\n\nThree patients with advanced, metastatic cancer and the following characteristics are presented: a 71-year-old woman with ovarian cancer and BRCA2 mutation identified in ctDNA and tumor tissue was treated with a PARP inhibitor and achieved partial response by RECIST (Response Evaluation Criteria in Solid Tumors) for 22.6+ months; a 40-year-old woman with adenoid cystic carcinoma of the parotid gland was treated with a MEK/RAF pathway inhibitor on the basis of RAF1 amplification on ctDNA analysis and had stable disease for 20.2 months; and a 56-year-old woman with breast cancer and a BRCA1 mutation identified by ctDNA analysis was treated with a PARP inhibitor and achieved stable disease for 9.1 months. All three patients are alive at the time of this report.\n\nConclusions:\n\nThese results suggest that ctDNA analysis can contribute to selection of targeted therapy in patients with advanced, metastatic cancer. Prospective clinical trials to evaluate and optimize ctDNA biomarkers, as well as the integration of novel and/or alternative targeted therapies, are warranted to fully assess the role of ctDNA analysis in cancer therapy.\n\nTrial registration:\n\nwww.clinicaltrials.gov (NCT02152254). Registered May 28, 2014. https://www.clinicaltrials.gov/ct2/show/NCT02152254. MD Anderson protocol # PA12-1161 (approval ID IRB1 FWA00000121) and # PA11-0377 (approval ID IRB4 FWA00005015).\n\ncell-free DNA\ncirculating tumor DNA\ngenomic profiling\npersonalized therapy\nprecision medicine\ntargeted therapy\nnational institutes of health https://doi.org/10.13039/100000002 P30 CA016672 Donor funds from Jamie’s Hope, Mr. and Mrs. Zane W. Arrott, and Mr. and Mrs. Steven McKenzie for Dr. Tsimberidou’s Personalized Medicine Program cover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nGenomic alterations play an important role in carcinogenesis, disease progression, resistance and response to targeted therapy. The genetic heterogeneity across tumor types complicates the management of these diseases. Using the genomic profiles of individual patient tumors, precision medicine helps optimize treatment selection to improve clinical outcomes for patients with cancer.1 Mutations that serve as biomarkers of tumor progression and response can be found in cell-free DNA collected from the plasma of individual patients. Analysis of this circulating tumor DNA (ctDNA), therefore, offers a promising, non-invasive, and personalized diagnostic approach to selecting treatment and patients for enrollment in clinical trials.\n\nTumor biopsy samples are typically analyzed to determine the tumor characteristics, but biopsy is not feasible for some patients because their tumors are not easily accessible or because the biopsy procedure is associated with significant risk. Also, samples obtained from biopsies can be insufficient for tumor analysis. The proportion of patients who are ineligible for molecular screening due to inaccessibility or high risk of tumor biopsy, and therefore are excluded from certain clinical trials offering targeted treatment based on molecular alterations, has not been systematically analyzed. In the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) study, it was estimated that 10% to 15% of patients with lung cancer did not have sufficient material for next-generation molecular testing.2 In an interim analysis of IMPACT2, an ongoing randomized study evaluating genomic profiling and targeted agents in metastatic cancer, of 391 patients who were enrolled in the first part of the study, 19 (4.86%) patients had inadequate tumor cells for analysis and biopsy was not feasible or tumor was not accessible in 15 (3.84%) patients. Overall, 213 (54.48%) of 391 received anticancer therapy (Tsimberidou et al., Npj Precision Oncology, in Press).\n\nCtDNA analysis was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is associated with significant risk, when tumor tissue is insufficient or inaccessible, and/or when repeated assessment of tumor molecular abnormalities is needed to optimize treatment.3\n\nWe previously reviewed the role of ctDNA in guiding targeted therapy in clinical trials that involved ctDNA analysis of specific tumors and across tumor types.3 CtDNA analysis based on epidermal growth factor receptor (EGFR) and v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) has been well established for selecting treatment for patients with advanced non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), respectively.4,5 However, the assessment of ctDNA and clinical trials that involve ctDNA analysis in other tumor types are still needed. Herein, we describe encouraging clinical outcomes of three patients with advanced metastatic cancer who received matched targeted therapy based on the results of ctDNA analysis.\n\nCase presentation\n\nCase presentation 1: Patient (ID 001)\n\nA 71-year-old woman was diagnosed with metastatic ovarian cancer in October 2010. She had been experiencing symptoms of vaginal dryness, dyspareunia, and abdominal and lower back pain. Magnetic resonance imaging (MRI) of the pelvis demonstrated a complex adnexal mass and computed tomography (CT) imaging studies demonstrated a lesion in the upper lobe of the left lung, and an adenoma of the left adrenal gland. Transvaginal ultrasonography confirmed a multilocular mass (6.0 × 5.0 × 5.6 cm) centered in the right adnexal region. The mass had multiple irregular thick septa and a soft tissue component with definite vascular flow in the regions of echogenic soft tissue and was highly suggestive of cystadenocarcinoma. The patient underwent a laparoscopic bilateral salpingo-oophorectomy, and the surgical pathology report demonstrated ovarian high-grade serous carcinoma with extension to the fallopian tube surface and fimbrial end in the right ovary and tube, and metastatic to the omentum. In November 2010, the patient was treated with six cycles of carboplatin and paclitaxel followed by 11 cycles of paclitaxel consolidation therapy. CT imaging studies demonstrated no evidence of disease at 5 months after treatment and annually for 3 years. Three years after treatment, she presented to the clinic with increasing pain and pressure in the lower abdomen, including pain with urination. CT scans demonstrated diffuse peritoneal carcinomatosis, evidenced by multiple nodular masses noted within the peritoneum and the supracolic omentum, and small volume ascites. She was retreated with six cycles of carboplatin and paclitaxel, and restaging scans demonstrated improvement in the peritoneal carcinomatosis and no gross CT evidence of residual disease. She had no evidence of disease for 17 months, and then CT scans showed interval development of a heterogeneous soft tissue lesion in the pelvis compatible with recurrent disease. She underwent tumor reductive surgery followed by six cycles of carboplatin and paclitaxel. Molecular analysis using formalin-fixed paraffin-embedded (FFPE) tissue of the most recently resected pelvic mass demonstrated tumor protein p53 (TP53) mutation and breast cancer type 2 (BRCA2) somatic mutation (Table 1). The disease responded to treatment with carboplatin and paclitaxel but recurred after 20 months and the patient was referred to the Department of Investigational Cancer Therapeutics in July 2017. She was enrolled on a clinical trial that included carboplatin, paclitaxel and immunotherapy. Her best response was immune-related partial response (PR). On cycle 19, day 22, CT images demonstrated increasing size and number of nodules within the peritoneum consistent with increasing metastatic disease; a growing metastasis was also noted in segment five of the liver. ctDNA analysis performed 13 months prior to disease progression demonstrated the following alterations: neurofibromin 1 (NF1), splice site SNV 1.9, TP53 V157F 0.2, guanine nucleotide binding protein, alpha stimulating activity polypeptide (GNAS) R201H 0.2, BRCA2 R3052W 0.1 (Table 1). On the basis of this information and evidence of a BRCA2 somatic mutation in the pelvic mass, the patient was enrolled on a clinical trial of a poly (ADP-ribose) polymerase (PARP) inhibitor administered daily. She underwent genetic counseling, and testing for germline BRCA1 and BRCA2 mutations was negative. Thus far, she has received 21 cycles of the PARP inhibitor, and her best RECIST response was PR (76% decrease from baseline per RECIST 1.1) (Figure 1). Her treatment is ongoing [progression-free survival (PFS) = 22.6+ months] (Table 2). The patient experienced grade 3 anemia that started during cycle 3 and was treated with transfusion of red blood cells (average, 2 units monthly). On cycle 7, day 1, she required a dose adjustment consisting of a 25% reduction in the PARP inhibitor dose and a decrease of days of treatment to 3 weeks on, 1 week off, after which she tolerated the treatment without the need for transfusion.\n\nTable 1. Genomic analysis using tissue and ctDNA samples.\n\nPt. ID\tCollection date\tSample source\tGenomic alterations\tPanel, no. of clinically relevant genes\t\n001\t16 June 2015\tPelvic mass\tTP53 V157F\tSolid tumor genomic assay V2, 146 genes\t\n\t\t\tBRCA2 R3052W\t\t\n\t20 July 2017\tBlood\tBRCA2 R3052W\tGuardant360, 73 genes\t\n\t\t\tNF1 splice site\t\t\n\t\t\tTP53 V157F\t\t\n\t\t\tGNAS R201H\t\t\n002\t21 July 2017\tBlood\tRAF1 amplification\tGuardant360, 73 genes\t\n\t25 September 2017\tLiver\tNone\tSolid tumor genomic assay V1, 134 genes\t\n\t22 November 2019\tLiver\tBRAF V600dup\tTempus × T assay, 596 genes\t\n\t\t\tMYB-NFIB chromosomal rearrangement\t\t\n\t\t\tKMT2D Q2696 Stop gain – LOF\t\t\n003\t29 January 2015\tLung\tATM loss exons 57–63\tFoundationOne, 315 genes\t\n\t\t\tNOTCH2 A3F\t\t\n\t\t\tESR1 Y537S\t\t\n\t\t\tCCND1 amplification\t\t\n\t\t\tEMSY amplification\t\t\n\t\t\tFGF19 amplification\t\t\n\t\t\tFGF3 amplification\t\t\n\t\t\tFGF4 amplification\t\t\n\t\t\tMCL1 amplification - equivocal\t\t\n\t15 October 2018\tBlood\tATM M3011T\tLiquid biopsy panel, 70 genes\t\n\t\t\tBRCA1 Q356*\t\t\n\t\t\tESR1 Y537S\t\t\n\t\t\tTP53 A159V\t\t\n\t\t\tTP53 P152L\t\t\nATM, ATM serine/threonine kinase; BRAF, rapidly accelerated fibrosarcoma homolog B; BRCA1, breast cancer type 1; BRCA2, breast cancer type 2; CCND1, Cyclin D1; EMSY, BRCA2 interacting transcriptional repressor; ESR1, estrogen receptor 1; FGF, fibroblast growth factor; GNAS, guanine nucleotide binding protein, alpha stimulating activity polypeptide; KMT2D, histone-lysine N-methyltransferase 2D; LOF, loss of function; MCL1, myeloid cell leukemia 1; MYB-NFIB, myeloblastosis virus oncogene – nuclear factor 1 B-type; NF1, neurofibromatosis type 1; NOTCH2, notch receptor 2; RAF1, rapidly accelerated fibrosarcoma 1; TP53, tumor protein p53.\n\nMolecular alterations identified by ctDNA analysis and used to select matched therapy are presented in bold text.\n\nTable 2. Clinical outcomes of three patients with advanced solid tumors who received matched therapy based on ctDNA analysis.\n\nPt. ID\tctDNA biomarker\tMatched therapy\tBest RECIST response\tPFS*, months\tProgr.status\tSubsequent Rx\tSurvival status\tOS†, months\t\n001\tBRCA2 R3052W\tPARP inhibitor\tPR\t22.6+\tN/A\tN/A\tAlive\t22.6+\t\n002\tRAF1 amplification\tMEK/RAF pathway inhibitor\tSD\t20.2\tPD\tInvestigational\tAlive\t28.4+\t\n003\tBRCA1 Q356*\tPARP inhibitor\tSD\t9.1\tPD\tDoxorubicin; radiotherapy\tAlive\t14.8+\t\nN/A, non-applicable; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; Progr., progression; Rx, therapy; SD, stable disease.\n\nBRAC1, breast cancer type 1; BRAC2, breast cancer type 2; MEK, mitogen-activated protein kinase kinase; PARP, poly (ADP-ribose) polymerase; RAF1, rapidly accelerated fibrosarcoma 1.\n\n* Progression-free survival is measured in months from cycle 1, day 1 to time of radiologic scan showing progressive disease.\n\n† Overall survival is measured in months from cycle 1, day 1 to the most recent time of this report.\n\nFigure 1. Changes in tumor measurement from baseline in patient 001, who underwent treatment with PARP inhibitor on the basis of ctDNA analysis showing BRCA2 R3052W mutation. (a) Scatter plot illustrates changes in lesion tumor burden. Computed tomography (CT) scan data at the most recent time prior to cycle 1, day 1 is chosen as baseline (time 0). The horizontal (x) axis shows time at restaging CT scans as months from baseline. The vertical (y) axis shows percentage of change in tumor measurement from baseline. Each dot represents a data point collected at each restaging CT scan. The blue line represents PR (⩾30% decrease in tumor measurements from baseline, based on RECIST 1.1). (b) Scatter plot illustrates changes in tumor marker levels over time. (c) Representative CT images from the patient at baseline. (d) Representative CT images from the patient after 20.6 months of targeted therapy with PARP inhibitor.\n\nRed arrows indicate target lesions.\n\nCase presentation 2: Patient (ID 002)\n\nA 40-year-old woman was first diagnosed in 2007 with adenoid cystic carcinoma of the left parotid gland and bone metastases. She was a non-smoker and had a pertinent family history of multiple cancers, notably of the brain, stomach, and skin. The patient underwent superficial parotidectomy with apparently negative margins followed by post-operative adjuvant radiotherapy. Subsequent imaging revealed a lytic lesion at the L3 vertebral body; biopsy did not demonstrate metastatic tumor. She had no evidence of disease until 2013, when a positron emission tomography (PET)/CT revealed increased activity in the L3 vertebra. The patient experienced back pain while lifting heavy objects or when the lesion was percussed, post-operative paresthesia in the lobule and tragus of the left ear and stiffening of the left neck. In October 2013, she received stereotactic radiation therapy to the L3 vertebra (24 Gy to the gross tumor volume and 16 Gy to the clinical target volume). Three months later, PET/CT imaging studies demonstrated no evidence of FDG-avid metastasis.\n\nShe had no evidence of active disease for 33 months, until October 2016, when MRI and PET/CT imaging studies demonstrated left pulmonary metastasis, an enlarging lesion at L3–L4 consistent with progressive disease. She was referred to the Department of Investigational Cancer Therapeutics in February 2017. She was treated with an investigational combination therapy comprising a STAT3 inhibitor and nivolumab for eight cycles. Her best RECIST response was stable disease (SD), with a 13% decrease in tumor measurements from baseline to cycle 3, day 26 (RECIST 1.1). She was taken off protocol in July 2017 owing to disease progression that included liver metastases. Possibly related adverse events included grade 1 diarrhea and abdominal cramps.\n\nMolecular diagnostic solid tumor genomic assay using FFPE slides from a liver biopsy performed in September 2017 did not identify any somatic mutations (Table 1). However, ctDNA analysis using the patient’s blood sample demonstrated a strongly positive rapidly accelerated fibrosarcoma 1 (RAF1) amplification, with a magnitude in the 50th to 90th percentile (Table 1). On the basis of this finding, the patient was started on a clinical trial with a mitogen-activated protein kinase kinase/ rapidly accelerated fibrosarcoma (MEK/RAF) pathway inhibitor in January 2018. Her best RECIST response was SD with an 18% decrease in tumor measurements (RECIST 1.1) after 10 cycles (Figure 2). She received 29 cycles of the study drug and was taken off study owing to progressive disease confirmed by CT imaging studies. PFS duration was 20.2 months and overall survival duration was 28.4+ months. Adverse events possibly associated with MEK/RAF pathway inhibitor were all grade 1 and included intermittent diarrhea and vomiting; maculopapular and acneiform rash; neutropenia; blurry vision; and hair thinning.\n\nFigure 2. Changes in tumor measurement from baseline in patient 002, who underwent treatment with MEK/RAF pathway inhibitor on the basis of ctDNA analysis showing RAF1 amplification. (a) Representative computed tomography (CT) images from the patient at baseline. (b) Representative CT images from the patient after 6.8 months of treatment with MEK/RAF pathway inhibitor.\n\nRed arrows indicate target lesions.\n\nIn November 2019, the patient underwent a core needle biopsy of the liver for completion of molecular profiling, which demonstrated rapidly accelerated fibrosarcoma homolog B (BRAF) V600dup and myeloblastosis virus oncogene – nuclear factor 1 B-type (MYB-NFIB) chromosomal rearrangement, biologically relevant histone-lysine n-methyltransferase 2D (KMT2D) genomic variant, negative programmed death-ligand 1 (PDL1) expression, normal DNA mismatch repair protein expression, and RNA sequencing demonstrating fibroblast growth factor receptor 2 (FGFR2) and fibroblast growth factor receptor 1 (FGFR1) overexpression (Table 1). Two months later, she underwent transcatheter arterial hepatic embolization of the larger liver metastases. The patient was alive at the time of this report (Table 2). She did not experience any serious adverse events and did not require any blood transfusions.\n\nCase presentation 3: Patient (ID 003)\n\nA 56-year-old woman with a history of breast cancer was referred to the Department of Investigational Cancer Therapeutics in January 2015. She had no pertinent medical history and was in good health until early 2005, when she felt a mass in her left breast. She was a non-smoker and had a family history of breast cancer and prostate cancer. Physical examination demonstrated a 3 × 3 cm mass in the 10 to 11-o’clock position in the superior aspect of the left breast and a 2 cm lymph node in the left axilla. Ultrasound-guided core needle biopsy performed in February 2005 demonstrated an estrogen receptor- and progesterone receptor-positive, human epidermal growth factor receptor 2 (HER-2/neu)-negative invasive mammary carcinoma of the left breast [modified Black’s nuclear grade 1 (well differentiated)], carcinoma in situ, low grade, solid type, without necrosis). CT scans indicated no evidence of metastasis; however, fine-needle aspiration of the left axilla lymph nodes demonstrated metastatic carcinoma consistent with the primary breast tumor.\n\nIn March 2005, the patient was enrolled on a clinical trial that included weekly paclitaxel chemotherapy for 12 cycles followed by six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide. Four months later, imaging studies indicated a reduction in tumor size. In September 2005, she underwent a left skin-sparing total mastectomy with axillary lymph node dissection followed by delayed reconstruction using a submuscular tissue expander. Then, from October to December 2005, she underwent post-operative adjuvant radiation therapy (50 Gy in 25 fractions to the left central chest and left lateral chest wall with an additional 10 Gy boost to the tumor bed). She also intermittently received Tamoxifen between 2005 and 2008. In December 2006, imagining studies demonstrated bone metastasis and the patient was treated with radiation therapy and anastrozole plus fulvestrant from December 2006 to March 2014. The bone disease stabilized, but she had disease progression in her lungs and lymph nodes. Although her tumor did not harbor an alteration in the PI3K/Akt/mTOR pathway, she was treated with the standard-of-care exemestane and everolimus from March 2014 to January 2015.\n\nIn January 2015, CT scans demonstrated increasing thoracic lymphadenopathy and pulmonary metastatic disease, and a nuclear medicine bone scan demonstrated bone metastasis involving the left ilium, acetabulum, and ischium. The patient was referred to the Department of Investigational Cancer Therapeutics in January 2015 and underwent biopsy of a lung tumor. Molecular profiling of the tumor demonstrated the following genomic alterations: ATM serine/threonine kinase (ATM) loss in exons 57 to 63, notch receptor 2 (NOTCH2) A3F, estrogen receptor 1 (ESR1) Y537S, and amplification of the following genes: cyclin D1 (CCND1), myeloid cell leukemia 1 (MCL1), BRCA2 interacting transcriptional repressor (EMSY), fibroblast growth factor 19 (FGF19), fibroblast growth factor 3 (FGF3), and fibroblast growth factor 4 (FGF4) (Table 1). Early assessments suggested that preclinical models with increased cyclin D1 or cyclin-CDK-Rb pathway activation may have increased sensitivity to CDK4/6 inhibitors.6,7 However, the patient did not receive a CDK4/6 inhibitor because clinical trials were not available at that time. She was presented at the multidisciplinary conference for optimization of treatment selection. On the basis of tumor molecular profiling demonstrating multiple mutations in FGF (FGF19, FGF3, and FGF4), the patient was offered an investigational therapy comprising FGFR inhibitor, but she pursued treatment with eribulin; after four cycles she developed disease progression. Subsequently, she was treated with 11 cycles of fulvestrant and palbociclib and was taken off study owing to progressive disease in August 2017.\n\nOn the basis of her tumor’s NOTCH2 A3F alteration, in October 2017, the patient was enrolled on a clinical trial consisting of a NOTCH inhibitor, cisplatin, and gemcitabine. Her best RECIST response was PR per RECIST 1.1 criteria on cycle 12, day 19. She received 22 cycles of the investigational drug combination for 19 months and was taken off study owing to disease progression. Adverse events included impaired hearing and thrombocytopenia.\n\nThe patient underwent genetic counseling, and testing for germline BRCA1 and BRCA2 mutations was negative. CtDNA analysis in October 2018 demonstrated multiple somatic mutations which included a breast cancer type 1 (BRCA1) nonsense mutation on exon 10 (Table 1). On the basis of these findings, the patient was enrolled on a clinical trial with a PARP inhibitor. Her best RECIST response was SD with a 14% decrease in tumor measurement from baseline per RECIST 1.1, and the PFS duration was 9.1 months (Figure 3 and Table 2). Imaging studies in January 2020 demonstrated evidence of progressive disease and she was taken off study. Subsequently, she received radiotherapy and doxorubicin. At the time of this report, the patient was still alive, and the overall survival duration was 14.8+ months (Table 2).\n\nFigure 3. Changes in tumor measurement from baseline in patient 003, who underwent treatment with PARP inhibitor on the basis of ctDNA analysis showing BRCA1 Q356* mutation. (a) Representative computed tomography (CT) images from the patient at baseline. (b) Representative CT images from the patient after 6.5 months of treatment with PARP inhibitor. (c) Representative positron emission tomography (PET) overview image from the patient at baseline. (d) Representative PET overview image from the patient after 6.5 months of treatment with PARP inhibitor.\n\nRed arrows indicate target lesions.\n\nDiscussion and conclusions\n\nThe clinical significance of ctDNA analysis is evolving. The FDA has approved the use of next-generation sequencing (NGS) analysis as a companion diagnostic device for multiple biomarkers detected by ctDNA analysis using plasma specimens of patients with NSCLC (EGFR mutations for the use of gefitinib, osimertinib and erlotinib; and ALK rearrangements for treatment with alectinib), prostate (BRCA1 and BRCA2 alterations for the use of rucaparib and olaparib; and ATM alterations for the use of olaparib), ovarian (BRCA1 and BRCA2 alterations for the use of rucaparib), and breast cancer (PI3K mutations for the use of alpelisib). CtDNA analysis is also used for KRAS in CRC5 and in the management of resistance to ALK inhibitors in lung cancer.8 However, ctDNA analysis has not been systematically validated for patients with other tumor types. If the specific genomic alterations associated with these FDA-approved drugs are not detected in the blood, then tumor biopsies should be performed to identify these alterations.\n\nIn this case series, the use of ctDNA analysis alone or in combination with tumor molecular profiling was associated with encouraging clinical outcomes in three patients with advanced, metastatic cancer treated with targeted therapy. One patient had a durable PR of 22.6+ months as evidenced by CT imaging and tumor marker monitoring (Figure 1); the other two patients had SD lasting for 20.2 months and 9.1 months, respectively (Table 2). Our data demonstrate that in heavily pretreated patients with advanced, metastatic cancer, targeted therapy selected on the basis of ctDNA and/or tumor genomic analysis was associated with encouraging results. Our observation emphasizes the need to systematically analyze ctDNA in correlation with tumor genomic analysis. Further, the role of ctDNA analysis should be assessed in prospective clinical trials for selection of personalized therapy in individual patients.\n\nIn our study, patient ID 002, who received MEK/RAF pathway inhibitor on the basis of ctDNA analysis demonstrating a strongly positive RAF1 amplification, had disease stabilization for 20.2 months and overall survival (OS) >28.4+ months. Genomic analysis using tumor biopsy also demonstrated BRAF_V600dup alteration. Tumor harboring both RAF amplification and BRAF V600dup may have sensitivity to treatment with MEK/RAF inhibitors, and our results warrant further investigation. There is minimal evidence on RAF1 amplification and enhanced tumor response to targeted therapies. Overexpression of RAF1 promotes c-Raf signaling in vitro, and preclinical studies have suggested that tumors with activating c-Raf signaling may be more sensitive to MEK inhibition.9–11 Tumors with RAF1 amplification therefore might benefit from MEK inhibitor therapy. Studies conducted by other investigators in a phase III, randomized clinical trial demonstrated that patients with melanoma harboring either RAF1, KRAS or CCND1 amplification who received carboplatin, paclitaxel, and sorafenib, had a longer OS and PFS compared with only carboplatin and paclitaxel.12 The outcomes were attributed to targeting of RAF1 by sorafenib. Hence, it is possible that RAF1 amplification in this tumor type might sensitize cells to sorafenib and other multi-tyrosine kinase inhibitors.\n\nBRAF_V600dup has been reported to be an activating alteration. This alteration is a duplication of codon V600, a “hotspot” codon located within the BRAF kinase domain (amino acids 457–717), which is commonly mutated in cancer. Codon V600 is important for maintaining the Asp-Phe-Gly (DFG) motif of BRAF in an inactive state.13 Alterations at codon V600 increase BRAF activity by stabilizing the active conformation of BRAF. Several studies conducted by other investigators demonstrated that multiple missense mutations at V600 promote constitutive activation of BRAF and alterations at K601 and T599I promote BRAF kinase activity.13–17 These alterations and other overlapping deletion and/or insertion events have been reported to be activating in vitro as evidenced by the activation of BRAF kinase activity, increase in MEK and ERK signaling, and transformation in NIH-3T3 cells.18\n\nThe effect of BRAF inhibitors on tumors harboring activating non-BRAF V600 mutations is unclear. Limited preclinical data suggest that the majority of non-BRAF V600 mutations are associated with decreased response or resistance to BRAF inhibitors, vemurafenib and dabrafenib.19,20 In contrast, other investigators reported that activating non-V600 variants may retain some sensitivity to dabrafenib.21 Some preclinical data indicate that MEK and ERK inhibitors may be effective for tumors harboring non-BRAF V600 mutations.21–23\n\nPlasma ctDNA analysis may address tissue heterogeneity by capturing somatic alterations that represent multiple metastatic sites; therefore, it may be more informative than tissue molecular profiling. These alterations may indicate tumor sensitivity to targeted therapies or resistance to treatment. ctDNA analysis is associated with a shorter turnaround time compared with tumor tissue molecular analysis and eliminates the risks associated with invasive biopsies. Identification of tumor genomic alterations using ctDNA analysis also may help select patients for enrollment in clinical trials.\n\nThe use of different panels and genomic assays in our study may contribute to the differences in molecular alterations found in tumor biopsy versus ctDNA. Other factors may include the methodology used for genomic assays, tumor heterogeneity, and tumor burden at the time of diagnosis and at the time of disease progression. Notably, in patient ID 002, RAF1 amplification detected using ctDNA analysis was not found in tumor analysis (Table 1). The results are consistent with the concept that ctDNA analysis may be more representative of the overall tumor molecular profiling, regardless of the location of the tumor.\n\nThe practice of ordering ctDNA analysis when response to ongoing therapy starts to wane may allow for optimized treatment selection without delay at the time of disease progression. Patients with advanced, metastatic cancer typically have a higher total systemic tumor burden compared with that of patients with early stage disease and, therefore, higher ctDNA levels.24 For instance, in CRC, the ctDNA levels decreased after tumor resection and generally increased with the presentation of new lesions evidenced by imaging scans.24\n\nCtDNA analysis and selected targeted treatments have been well established4,5,25,26 in CRC and NSCLC, and the concordant rates between ctDNA and matched tissue biopsies across other advanced/metastatic solid tumors range from 48% to 100%. The respective published data include patients with breast cancer,27 castration-resistant prostate cancer,28 pancreatic cancer,29 neuroblastoma,30 and melanoma.31\n\nAnalysis of ctDNA and tumor tissue samples in patients with metastatic breast cancer using droplet digital polymerase chain reaction analysis reported an overall concordance rate of 74.3% in ESR1 mutation status,27 indicating acquired resistance to endocrine therapy.27 In patients with metastatic, castration-resistant prostate cancer, the concordance between ctDNA and matched metastatic tissue biopsies was 100% in somatic mutations and 88.9% for individual copy number calls of the driver genes androgen receptor (AR), BRCA2, ATM, phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), TP53, and RB transcriptional corepressor 1 (RB1).28 In patients with advanced pancreatic ductal adenocarcinoma, the concordance rates between ctDNA and tumor tissue DNA alterations were 61% for TP53 and 52% for KRAS mutations.29 For KRAS alterations, concordance between ctDNA and tumor tissue DNA was significantly higher for metastatic than for primary tumors.29\n\nOne 83-year-old male patient with advanced pancreatic ductal adenocarcinoma (PDAC) treated with trametinib based on evidence of MEK pathway (GNAS, KRAS, and NF1) mutations, remained on treatment for 6+ months; although he was unable to undergo CT due to renal insufficiency, the levels of total ctDNA and CA19-9 significantly decreased.29\n\nIn patients with neuroblastoma, the concordance rate between ctDNA and tumor tissue for one of three anaplastic lymphoma kinase (ALK) mutational hotspots, the ALK F1174L mutation, was 100%.30 In patients with metastatic melanoma, the concordance rate between ctDNA from plasma compared with tumor tissue ranged from 75% to 100% (average, 89%).31\n\nSerial monitoring of ctDNA can be used to assess clonal evolution, predict progressive disease, and identify resistant clones. Other investigators have reported on ctDNA analysis in diverse solid tumors including advanced breast, ovarian, lung, and colorectal cancers.32–35 CtDNA clonal mutations were assessed to monitor tumor burden and disease progression in patients with advanced gastric cancer.36 For instance, serial monitoring of ctDNA samples from patients with gastric cancer and evaluation of the molecular tumor burden index (mTBI) identified progressive disease a mean of 18 weeks before it was seen on radiographic results. In patients who received anti-HER2 therapy, ctDNA analysis identified 32 expanding mutations potentially related to trastuzumab resistance. In patients who received chemotherapy, prediction of progressive disease using mTBI was validated with 94% sensitivity. Higher mTBI (⩾1%) in pre-treatment ctDNA was associated with shorter PFS.36\n\nMicrosatellite instability (MSI) and high tumor mutation burden (TMB-High) are promising pan-tumor biomarkers for the selection of patients to receive checkpoint blockade immunotherapy. Studies conducted by other investigators demonstrated the feasibility of using ctDNA analysis to assess MSI and TMB-high status.37,38 However, sensitive detection of MSI using ctDNA is still in early phases of development owing to technical and bioinformatics challenges including efficient molecular capture, sequencing, mapping, variant calling, error correction at microsatellite loci, the highly repetitive genomic context and low tumor fraction in circulation, high level of normal cell contamination, and technical noise due to polymerase slippage. Other factors affecting the accuracy of MSI detection using ctDNA and associated with discrepancies between studies include the number and type of microsatellite markers used, tumor cell fraction, and intratumor and intertumor heterogeneity.39 In patients with gastric cancer, high MSI status, as assessed by ctDNA analysis, was associated with favorable clinical response to immunotherapy.38 MSI detection using ctDNA sequencing demonstrated high specificity, precision, and sensitivity up to a limit of 0.1% tumor content. CtDNA analysis detected 87% of tissue with high MSI and 99.5% of microsatellite stable tissue, with an overall accuracy of 98.4% and a 95% positive predictive value. Objective responses were noted in 63% of these patients.38 Ongoing studies are investigating the role of ctDNA in assessment of MSI and TMB-high status as predictive biomarkers for the selection of checkpoint inhibitors.\n\nEncouraging results have been reported using ctDNA analysis to select targeted therapy across tumor types. The TARGET (Tumour chARacterisation to Guide Experimental Targeted therapy) study, which was initiated in 2015, matches patients with diverse advanced tumors to early-phase clinical trials based on the tumor molecular abnormalities identified by ctDNA analysis.40 In 100 patients (Part A) with advanced colorectal cancer, breast cancer, NSCLC, small-cell lung carcinoma, sarcoma, prostate cancer, cholangiocarcinoma, small bowel cancer, melanoma, adrenal cancer, solitary fibrous tumor, cancer of unknown primary, or other cancers, the concordance rate between mutations identified in ctDNA and in the tumor tissue was 70%. Genomic profiling of ctDNA using NGS identified actionable mutations in 41 patients, of whom 11 patients received a matched therapy and 17 patients received a non-matched therapy.40 Four of the 11 patients treated with targeted therapy had a PR lasting for 8, 12, 18, and 20 months, respectively; and four of the 17 patients treated with non-matched therapy had SD (no objective response was noted). The study is accruing patients in Part B with a planned enrollment of 450 patients over 3 years to compare clinical outcomes between matched and non-matched therapies.40 The TARGET study indicates the feasibility of using ctDNA analysis to guide targeted therapy in early-phase clinical trials. Notably, in August 2020, the FDA approved Guardant360 CDx, the first liquid biopsy companion diagnostic approved to provide information on multiple solid tumor biomarkers.41 In October and November 2020, the FDA also approved FoundationOne Liquid CDx test (Foundation Medicine, Inc.) as a companion diagnostic device for multiple additional biomarkers detected in cell-free DNA isolated from plasma specimens.42\n\nClinical trials that allow ctDNA analysis for selection of targeted therapy are in development, including the TAPUR (Targeted Agent and Profiling Utilization Registry) study, a non-randomized, open-label, multi-basket, pragmatic phase II precision oncology trial that integrates tumor genomic profiling using tumor biopsy and/or liquid biopsy to match patients with diverse advanced cancers to targeted anticancer agents outside of their FDA-approved indications (NCT02693535).43 The NEXT-2 [Next Generation pErsonalized tX (Therapy) with plasma DNA] trial is another ongoing prospective study being conducted in Korea that evaluates the role of ctDNA in refractory solid tumors (NCT02140463).44 The investigators reported that 30 (15.5%) of 195 patients who underwent comprehensive ctDNA genomic profiling were enrolled on clinical trials with matched therapy and noted objective responses in six of nine patients with gastric cancer, 13 of 15 patients with NSCLC, one of two patients with melanoma, and zero of one patient in the other tumor types category.44\n\nLimitations to ctDNA analysis are associated with discordance between ctDNA and tumor tissue genomic analysis due to biologic and technical differences (sensitivity and specificity), metastatic sites, histology, time of treatment administration prior to blood/plasma collection, low tumor burden, and absence of a primary tumor.25,45–47 CtDNA is secreted by tumor cells, phagocyte-engulfed tumor cells, and necrotic or apoptotic tumor cells, and therefore reflects tumor from all sites of disease.3 In addition, genomic analysis using only ctDNA may exclude other biomarkers. Analysis of circulating RNAs, circulating tumor cells, and exosomes may overcome this challenge.45\n\nIn conclusion, ctDNA and tumor profiling for treatment optimization for patients with advanced solid tumors requires greater precision. Although the role of ctDNA in guiding targeted treatments is well established in NSCLC and in CRC,4,5 the assessment of ctDNA and its clinical significance in other tumor types remains to be validated, despite some encouraging results. Prospective clinical trials involving ctDNA analysis and targeted agents are ongoing and/or awaiting results. ctDNA analysis at the time of diagnosis, or early evidence of progressive disease during ongoing treatment, will yield significant insights into the evolution of the patient’s tumor biology, accelerate drug development, and contribute to the implementation of precision medicine to improve clinical outcomes.\n\nWe thank the patients, their families, and caregivers for participating in the study.\n\nAuthors’ contributions: MFN and HHC contributed to literature search, data acquisition, data analysis, data interpretation and writing the manuscript. DV contributed to data acquisition, data analysis, data interpretation, and review of the manuscript. AMT (corresponding author) conceptualized the manuscript, contributed to patient enrollment, patient treatment and assessment, data analysis, data interpretation and writing the manuscript. All authors read and approved the final manuscript.\n\nFunding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by donor funds from Jamie’s Hope, Mr. and Mrs. Zane W. Arrott, and Mr. and Mrs. Steven McKenzie for Dr. Tsimberidou’s Personalized Medicine Program. This work was also supported in part by the National Institutes of Health/National Cancer Institute award number P30 CA016672 (University of Texas MD Anderson Cancer Center).\n\nConflict of interest statement: Apostolia M. Tsimberidou: Clinical Trial Research Funding/Grant Support: IMMATICS, Parker Institute for Cancer Immunotherapy, Tempus, OBI Pharma, EMD Serono, Baxalta, ONYX, Bayer, Boston Biomedical, Placon Therapeutics, Karus Therapeutics, Tvardi, CPRIT; Travel: ASCO, Japanese Society of Medical Oncology.\n\nConsulting or Advisory Role: Covance, Genentech, Tempus\n\nDavid J. Vining: Other ownership interests: VisionSR, Majority owner and CEO, multimedia structured reporting for use in advancing medical research; Bracco Diagnostics, Inventor, virtual colonoscopy-related products for colorectal cancer imaging.\n\nThe remaining authors have no competing interests.\n\nEthics approval and consent to participate: The protocol was approved by the FDA and the Institutional Review Board at The University of Texas MD Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All the study participants provided written informed consent before enrollment on the individual clinical trials in which they participated.\n\nConsent for publication: Patient consent for publication is not required. Patients consented to participate in the study.\n\nORCID iD: Apostolia-Maria Tsimberidou https://orcid.org/0000-0003-2713-233X\n\nAvailability of data and material: Data are available upon reasonable request. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request and approval from study sponsor and institution according to available guidelines at time of request.\n==== Refs\nReferences\n\n1 Said R Tsimberidou AM . Basket trials and the MD Anderson precision medicine clinical trials platform. Cancer J 2019; 25 : 282–286.31335392\n2 Tam AL Papadimitrakopoulou V Wistuba II , et al . The value of interventional radiology in clinical trial teams: experience from the BATTLE lung cancer trials. Clin Radiol 2021; 76 : 155.e25-155.e34.\n3 Said R Guibert N Oxnard GR , et al . Circulating tumor DNA analysis in the era of precision oncology. Oncotarget 2020; 11 : 188–211.32010431\n4 Oxnard GR Thress KS Alden RS , et al . 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RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study. Ann Oncol 2018; 29 : 1211–1219.29438522\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1758-8340", "issue": "13()", "journal": "Therapeutic advances in medical oncology", "keywords": "cell-free DNA; circulating tumor DNA; genomic profiling; personalized therapy; precision medicine; targeted therapy", "medline_ta": "Ther Adv Med Oncol", "mesh_terms": null, "nlm_unique_id": "101510808", "other_id": null, "pages": "17588359211001538", "pmc": null, "pmid": "33995588", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "31011204;19376813;31358542;26644315;26560360;22508966;26307133;31335392;20551065;31383735;10684259;19874578;23563269;29438522;19010912;33268083;31506389;29206995;27354477;32010431;22752848;10764150;21388974;28419195;31031019;28778025;25706985;28947956;15035987;25934077;31015557;30312528;31527165;25653133;24569458;32913970;18670422;16144912;21190184;29700206;24658074;28368441;31801585;15046639", "title": "Prolonged response to treatment based on cell-free DNA analysis and molecular profiling in three patients with metastatic cancer: a case series.", "title_normalized": "prolonged response to treatment based on cell free dna analysis and molecular profiling in three patients with metastatic cancer a case series" }

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"drugtreatmentdurationunit": null, "medicinalproduct": "NO DRUG NAME" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TAMOXIFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "2008", "drugenddateformat": "602", "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMOXIFEN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ERIBULIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERIBULIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FULVESTRANT" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "11 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FULVESTRANT." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoacusis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NAQVI M, VO H, VINING D, TSIMBERIDOU A. PROLONGED RESPONSE TO TREATMENT BASED ON CELL FREE DNA ANALYSIS AND MOLECULAR PROFILING IN THREE PATIENTS WITH METASTATIC CANCER: A CASE SERIES. THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY. 2021 MAR 24?13:.", "literaturereference_normalized": "prolonged response to treatment based on cell free dna analysis and molecular profiling in three patients with metastatic cancer a case series", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210520", "receivedate": "20210520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19280580, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Carfilzomib is a second-generation proteasome inhibitor that irreversibly inhibits chymotrypsin-like (CT-L) activities of the proteasome, and is indicated for relapsed or refractory multiple myeloma. Cardiotoxicity is a well-established adverse effect of carfilzomib. The extent of cardiac toxicity in the literature spans anywhere from palpitations to cardiac arrest, with the most commonly reported manifestation being new-onset or worsening heart failure. A pre-clinical study of the pharmacokinetics and pharmacodynamics of carfilzomib given via intravenous bolus or 30-minute infusion in rats showed that carfilzomib can strongly induce apoptosis and potently damage cardiac myocytes at clinically relevant concentrations. Moreover, the mortality rate with the bolus administration was 44% whereas the same dose administered as a 30-minute infusion did not result in mortality. There remains limited clinical data regarding the safety of carfilzomib at doses of 27-56 mg/m2 based on infusion times as these doses have not been well studied. This retrospective review was conducted to evaluate the safety of carfilzomib at doses >27 mg/m2 at all infusion times.", "affiliations": "Department of Pharmacy, 12297 New York University Langone Medical Center , New York, NY.;Department of Pharmacy, 12297 New York University Langone Medical Center , New York, NY.;Department of Pharmacy, 12297 New York University Langone Medical Center , New York, NY.;Department of Pharmacy, 12297 New York University Langone Medical Center , New York, NY.", "authors": "Kim|Gee Youn|GY|;Ahuja|Tania|T|;Papadopoulos|John|J|;Cirrone|Frank|F|", "chemical_list": "D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib", "country": "England", "delete": false, "doi": "10.1177/1078155217729564", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "25(1)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Carfilzomib; cancer; cardiotoxicity; infusion time; multiple myeloma", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066126:Cardiotoxicity; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D012189:Retrospective Studies", "nlm_unique_id": "9511372", "other_id": null, "pages": "229-233", "pmc": null, "pmid": "28914153", "pubdate": "2019-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Cardiotoxicity with carfilzomib at doses greater than 27 mg/m2: A case series.", "title_normalized": "cardiotoxicity with carfilzomib at doses greater than 27 mg m2 a case series" }

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{ "abstract": "BACKGROUND Giant carotid intracavernous aneurysm refers to those lesions larger than 2.5 cm and derived from a cavernous segment, accounting for about 30% of all intracranial tumors. Dynamic CT perfusion imaging (PCT) is a common method recently employed to evaluate cerebral perfusion. This study investigated the efficacy and clinical application of intraoperative CT in the surgery for giant symptomatic carotid intracavernous aneurysm. MATERIAL AND METHODS A retrospective analysis was performed on 23 cases with giant symptomatic carotid intracavernous aneurysm. BTO testing was performed before surgery. Differential treatments were performed based on the condition of aneurysm, and some patients received intraoperative PCT. Postoperative anti-coagulation was given with DSA or CTA follow-up examinations at 3-6 months, 1 year, and 2 years after surgery. RESULTS A total of 17 patients received aneurysm isolation coupled with high-flow bypass surgery. Among those, 9 developed early-onset neurological function after surgery, with gradual recover within 6 months. One coma patient died 25 months after discharge. One patient had aneurysm isolation with clapping of anterior communicating artery, and the other 5 cases received artery clapping only. In those patients, 4 had improvement at early phase, while 1 patient had numbness of the oculomotor nerve. Six patients received surgery in the CT room, including 5 cases with single proximal ligation of the internal carotid artery plus 1 aneurysm isolation combined with high-flow bypass surgery. CONCLUSIONS Intraoperative PCT can provide objective evidence and effective evaluation of cerebral perfusion.", "affiliations": "Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).;Department of Neurosurgery, General Hospital of PLA, Beijing, China (mainland).", "authors": "Xue|Zhe|Z|;Wang|Fuyu|F|;Sun|Zhenghui|Z|;Zhang|Hui|H|;Wu|Chen|C|;Kong|Dongsheng|D|;Xu|Bainan|B|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.12659/msm.902225", "fulltext": "\n==== Front\nMed Sci MonitMed. Sci. MonitMedical Science MonitorMedical Science Monitor : International Medical Journal of Experimental and Clinical Research1234-10101643-3750International Scientific Literature, Inc. 2864079310.12659/MSM.902225902225Clinical ResearchIntraoperative Computed Tomography (CT) for Treating Giant Carotid Intracavernous Aneurysms Xue Zhe ACEWang Fuyu AGSun Zhenghui BCEZhang Hui BDWu Chen BDKong Dongsheng CEFXu Bainan BDFDepartment of Neurosurgery, General Hospital of PLA, Beijing, P.R. ChinaCorresponding Authors: Bainan Xu, e-mail: [email protected], Zhenghui Sun, e-mail: [email protected] 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\n2017 22 6 2017 23 3054 3063 03 11 2016 01 12 2016 © Med Sci Monit, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Background\nGiant carotid intracavernous aneurysm refers to those lesions larger than 2.5 cm and derived from a cavernous segment, accounting for about 30% of all intracranial tumors. Dynamic CT perfusion imaging (PCT) is a common method recently employed to evaluate cerebral perfusion. This study investigated the efficacy and clinical application of intraoperative CT in the surgery for giant symptomatic carotid intracavernous aneurysm.\n\nMaterial/Methods\nA retrospective analysis was performed on 23 cases with giant symptomatic carotid intracavernous aneurysm. BTO testing was performed before surgery. Differential treatments were performed based on the condition of aneurysm, and some patients received intraoperative PCT. Postoperative anti-coagulation was given with DSA or CTA follow-up examinations at 3–6 months, 1 year, and 2 years after surgery.\n\nResults\nA total of 17 patients received aneurysm isolation coupled with high-flow bypass surgery. Among those, 9 developed early-onset neurological function after surgery, with gradual recover within 6 months. One coma patient died 25 months after discharge. One patient had aneurysm isolation with clapping of anterior communicating artery, and the other 5 cases received artery clapping only. In those patients, 4 had improvement at early phase, while 1 patient had numbness of the oculomotor nerve. Six patients received surgery in the CT room, including 5 cases with single proximal ligation of the internal carotid artery plus 1 aneurysm isolation combined with high-flow bypass surgery.\n\nConclusions\nIntraoperative PCT can provide objective evidence and effective evaluation of cerebral perfusion.\n\nMeSH Keywords\nAcidosis, Renal TubularAneurysmCavernous SinusGastric BypassIntracranial Aneurysm\n==== Body\nBackground\nGiant carotid intracavernous aneurysm refers to those lesions larger than 2.5 cm, which are derived from the cavernous segment. They account for about 30% of all giant intracranial tumors [1], with more female patients [2]. Clinically, it is manifested as headache and compression of cranial nerve III to VI, with less subarachnoid hemorrhage. Current curative indication mainly includes symptomatic aneurysm, and regular follow-ups are required for asymptomatic lesions until manifestation [2–4]. Giant symptomatic internal carotid intracavernous aneurysm can be treated by proximal blockade [5], vascular bypass conjunction with proximal blockade or aneurysm isolation [6,7], direct surgical clapping [8], or interventional therapy [9–11]. Due to the wide neck and huge volume of these aneurysms, and the protection of the cranial nerve inside the cavernous area, direct clapping is very difficult and not suitable for all patients. For giant or large intracavernous aneurysms, intervention and embolization have unsatisfactory efficacy [12]. Single proximal blockade can benefit patients and vascular bypass in conjunction with proximal blockade or aneurysm isolation is also a common treatment strategy. In recent years, flow-diverting stents (FDSs) have been developed and especially designed to reduce the flow velocity vortex within the aneurysm and can improve the laminar flow in the main artery and surrounding branches [13]. Computation hemodynamics suggests that a stent with an overall porosity of 50% to 70% (30–50% metallic coverage) will significantly reduce the inflow rate into an aneurysm [14]. In theory, FDSs could treat aneurysms no regardless of location and could be deployed covering collateral vessels that are not occluded. Initial clinical experiences with the use of FDSs in the treatment of visceral and peripheral aneurysms have yielded satisfactory results in technical success, aneurysm thrombosis and shrinkage, and branch vessel patency. Better results are achieved 12 months after the procedure rather than at 6 months in aortic aneurysms. Importantly, there have been no aneurysm ruptures reported after treatment with an FDS [13].\n\nIt is critical to evaluate the compensation of lateral circulation, regardless of the treatment strategy. Balloon test occlusion (BTO) is a safe and effective way to evaluate cerebral resistance after tumor-bearing artery blockade [15]. The combination of BTO assay with semi-quantitative/quantitative evaluation for focal cerebral blood flow, such as SPECT [16–18], xenon CT [19, 20], and PET scan [21], can further lower the false-negative rate. Dynamic CT perfusion imaging (PCT) is a common method recently used to evaluate cerebral perfusion. The direct application of PCT in surgery can provide objective evidence of cerebral blood perfusion, and can work as an effective monitoring approach [22]. Our group has used PCT in aneurysm surgery.\n\nMaterial and Methods\nGeneral information\nWe recruited a total of 23 patients with giant symptomatic carotid intracavernous aneurysm in the General Hospital of the PLA from February 2007 to March 2013, including 3 males and 20 females, ages 24–68 years (average age=54.7 years). Major manifestations of aneurysm included headache and compression of cranial nerves, including 6 cases with optical nerve affected, 12 cases with oculomotor nerve, 4 cases with trigeminal nerve, and 1 patient with abducent nerve injury. There were 8, 1, and 1 patients having headache, dizziness, and vertigo, respectively. All patients had confirmed diagnosis by DSA, showing 12 and 11 lesions at left and right hemisphere, respectively. Diameters of all lesions were larger than 2.5 cm. This study was approved by the Medical Ethics Committee of General Hospital of PLA. Informed consents were obtained from all patients prior to the study.\n\nPre-operative evaluation\nBTO assay was performed 30 min before surgery to observe compensation of anterior/posterior circulation, coupled with neurological function evaluation. If compensation showed no symptom, blood pressure was further lowered by 20% to observe the existence of neurological dysfunction.\n\nAneurysm isolation coupled with high-flow bypass\nSurgical indications included those with unsatisfactory compensation before surgery or those with neurological dysfunction. Using the great saphenous vein as the transplant vessel, external carotid and M2 segment of cerebral middle brain were ligated, followed by isolation of the aneurysm. During the surgery, microvascular Doppler was used to quantify blood flow velocity of recipient and implanted vessels. Neurological function was monitored by electrophysiology approach. Some patients further received ICG testing for measuring flow of transplanted vessels, while some patients were evaluated for perfusion via intraoperative PCT.\n\nAneurysm isolation or blockade of internal carotid artery starting point\nSurgical indications included satisfactory compensation before surgery or with neurological symptoms. We performed 2–3 weeks of neck compression training before surgery with preparation for bypass surgery. The inner carotid artery was first exposed during the surgery, along with exposure of the external and common carotid arteries. The inner carotid artery was temporarily clamped for observing neurological-pathology conditions. Some patients underwent intraoperative PCT for monitoring ischemia condition. The absence of ischemia manifestation indicated aneurysm isolation or proximal blockade; otherwise, the surgery was combined with bypass. After finishing isolation or proximal blockade operations, patients were awakened and underwent intubation for another 30-min observation to evaluate neurological function. No abnormality signalled the end of surgery; otherwise, combined bypass surgery was performed.\n\nPCT imaging during surgery\nImaging was performed in the CT room during surgery. CT perfusion was first carried out before surgery. Re-scanning of perfusion and CTA examination were performed after temporary blockade. Areas of interests were the blood supply region from the cerebral middle artery and anterior artery closest to the basal ganglia layer. Cerebral blood flow (CBF), cerebral blood volume (CBV), and time to peak (TTP) were obtained from all areas of interests, along with relative perfusion indexes, including rCBV, rCBV, and rTTP. Perfusion indexes were compared between surgical and intact hemispheres, and relative perfusion indexes were compared before and after surgery.\n\nPostoperative treatment and follow-ups\nAll patients received heparin as anti-coagulation treatment for 24 h, followed by oral ingestion of anti-platelet drugs. Bedside ultrasound was employed to test the flow of transplanted vessels. CT or MRI was used to observe the occurrence of thrombosis or hemorrhage. Before discharge, DSA or CTA was used for re-check. Patients were asked to return for re-examination by DSA or CTA at 3–6 month after discharge. Further follow-ups were performed at 1 year and 2 years. Patients who could not attend follow-ups in person were told by telephone to go to a nearby hospital for re-examination.\n\nResults\nAneurysm isolation coupled with high-flow bypass surgery\nA total of 17 patients (3 males and 14 females) presented improvements of symptoms early after surgery, including 1 case with oculomotor nerve affected, 1 patient with optic nerve dysfunction, and 1 patient with headache. Newly-formed neurological dysfunction after surgery included 1 optic nerve injury, 3 patients with oculomotor nerve injury, 1 headache, and 1 dazzle case, plus 1 transient aphasia, 1 patient having tracheotomy due to cough and fatigue (patient had choking before surgery, with bilateral spinal artery occlusion on DSA), and 1 coma patient due to occlusion of the transplanted artery (Table 1). All these cranial nerve symptoms gradually resolved by 2–6 month after surgery. The middle-to-long-term result showed scores of 5 in GOS in 13 patients within 3 months to 6 years and at 3-month follow-up. The patient with tracheotomy had the tube removed 1 month later, followed by rehabilitation; this patient still required daily care at the time of follow-up. The coma patient received treatment in a local hospital and died 25 months later. Two patients were lost to follow-up.\n\nAneurysm isolation or blockade of internal carotid artery starting point\nA total of 6 patients (all females) received such treatment. Among these, 1 patient had clapping of the anterior communicating artery coupled with isolation of the internal carotid artery aneurysm. This patient presented transient indifference, which was improved after elevating blood pressure and vasodilation. All 5 patients received single blockade, and symptom improvements were observed, including 2 cases with optic nerve injury, 1 case with oculomotor nerve affected, and 1 headache case (Table 1). Newly-formed neurological dysfunction occurred after surgery, including 1 patient with oculomotor nerve injury, which gradually recovered after 2 months, and 1 patient with headache improved by vasodilation. Long-term, all 6 patients had GOS scores of 5 within the follow-up period (9–15 months).\n\nPCT imaging results\nSix patients received PCT during the surgery. Among these, 5 had proximal ligation of the internal carotid artery, and 1 had aneurysm isolation coupled with high-flow vessel bypass surgery. One patient had an approximately 50% decrease in somatosensory-induced potential after temporary blockade of the proximal internal carotid artery, and PCT showed improved perfusion after surgery, indicating direct proximal blockade. One case showed a minor (less than 50%) decrease in somatosensory-induced potential after temporary blockade of the proximal internal carotid artery, and PCT showed no change in perfusion after surgery, indicating direct proximal blockade.\n\nReport of typical cases\nCase 1\nFemale, 65 years old, admitted as “Intermittent headache and double vision for 1 year”. Physical exam showed blepharoptosis of the right upper eyelid. Head MRI indicated a round-shaped parasellar lesion on the right hemisphere, and DSA suggested a giant aneurysm in the cavernous segment of the right internal carotid artery. Isolation of the aneurysm combined with high-flow bypass surgery was performed. During the surgery, the internal carotid artery was exposed, along with external and common carotid arteries. A front temporal approach was used. Using the great saphenous vein as the transplant vessel, the external carotid and M2 segment of cerebral middle brain were ligated, followed by isolation of the aneurysm. After surgery, headache was improved, along with recovered numbness of the oculomotor nerve. No sign of aneurysm was found in postoperative DSA, indicating satisfactory hemodynamics of the transplanted vessel. Imagining of the right cerebral middle artery and anterior artery showed no abnormalities (Figure 1).\n\nCase 2\nFemale, 63 years old, admitted as “Blepharoptosis of right upper eyelid for 3 months”. Physical exam showed blepharoptosis of the right upper eyelid. Head CT and MRI indicated a round parasellar lesion on the right hemisphere, and DSA suggested a giant aneurysm in the cavernous segment of the right internal carotid artery. After 1-week neck compression training, blockade of the right internal carotid artery was chosen for surgery. Pre-operative PCT indicated a large hypo-perfusion area in the right temporal lobe. After temporary blocking of the right internal carotid artery, intraoperative PCT indicated significantly improved right temporal perfusion. Intraoperative CTA showed no image of right inner carotid artery from the starting points, plus satisfactory imaging of right cerebral middle/anterior arteries. Blockade of the right inner carotid artery was thus performed. No postoperative complications occurred, and there was gradual recovery of oculomotor nerve numbness (Figures 2, 3).\n\nCase 3\nFemale, 29 years old, admitted as “Blurred vision in left eye for 4 years, plus headache for 2 months”. Physical exam showed normal right eye vision. Head CT and MRI indicated a round lesion in the left parasellar region, accompanied by calcification. CTA and DSA suggested a giant aneurysm of the intracavernous segment of the left inner carotid artery. Surgery was performed using isolation of the left inner carotid artery intracavernous aneurysm accompanied by high-flow bypass by the great saphenous vein. Pre-operative PCT showed worse perfusion in the left cerebral hemisphere. Intraoperative PCT suggested similar results. Re-examination after bypass surgery via CTA showed good hemodynamics in bridge vessels, and imaging of left cerebral middle/anterior artery revealed good recovery after surgery (Figure 4).\n\nDiscussion\nClinical symptoms of intracavernous aneurysm include headache or compression of cranial nerves, and most cases have benign history with few suffering subarachnoid hemorrhage [2,21]. Therefore, current indications of surgery mainly refer to large or giant symptomatic aneurysm [2–4]. In our department, the choice of aneurysm treatment was stipulated by the surgical team and intervention clinicians, in consideration of the patient’s opinion and economic conditions, thus benefiting patient care via individualized treatment.\n\nBTO assay can be used before treating intracavernous aneurysm of the carotid artery. This assay is an effective and safe method for evaluating ischemia resistance of a tumor-bearing artery after blockade [15]. Combined treatment with bypass surgery is required when BTO assay indicates unsatisfactory hemodynamic compensation or symptoms. Even in BTO-negative patients, there was a 5–20% chance of cerebral infarction after blocking the artery. Therefore, BTO results alone are not completely reliable [23]. Currently, multiple methods, including SPECT [14–16], xenon CT [19,20], PET [21], and TCD [24], can evaluate focal cerebral blood flow volume quantitatively or semi-quantitatively. The combination of BTO with these assays thus can improve accuracy of quantification of cerebral tissue ischemia, but requires multiple procedures [7,24]. In this study, we used depressurization assay with 15-min observation for neurological function evaluation and monitoring after depressing blood pressure by 20~30%. The combination with BOT can help to improve predicative value of the assay. In this study, all 17 patients had unsatisfactory blood flow compensation via pre-operative BTO assay, or had good compensation but with symptoms, or the presentation of symptoms after managing hypotension. After high-flow bypass surgery, most patients had certain levels of improvements.\n\nIn recent years, intraoperative PCT has been widely used to evaluate resistance to ischemia of brain tissues [22], with satisfactory effects. A total of 6 patients received perfusion PCT imaging after surgery. Among those, 2 patients had clear depression of somatosensory-induced potential after blockading the proximal inner carotid artery, and PCT showed no change in blood supply, leading to the direct blockade of proximal vessels. Therefore, intraoperative PCT is an effective approach.\n\nMost common approaches for treating intracavernous aneurysm include proximal blockade or aneurysm isolation coupled with vascular bypass surgery. In this study, 17 patients received aneurysm isolation plus high-flow bypass surgery using the giant saphenous vein as the bridging vessel, which was further ligated onto the descending branch of the external carotid artery and cerebral middle artery. By this approach, no clapping of the inner carotid artery is required when clapping, thus reducing the incidence of ischemia. During the preparation of the subcutaneous tunnel and skull window, it is necessary to keep transplanted vessels from being compressed. One patient developed cerebral ischemia and coma due to blockade of the transplanted vessel and died 2 years later, suggesting that transplanted vessel blockade is a major factor causing ischemic stroke after surgery. This is related to multiple factors, including the selection of transplanted vessels, matching of vessels, ligation technique, postoperative blood pressure management, and anti-coagulation and anti-platelet drugs. One patient had onset of dazzles and choking before surgery, as supported by blockade of the bilateral spinal artery. After surgery, this patient had worse coughing reflex and underwent tracheotomy. At 6-year follow-up, the patient was still in a wheelchair but has satisfactory results in general conditions, further indicating the importance of vascular condition before surgery for patient prognosis.\n\nFor those patients with satisfactory resistance for proximal blockade in BTO assay, isolation of the aneurysm or blockade of the proximal inner carotid artery might be effective and safe approaches. In all 6 patients with BTO resistance, surgery was performed after 2–3 weeks of continuous neck compression training. The preparation for bypass surgery was performed before surgery, in which temporally proximal blockade was first performed. One patient only received 30-min electrophysiological monitoring and the other 5 received simultaneous examinations including electrophysiology and intraoperative PCT, both of which had no abnormality. Proximal blockade was then performed. Two patients presented headache and dazzle after surgery, and were all discharged after treatment. Four patients showed improvement of symptoms. Blockade caused by thrombosis detachment is a common complication, with 5–10% incidence [25]. During this study, all 6 patients had no severe complication of thrombosis. Proximal clapping can be performed on either the common carotid artery or internal carotid artery. Some scholars believe that these 2 ischemia-related complications are different, while others disagree with this opinion. We chose blockade of the inner carotid artery, which is the tumor-bearing vessel. Therefore, direct blockade of the aneurysm accelerates the velocity of thrombosis formation and can improve symptoms. In this group, only 2 patients had headache or dazzle symptoms, and these were improved after treatment. Other scholars [5] utilized chronic clapping of carotid artery to treat intracavernous aneurysm, which, however, had relatively higher incidence of thrombosis, and incomplete blockade of aneurysm. The application of anti-coagulation and anti-platelet treatment can help to decrease the incidence of ischemic episodes. A previous report indicated potential decrease of thrombosis events by interventional blockade proximal to the tumor neck [6]. Other groups also found that proximal blockade of the inner carotid artery generates new aneurysms or enlarges original tumors [26]. This study, however, did not find de novo aneurysm, indicating certain preventive effects by post-op management of blood pressure.\n\nIn addition to blockade of the proximal inner carotid artery in the treatment of aneurysm, flow-diverting stents (FDSs) are a new alternative treatment approach for aneurysms that takes into account their unique characteristics. The largest published experience to date comes from use of FDSs in visceral aneurysms, and the results are very encouraging, with a significant incidence of aneurysm thrombosis and shrinkage during follow-up and without any branch vessel occlusion. In terms of peripheral aneurysms, FDSs have been widely used in the treatment of iliac, popliteal, and subclavian aneurysms. In these anatomic areas, significant collateral branches have to be preserved, including the internal iliac artery, the genicular arteries, and the vertebral arteries, respectively [13].\n\nThis study has certain limitations. Firstly, it has a relatively smaller sample size and short follow-up periods, in which loss to follow-up gradually increased. The outcome of long-term follow-up has been found to be important for the choice between proximal ligation and aneurysm isolation combined with bypass procedure [27]. Based on previous studies, the incidence of ischemia episodes is lower in the short term, but needs further long-term evaluation in the future. Secondly, the method for evaluating hemodynamic compensation needs to be elaborated, due to the occurrence of ischemia complications even after the surgical optimization based on pre-operative evaluation [28]. In early-phase cases, we preferred the aneurysm isolation combined with bypass procedure, which is mature technique with fewer complications. However, the use of bypass surgery in all cases is just based on safeguarding the blood supply, because some patients actually had satisfactory long-term outcomes without bypass. Therefore, the treatment strategy needs to be refined based on evaluation before and during surgery. Patients still need to be prepared for bypass surgery at the time of proximal ligation. However, new symptoms may develop after surgery, and long-term follow-up data are needed to evaluate the efficacy of proximal ligation. Intraoperative electrophysiology monitoring also has certain limitations, as it cannot reflect the consistency between clapping of aneurysm/adjacent vessels and cerebral perfusion, in addition to false-positive and false-negative results, which can be affected by anesthesia, electrical devices, and surgical operation, although intraoperative PCT combined with CTA provides more information. Factors during the surgery should be carefully controlled, including blood pressure, consistency between pre- and intraoperative scanning, dosage of imaging reagent, and radiation dosage. Moreover, large-cohort clinical studies are required to comprehensively analyze results of electrophysiology monitoring and PCT imaging.\n\nConclusions\nThe use of PCT during surgery can provide objective and timely evidence for cerebral blood perfusion and is an effective monitoring method.\n\nDisclosure of conflict of interest\n\nNone.\n\nSource of support: Departmental sources\n\nFigure 1 Report of patient A, with isolation of giant intracavernous aneurysm on right side plus high-flow bypass surgery. (A) Illustration of aneurysm isolation combined with high-flow bypass surgery. (B) DSA image of giant intracavernous aneurysm before surgery. (C) Postoperative DSA results showed no indication of aneurysm, good hemodynamics of transplanted vessel, and satisfactory images of right cerebral middle/anterior artery.\n\nFigure 2 Patient B undergoing blockade at starting point of right giant intracavernous aneurysm of inner carotid artery. (A) Pre-operative head CT showed high-density round lesion on right parasellar region (red arrow). (B) Head CT showed round vacuoles at right parasellar region (red arrow). (C) Pre-operative DSA indicated giant aneurysm of intracavernous segment in inner carotid artery (red arrow). (D) After blocking of inner carotid artery initiating point, intraoperative CTA showed no imaging of distal end in inner carotid artery, while right cerebral middle artery (red arrow) and anterior artery had good imaging.\n\nFigure 3 Pseudo-colored image of intraoperative PCT in patient B. (A) Lower rCBF value (0.81) of right temporal lobe before surgery. (B) Higher CBF value (1.41) in right temporal lobe during the surgery after temporal blockade of right inner carotid artery. (C) Similar rCBV value (1.01) between right and left temporal lobe before surgery. (D) Higher rCBV value (1.31) in right temporal lobe during the surgery after temporal blockade of right inner carotid artery. (E) Significantly elongated TTP in right temporal lobe compared to left hemisphere before surgery (rTTP value=1.39). (F) Similar TTP (rTTP=1.00) between right and left temporal lobe in surgery after temporal blockade of right inner carotid artery.\n\nFigure 4 Isolation of left inner carotid artery intracavernous aneurysm coupled with high-flow vessel bypass surgery using giant saphenous vein. (A) Pre-operative head CT showed a round high-density region in the left parasellar area, accompanied with calcification (red arrow). (B) Head MRI indicated a round vacuole in the left parasellar region, accompanied with thrombosis formation (red arrow). (C) CTA indicated a giant aneurysm within the intracavernous segment of the left inner carotid artery (maximal diameter, 25.9 mm). (D) Pre-operative DSA indicated a giant aneurysm in the intracavernous segment of the left inner carotid artery. (E) Intraoperative CTA showed good hemodynamics of bridge vessels (read arrow), and no image at initiating point of left inner carotid artery. (F) Intraoperative CTA showed good imaging of left cerebral artery (red arrow) and anterior artery after bypass surgery.\n\nTable 1 Outcomes of patients after surgery.\n\nTreatments\tn\t\nAneurysm isolation coupled with high flow bypass surgery\t17\t\n Optic nerve injury\t1\t\n Oculomotor nerve injury\t3\t\n Headache\t1\t\n Dazzle\t1\t\n Transient aphasia\t1\t\n Tracheotomy\t1\t\n Coma\t1\t\nAneurysm isolation or blockade of internal carotid artery starting point\t6\t\n Clapping of anterior communicating artery coupled with isolation of internal carotid artery aneurysm\t1\t\n Single blockade\t5\t\n Optic nerve injury\t2\t\n Oculomotor nerve\t1\t\n Headache\t1\n==== Refs\nReferences\n1 Dengler J Maldaner N Bijlenga P Quantifying unruptured giant intracranial aneurysms by measuring diameter and volume – a comparative analysis of 69 cases Acta Neurochir (Wien) 2015 157 361 68 discussion 368 25502806 \n2 Stiebel-Kalish H Kalish Y Bar-On RH Presentation, natural history, and management of carotid cavernous aneurysms Neurosurgery 2005 57 850 57 discussion 857 16284555 \n3 Eddleman CS Hurley MC Bendok BR Batjer HH Cavernous carotid aneurysms: to treat or not to treat? Neurosurg Focus 2009 26 E4 \n4 ter Brugge KG Cavernous sinus segment internal carotid artery aneurysms: Whether and how to treat Am J Neuroradiol 2012 33 327 28 22300929 \n5 Niiro M Shimozuru T Nakamura K Long-term follow-up study of patients with cavernous sinus aneurysm treated by proximal occlusion Neurol Med Chir (Tokyo) 2000 40 88 96 discussion 97 10786096 \n6 Field M Jungreis CA Chengelis NL Symptomatic cavernous sinus aneurysms: Management and outcome after carotid occlusion and selective cerebral revascularization Am J Neuroradiol 2003 24 1200 7 12812955 \n7 Tacconi L Extracranial-intracranial bypass for the treatment of cavernous sinus aneurysms J Clin Neurosci 2006 13 1001 5 17070053 \n8 Dolenc V Direct microsurgical repair of intracavernous vascular lesions J Neurosurg 2009 58 824 31 \n9 van Rooij WJ Endovascular treatment of cavernous sinus aneurysms Am J Neuroradiol 2012 33 323 26 22033713 \n10 Starke RM Chalouhi N Ali MS Endovascular treatment of carotid cavernous aneurysms: Complications, outcomes and comparison of interventional strategies J Clin Neurosci 2014 21 40 46 23972560 \n11 Puffer RC Piano M Lanzino G Treatment of cavernous sinus aneurysms with flow diversion: Results in 44 patients Am J Neuroradiol 2014 35 948 51 24356675 \n12 Morita K Sorimachi T Ito Y Intra-aneurysmal coil embolization for large or giant carotid artery aneurysms in the cavernous sinus Neurol Med Chir (Tokyo) 2011 51 762 66 22123478 \n13 Sfyroeras GS Dalainas I Giannakopoulos TG Flow-diverting stents for the treatment of arterial aneurysms J Vasc Surg 2012 56 839 46 22840737 \n14 Liou TM Li YC Effects of stent porosity on hemodynamics in a sidewall aneurysm model J Biomech 2008 41 1174 83 18377914 \n15 Lesley WS Rangaswamy R Balloon test occlusion and endosurgical parent artery sacrifice for the evaluation and management of complex intracranial aneurysmal disease J Neurointerv Surg 2009 1 112 20 21994280 \n16 Sugawara Y Kikuchi T Ueda T Usefulness of brain SPECT to evaluate brain tolerance and hemodynamic changes during temporary balloon occlusion test and after permanent carotid occlusion J Nucl Med 2002 43 1616 23 12468510 \n17 Tomura N Omachi K Takahashi S Comparison of technetium Tc 99m hexamethylpropyleneamine oxime single-photon emission tomograph with stump pressure during the balloon occlusion test of the internal carotid artery Am J Neuroradiol 2005 26 1937 42 16155138 \n18 Shimizu H Matsumoto Y Tominaga T Parent artery occlusion with bypass surgery for the treatment of internal carotid artery aneurysms: Clinical and hemodynamic results Clin Neurol Neurosurg 2010 112 32 39 19875229 \n19 Gupta DK Young WL Hashimoto T Characterization of the cerebral blood flow response to balloon deflation after temporary internal carotid artery test occlusion J Neurosurg Anesthesiol 2002 14 2 123 29 11907392 \n20 Marshall RS Young WL Solomon RA Clinical utility of quantitative cerebral blood flow measurements during internal carotid artery test occlusions Neurosurgery 2002 50 5 996 1004 discussion 1004–5 11950402 \n21 Brunberg JA Horton JA Deveikis JP [15O]H2O positron emission tomography determination of cerebral blood flow during balloon test occlusion of the internal carotid artery Am J Neuroradiol 1994 15 725 32 8010276 \n22 Schichor C Rachinger W Zausinger S Intraoperative computed tomography angiography with computed tomography perfusion imaging in vascular neurosurgery: Feasibility of a new concept J Neurosurg 2010 112 722 28 19817544 \n23 Linskey ME Jungreis CA Yonas H Stroke risk after abrupt internal carotid artery sacrifice: Accuracy of preoperative assessment with balloon test occlusion and stable xenon-enhanced CT Am J Neuroradiol 1994 15 829 43 8059649 \n24 Bakke SJ Sorteberg W Angiographic balloon test occlusion and therapeutic sacrifice of major arteries to the brain Neurosurgery 2008 63 651 60 18824944 \n25 Hauck EF Welch BG White JA Stent/coil treatment of very large and giant unruptured ophthalmic and cavernous aneurysms Surg Neurol 2009 71 1 19 24 discussion 24 18423540 \n26 Fujiwara S Fujii K Fukui M De novo aneurysm formation and aneurysm growth following therapeutic carotid occlusion for intracranial internal carotid artery (ICA) aneurysms Acta Neurochir (Wien) 1993 120 20 25 8434512 \n27 Date I Ohmoto T Long-term outcome of surgical treatment of intracavernous giant aneurysms Neurol Med Chir (Tokyo) 1998 38 62 69 10234980 \n28 Souto AAD Domingues F Espinosa G Complex paraclinoidal and giant cavernous aneurysms: importance of preoperative evaluation with temporary balloon occlusion test and SPECT Arq Neuropsiquiatr 2006 64 768 73 17057883\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1234-1010", "issue": "23()", "journal": "Medical science monitor : international medical journal of experimental and clinical research", "keywords": null, "medline_ta": "Med Sci Monit", "mesh_terms": "D000328:Adult; D000368:Aged; D002343:Carotid Artery, Internal; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D007430:Intraoperative Care; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "9609063", "other_id": null, "pages": "3054-3063", "pmc": null, "pmid": "28640793", "pubdate": "2017-06-22", "publication_types": "D016428:Journal Article", "references": "18824944;12468510;17057883;22300929;16284555;11907392;22123478;22033713;24356675;8059649;21994280;8010276;6854374;19875229;22840737;10234980;18377914;25502806;12812955;10786096;18423540;16155138;11950402;19817544;17070053;19409005;8434512;23972560", "title": "Intraoperative Computed Tomography (CT) for Treating Giant Carotid Intracavernous Aneurysms.", "title_normalized": "intraoperative computed tomography ct for treating giant carotid intracavernous aneurysms" }

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{ "abstract": "The case report of botulinum toxin treatment of gastroparesis in a patient following allogenic bone marrow transplantation is described. The causes of gastroparesis and methods of prevention and treatment are discussed. It was noted that pyloric injection of botulinum toxin can improve symptoms and gastric emptying.", "affiliations": "National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.", "authors": "Galstyan|G M|GM|;Pashkova|M V|MV|;Popova|O Y|OY|;Makarova|P M|PM|;Dubnyak|D S|DS|;Kuzmina|L A|LA|;Parovichnikova|E N|EN|", "chemical_list": "D001905:Botulinum Toxins", "country": "Russia (Federation)", "delete": false, "doi": "10.26442/terarkh201890160-64", "fulltext": null, "fulltext_license": null, "issn_linking": "0040-3660", "issue": "90(1)", "journal": "Terapevticheskii arkhiv", "keywords": "bone marrow transplantation; botulinum toxin; cyclosporine A; cytomegalovirus infection; foscarnet; ganciclovir; gastroparesis; immunosuppressive therapy; pyloric injection; tacrolimus; «graft-versus-host disease", "medline_ta": "Ter Arkh", "mesh_terms": "D001853:Bone Marrow; D016026:Bone Marrow Transplantation; D001905:Botulinum Toxins; D005746:Gastric Emptying; D018589:Gastroparesis; D006801:Humans", "nlm_unique_id": "2984818R", "other_id": null, "pages": "60-64", "pmc": null, "pmid": "30701760", "pubdate": "2018-02-14", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation.", "title_normalized": "treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation" }

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null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "COLISTIMETHATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACTERIAL SEPSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLISTIMETHATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FOSCARNET" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSCARNET" } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired gastric emptying", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute graft versus host disease in intestine", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GALSTYAN G, PASHKOVA M, POPOVA O, MAKAROVA P, DUBNYAK D AND KUZMINA LA, ET AL. TREATMENT OF GASTROPARESIS WITH BOTULINUM TOXIN IN PATIENT AFTER ALLOGENIC BONE MARROW TRANSPLANTATION. TERAPEVTICHESKII ARKHIV 2018?90 (1):60-64.", "literaturereference_normalized": "treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation", "qualification": "3", "reportercountry": "RU" }, "primarysourcecountry": "RU", "receiptdate": "20190218", "receivedate": "20190218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15975197, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "RU-BAUSCH-BL-2019-005046", "fulfillexpeditecriteria": "1", "occurcountry": "RU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONTINUED FOR 12 DAYS", "drugenddate": "2016", "drugenddateformat": "602", "drugindication": "IMPAIRED GASTRIC EMPTYING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20161026", "drugstartdateformat": "102", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ANIDULAFUNGIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, 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"drugstartdateformat": "610", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022246", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PERISTALSIS VISIBLE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": "3", "drugadministrationroute": null, 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null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201611", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POLYMYXIN B." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201611" } }, "primarysource": { "literaturereference": "GALSTYAN G, PASHKOVA M, POPOVA O, MAKAROVA P, DUBNYAK D, KUZMINA L. TREATMENT OF GASTROPARESIS WITH BOTULINUM TOXIN IN PATIENT AFTER ALLOGENIC BONE MARROW TRANSPLANTATION. 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null, "drugindication": "GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MOXIFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MOXIFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORIPENEM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTAZIDIME" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTAZIDIME." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Impaired gastric emptying", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood pressure decreased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201611" } }, "primarysource": { "literaturereference": "GALSTYAN GM, PASHKOVA MV, POPOVA OY, MAKAROVA PM, DUBNYAK DS, KUZMINA LA ET AL. TREATMENT OF GASTROPARESIS WITH BOTULINUM TOXIN IN PATIENT AFTER ALLOGENIC BONE MARROW TRANSPLANTATION. TERAPEVTICHESKII ARKHIV. 2018?90(1):60-4", "literaturereference_normalized": "treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation", "qualification": "3", "reportercountry": "RU" }, "primarysourcecountry": "RU", "receiptdate": "20190218", "receivedate": "20190218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15977189, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "RU-PFIZER INC-2019072731", "fulfillexpeditecriteria": "1", "occurcountry": "RU", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORIPENEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.05 MG/KG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ANIDULAFUNGIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANIDULAFUNGIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTAZIDIME" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTAZIDIME." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG/KG, UNK", "drugenddate": "201611", "drugenddateformat": "610", "drugindication": "GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20161026", "drugstartdateformat": "102", "drugstructuredosagenumb": "3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "COLISTIMETHATE SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLISTIMETHATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE, TRIMETHOPRIM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MOXIFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201608", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MOXIFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "011153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG/KG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20161026", "drugstartdateformat": "102", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (3 COURSES OF 5-AZATHIOPRINE THERAPY)", "drugenddate": "201606", "drugenddateformat": "610", "drugindication": "MYELODYSPLASTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201603", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired gastric emptying", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood pressure decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201611" } }, "primarysource": { "literaturereference": "GALSTYAN, GM.. TREATMENT OF GASTROPARESIS WITH BOTULINUM TOXIN IN PATIENT AFTER ALLOGENIC BONE MARROW TRANSPLANTATION. TERAPEVTICHESKII ARKHIV. 2018?90(1):DOI:10.26442/TERARKH201890160-", "literaturereference_normalized": "treatment of gastroparesis with botulinum toxin in patient after allogenic bone marrow transplantation", "qualification": "3", "reportercountry": "RU" }, "primarysourcecountry": "RU", "receiptdate": "20200312", "receivedate": "20190220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15987549, "safetyreportversion": 6, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "RU-ASTELLAS-2019US006111", "fulfillexpeditecriteria": "1", "occurcountry": "RU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": "2016", "drugenddateformat": "602", "drugindication": "GASTROINTESTINAL HYPOMOTILITY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "0.05 MG/KG, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20161018", "drugstartdateformat": "102", "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION 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"reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pseudomonas infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastric atony", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft versus host disease in gastrointestinal tract", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erosive oesophagitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Erosive duodenitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired gastric emptying", 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{ "abstract": "Various factors may be responsible for blood pressure alterations during perioperative care. When these physiologic alterations require treatment, several therapeutic options are available. Clevidipine is an ultrashort-acting, intravenous L-type calcium channel antagonist of the dihydropyridine class. Anecdotal experience has demonstrated its efficacy in various clinical scenarios in the pediatric population. We report apparent resistance to the vasodilatory effects of clevidipine in a 13-year-old girl who presented for anesthetic care during posterior spinal fusion for neuromuscular scoliosis whose chronic medication regimen included aripiprazole and methylphenidate for the treatment of depression and attention-deficit/hyperactivity disorder. We discuss the potential interaction of aripiprazole and methylphenidate with the calcium channel antagonists and cellular mechanisms responsible for the resistance to the vasodilatory effects of clevidipine.", "affiliations": "The Ohio State University College of Medicine, Columbus, OH, USA.;Neuro and Critical Care, The Medicines Company, Parsippany, NJ, USA.;Department of Anesthesiology and Pain Medicine, The Ohio State University, Columbus, OH, USA; Department of Anesthesiology and Pain Medicine, Nationwide Children's Hospital, Columbus, OH, USA.", "authors": "Jacklen|M Alysse|MA|;Campagna|Jason A|JA|;Tobias|Joseph D|JD|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/JEP.S71914", "fulltext": "\n==== Front\nJ Exp PharmacolJ Exp PharmacolJournal of Experimental PharmacologyJournal of Experimental Pharmacology1179-1454Dove Medical Press 10.2147/JEP.S71914jep-6-011Case ReportClevidipine resistance in a patient taking aripiprazole and methylphenidate Jacklen M Alysse 1Campagna Jason A 2Tobias Joseph D 341 The Ohio State University College of Medicine, Columbus, OH, USA2 Neuro and Critical Care, The Medicines Company, Parsippany, NJ, USA3 Department of Anesthesiology and Pain Medicine, The Ohio State University, Columbus, OH, USA4 Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, OH, USACorrespondence: Joseph D Tobias, Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA, Tel +1 614 722 4200, Fax +1 614 722 4203, Email [email protected] 17 10 2014 6 11 14 © 2014 Jacklen et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The 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 Limited, provided the work is properly attributed.Various factors may be responsible for blood pressure alterations during perioperative care. When these physiologic alterations require treatment, several therapeutic options are available. Clevidipine is an ultrashort-acting, intravenous L-type calcium channel antagonist of the dihydropyridine class. Anecdotal experience has demonstrated its efficacy in various clinical scenarios in the pediatric population. We report apparent resistance to the vasodilatory effects of clevidipine in a 13-year-old girl who presented for anesthetic care during posterior spinal fusion for neuromuscular scoliosis whose chronic medication regimen included aripiprazole and methylphenidate for the treatment of depression and attention-deficit/hyperactivity disorder. We discuss the potential interaction of aripiprazole and methylphenidate with the calcium channel antagonists and cellular mechanisms responsible for the resistance to the vasodilatory effects of clevidipine.\n\nKeywords\nclevidipineblood pressurecalcium channel antagonistcontrolled hypotensionaripiprazoleposterior spinal fusionlabetalol\n==== Body\nIntroduction\nClevidipine (Cleviprex®, The Medicines Company, Parsippany, NJ, USA) is an ultrashort-acting, intravenous calcium channel antagonist approved for the control of blood pressure (BP) in adult patients when oral therapy is neither feasible nor desirable. Like nicardipine, it is a member of the dihydropyridine class. Clevidipine undergoes rapid metabolism by nonspecific blood and tissue esterases, resulting in a context-insensitive half-life of approximately 1 minute. Clinical trials in adult surgical and nonsurgical populations have demonstrated its efficacy in rapidly controlling BP in various clinical scenarios with a favorable adverse effect profile.1–3 Anecdotal experience in the pediatric population has further demonstrated its efficacy in various clinical scenarios.4–6 We report a 13-year-old girl with neuromuscular scoliosis who presented for anesthetic care during posterior spinal fusion with the plan to use clevidipine for controlled hypotension to limit intraoperative blood loss. Her chronic medication regimen included aripiprazole (Abilify®, Bristol-Myers Squibb, New York, NY, USA) and methylphenidate (Concerta®, Janssen Pharmaceuticals, Titusville, NJ, USA) for the treatment of depression and attention-deficit/hyperactivity disorder (ADHD). Despite increasing the infusion rate to a maximum of 5 µg/kg/min, no response was noted. We discuss the potential interactions of aripiprazole and methylphenidate with the calcium channel antagonists and cellular mechanisms responsible for the resistance to the vasodilatory effects of clevidipine.\n\nCase report\nInstitutional Review Board approval is not required for single case reports at Nationwide Children’s Hospital (Columbus, OH, USA). The patient was a 13-year-old, 51.3 kg female who presented for posterior spinal fusion for correction of neuromuscular scoliosis. Her past medical history was significant for progressive scoliosis unresponsive to conservative treatment, including bracing. Additional comorbid conditions included ADHD and depression. Pertinent past surgical history included laminectomy with release of a tethered spinal cord at age 11 years. Current medications included methylphenidate (36 mg once a day) and aripiprazole (10 mg once a day). Preoperative laboratory data including complete blood count, platelet count, and coagulation function were within normal limits. The patient was held nil per os for solids for 8 hours and clear liquids for 2 hours. In the perioperative surgical unit her BP was 123/69 mmHg, heart rate was 120 beats/minute, oxygen saturation was 99% while breathing room air, and body temperature was 36.6°C. The patient was brought to the operating room and standard American Society of Anesthesiologists monitors were placed. Anesthesia was induced via inhalation of sevoflurane in oxygen/nitrous oxide, and peripheral intravenous access was achieved. Fentanyl (100 µg) and propofol (1 mg/kg) were then administered and neuromuscular blockade was provided by rocuronium (0.6 mg/kg). Direct laryngoscopy was performed and a 6.0 mm cuffed endotracheal tube was placed. After anesthetic induction, a second large bore peripheral intravenous cannula and a radial arterial catheter were placed. Maintenance anesthesia consisted of desflurane in air/oxygen titrated to maintain the bispectral index at 40–60 and a remifentanil infusion adjusted from 0.05 µg/kg/min up to 0.3 µg/kg/min to maintain the mean arterial pressure (MAP) at 55–65 mmHg. The patient was positioned prone on a Jackson table. Normothermia was maintained using forced air warming. Per our usual routine, controlled hypotension using clevidipine was planned as part of the anesthetic technique to limit blood loss and the need for allogeneic blood products. The clevidipine infusion is initiated if the MAP cannot be maintained at <65 mmHg despite a remifentanil infusion of 0.3 µg/kg/min. Additional techniques to limit intraoperative blood loss and the need for allogeneic transfusions included the administration of tranexamic acid and intraoperative cell salvage. Motor and somatosensory evoked potentials were monitored intraoperatively throughout the surgery. During the procedure, despite a remifentanil infusion at 0.3 µg/kg/min, the MAP was ≥65 mmHg and clevidipine was added in an attempt to further decrease the MAP to 55–65 mmHg. The infusion was started at 1 µg/kg/min and increased every 2 minutes by 1 µg/kg/min. Despite the maximum suggested labeled clevidipine infusion of 5 µg/kg/min, the MAP remained at 70–75 mmHg. While continuing the clevidipine infusion, labetalol (incremental doses of 0.1 mg/kg) were required to achieve the target MAP of 55–65 mmHg. Following the second dose of labetalol (total of 0.2 mg/kg), the MAP decreased from 75–80 mmHg to 60–65 mmHg. Three more doses of labetalol (0.1 mg/kg) were administered over the next 75 minutes to maintain the MAP at 55–65 mmHg. Following completion of the surgical procedure, the patient’s trachea was extubated and she was transferred to the postanesthesia care unit in a stable condition. Postoperative analgesia was provided by hydromorphone administered by a patient-controlled analgesia device. She was admitted to the inpatient ward. The remainder of her postoperative course was unremarkable and she was discharged home on postoperative day 4.\n\nDiscussion\nThe administration of allogeneic blood products has been shown to have a negative impact on postoperative outcome following major surgical procedures.7 Given these concerns, several techniques are generally employed to limit intraoperative blood loss and therefore the need for allogeneic blood products. These techniques include appropriate positioning on the Jackson table to limit pressure on the abdomen and the engorgement of epidural veins, maintenance of normothermia, controlled hypotension, the administration of antifibrinolytic agents, and intraoperative cell salvage.7 Controlled hypotension, a technique commonly employed during major orthopedic surgery, involves the deliberate lowering of the MAP to 55–65 mmHg. Although several pharmacologic agents may be used for this purpose, our current clinical preference is the ultrashort-acting calcium channel antagonist clevidipine.8,9 In a previous retrospective report, clevidipine was shown to effectively provide controlled hypotension during spinal fusion in a cohort of 20 adolescents ranging in age from 14 years to 18 years and in weight from 46 kg to 96 kg.6 To maintain the MAP at 55–65 mmHg, the maintenance infusion rate of clevidipine varied from 1 µg/kg/min to 5 µg/kg/min, with an average infusion rate of 2.9±0.7 µg/kg/min. According to the clevidipine package insert, this dose is in the middle of the linear dose response range for the drug in adult patients. In this retrospective review and a more recent prospective trial, the patient in this report represents the only failure in a pediatric population.6,9 The patient whom we report was enrolled in an open-label, observational study focusing on the use of clevidipine for controlled hypotension during posterior spinal fusion for neuromuscular scoliosis. The outcome of that trial has been published previously, including mention of this patient who represented the only failure of clevidipine in that cohort of 50 patients.9 As noted in the current case report, there was no change in our patient’s MAP despite a clevidipine infusion that had been increased up to 5 µg/kg/min. The MAP remained at 70–75 mmHg. Control of the MAP was eventually achieved with the intermittent administration of labetalol during the remainder of the procedure. This being the only case to date representing a clinical failure of clevidipine in our clinical experience of approximately 200 patients over a 10-year period, it led us to consider possible drug–drug interactions with the patient’s current medications, including aripiprazole and methylphenidate.\n\nClevidipine is an intravenous ultrashort-acting, L-type calcium channel antagonist that directly and selectively acts on peripheral vascular smooth muscle to dilate resistance arterioles. As a third-generation dihydropyridine calcium channel antagonist, it acts to rapidly decrease and stabilize BP. Although it has no direct effects on cardiac function, its vasodilatory properties may lead to reflex tachycardia and, potentially, stimulation of the sympathetic nervous system. These effects, although present, have been shown to be less with the dihydropyridine calcium channel antagonists (nicardipine and clevidipine) than with other direct-acting vasodilators such as sodium nitroprusside.1–3 However, our clinical experience has suggested that reflex tachycardia may be more common with clevidipine than with nicardipine.4–6,9–11\n\nL-type calcium channel antagonists work at the terminal effect site for the sympathetic nervous system. Elevated sympathetic outflow eventually results in the release of norepinephrine, which binds to α-adrenergic receptors on vascular smooth muscle, resulting in membrane depolarization and opening of voltage gated L-type calcium channels. These channels allow calcium to enter the muscle cell, eventually resulting in vascular smooth muscle contraction. The dose response curves for clevidipine (and other L-type dihydropyridine calcium channel antagonists) depend on the level of sympathetic tone.12 In adults with severe intracranial hemorrhage or subarachnoid bleeding, significant rightward shifts in the dose response relationship for clevidipine have been noted (The Medicines Company, data on file). These patients are experiencing a powerful neutrally mediated vasopressor response and have elevated levels of plasma catecholamines.13 We postulate that chronic stimulation of the sympathetic nervous system in a patient taking medications such as aripiprazole and methylphenidate may be one plausible mechanism for the resistance to clevidipine that we observed in our patient.\n\nAripiprazole is an atypical quinolinone antipsychotic with approved use in the treatment of major depressive and psychotic disorders. It is a partial agonist at dopamine receptors (D2/D3) and a partial agonist at serotonin receptors (5-HT1A), thereby making it an aminergic agonist.14 Furthermore, aripiprazole has moderate affinity at other sites, including dopamine (D4), serotonin (5-HT2C, 5-HT7), α1-adrenergic, and H1 receptors. Previous anecdotal reports have documented the occurrence of hypertension during therapy with aripiprazole and resolution following its discontinuation.15–18 While none of these reports has conclusively demonstrated the mechanism for this hypertension, Borras and Constant18 noted successful treatment with propranolol, suggesting that the sympathetic nervous system with adrenergic hyperactivity was the primary mechanism for the alterations in BP.\n\nOur patient was also receiving methylphenidate as part of her chronic medication regimen. Alterations in BP have also been noted with methylphenidate, with the primary mechanism postulated to be the result of increased central and peripheral concentrations of dopamine, norepinephrine, and epinephrine.19 We would postulate that the combined effects of these two medications (aripiprazole and methylphenidate) may augment the normal surgical stress response that is mediated by the sympathetic nervous system. This sympathetic release of endogenous catecholamines, including norepinephrine and epinephrine, modulates perioperative alterations in BP, an effect appreciated even in patients without a prior history of hypertension.20 While an exact mechanism cannot be determined for the resistance to clevidipine noted in our patient, we would postulate that the combination of medications either increased the normal sympathetic response to surgery or potentiated the response at the level of the vascular smooth muscle. The involvement of the sympathetic nervous system is further supported by our patient’s response to labetalol, a mixed α- and β-adrenergic antagonist.\n\nIn summary, we present anecdotal evidence for resistance to the direct vasodilatory effects of clevidipine in a patient chronically receiving methylphenidate and aripiprazole. We would postulate that the mechanism involves the sympathetic nervous system with either increased release of endogenous catecholamines or an augmented effect of these agents on the smooth muscle of the vasculature. In such clinical scenarios, medications that act primarily through blocking the sympathetic nervous system or its peripheral effects, such as with labetalol, appear to be a logical choice for BP control.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1 Levy JH Mancao MY Gitter R Clevidipine effectively and rapidly controls blood pressure preoperatively in cardiac surgery patients: the results of the randomized, placebo-controlled efficacy study of clevidipine assessing its preoperative antihypertensive effect in cardiac surgery Anesth Analg 2007 105 918 925 17898366 \n2 Singla N Warltier DC Gandhi SD Treatment of acute postoperative hypertension in cardiac surgery patients: an efficacy study of clevidipine assessing its postoperative antihypertensive effect in cardiac surgery-2 (ESCAPE-2), a randomized, double-blind, placebo-controlled trial Anesth Analg 2008 107 59 67 18635468 \n3 Aronson S Dyke CM Stierer KA The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients Anesth Analg 2008 107 1110 1121 18806012 \n4 Towe E Tobias JD Preliminary experience with clevidipine in the pediatric population J Intensive Care Med 2010 25 349 352 20837631 \n5 Tobias JD Schechter WS Phillips A Clevidipine for perioperative blood pressure control in infants and children undergoing cardiac surgery for congenital heart disease J Pediatr Pharmacol Ther 2011 16 55 60 22477825 \n6 Tobias JD Hoernschemeyer DG Clevidipine for controlled hypotension during spinal surgery in adolescents J Neurosurg Anesthesiol 2011 23 347 351 21623231 \n7 Tobias JD Strategies for minimizing blood loss in orthopedic surgery Semin Hematol 2004 41 145 156 14872436 \n8 Tobias JD Controlled hypotension in children: a critical review of available agents Paediatr Drugs 2002 4 439 453 12083972 \n9 Kako H Gable A Martin D A prospective, open-label trial of clevidipine for controlled hypotension during posterior spinal fusion in adolescents J Pediatr Pharm Therap \n10 Tobias JD Hersey S Mencio GA Green NE Nicardipine for controlled hypotension during spinal surgery J Pediatr Orthop 1996 16 370 373 8728640 \n11 Tobias JD Nicardipine to control mean arterial pressure after cardiothoracic surgery in infants and children Am J Ther 2001 8 3 6 11304651 \n12 Pedrinelli R Tarazi RC Interference of calcium entry blockade in vivo with pressor responses to alpha-adrenergic stimulation: effects of two unrelated blockers on responses to both exogenous and endogenously released norepinephrine Circulation 1984 69 1171 1176 6143626 \n13 Myers MG Norris JW Hachniski VC Sole MJ Plasma norepinephrine in stroke Stroke 1981 12 200 204 7233464 \n14 Chen TY Tzeng NS Aripiprazole: a dopamine modulator that mimics methylphenidate in producing faster antidepressant effects Med Hypotheses 2013 81 183 185 23751312 \n15 Hsiao YL Chen SJ Shen TW Chang CH Chen ST Aripiprazole augmentation induced hypertension in major depressive disorder: a case report Prog Neuropsychopharmacol Biol Psychiatry 2011 35 305 306 21111018 \n16 Bat-Pitault F Delorme R Aripiprazole and hypertension in adolescents J Child Adolesc Psychopharmacol 2009 19 601 602 19877990 \n17 Yasui-Furukori N Fujii A Worsened hypertension control induced by aripiprazole Neuropsychiatr Dis Treat 2013 9 505 507 23723701 \n18 Borras L Constant EL Hypertension and aripiprazole Am J Psych 2005 162 12 \n19 Volkow ND Wang GJ Fowler JS Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma Psychopharmacology 2003 166 264 270 12589522 \n20 Nordlander M Pfaffendorf M van Wezel HB Calcium channel antagonists for perioperative blood pressure control Semin Cardiothor Vasc Anesth 1998 2 231 242\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1179-1454", "issue": "6()", "journal": "Journal of experimental pharmacology", "keywords": "aripiprazole; blood pressure; calcium channel antagonist; clevidipine; controlled hypotension; labetalol; posterior spinal fusion", "medline_ta": "J Exp Pharmacol", "mesh_terms": null, "nlm_unique_id": "101530345", "other_id": null, "pages": "11-4", "pmc": null, "pmid": "27186138", "pubdate": "2014", "publication_types": "D002363:Case Reports", "references": "25859171;11304651;22477825;7233464;21111018;14872436;12589522;16330611;12083972;21623231;19877990;18806012;6143626;17898366;18635468;8728640;23723701;23751312;20837631", "title": "Clevidipine resistance in a patient taking aripiprazole and methylphenidate.", "title_normalized": "clevidipine resistance in a patient taking aripiprazole and methylphenidate" }

[ { "companynumb": "US-JNJFOC-20141117721", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021121", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUSTAINED RELEASE TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATTENTION DEFICIT/HYPERACTIVITY DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "36", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPHENIDATE HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUSTAINED RELEASE TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "36", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPHENIDATE HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLEVIDIPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLEVIDIPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARIPIPRAZOLE." } ], "patientagegroup": "3", "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "51.3", "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood pressure decreased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Heart rate increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JACKLEN MA, CAMPAGNA JA, TOBIAS JD. CLEVIDIPINE RESISTANCE IN A PATIENT TAKING ARIPIPRAZOLE AND METHYLPHENIDATE. JOURNAL OF EXPERIMENTAL PHARMACOLOGY 2014;6:11-14.", "literaturereference_normalized": "clevidipine resistance in a patient taking aripiprazole and methylphenidate", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150524", "receivedate": "20150319", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10928678, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]

{ "abstract": "BACKGROUND\nThere have been several reports of bupropion insufflation since 2002 and 2 cases of intravenous bupropion use disorder since 2013. There are no documented cases of bupropion injection associated with tissue necrosis or psychosis.\n\n\nMETHODS\nWe report 2 cases of habitual intravenous bupropion injection by individuals with polysubstance use disorder and comorbid mental illness. The patients obtained bupropion as a result of physician deception, diversion or crime, and injected it to achieve a high. Both individuals experienced tissue and vascular complications, including tissue necrosis, cellulitis, and compartment syndrome in 1 patient. The other patient reported visual hallucinations and persecutory ideation that persisted for 3 days after his last use of the drug.\n\n\nCONCLUSIONS\nBupropion seems to have addictive effects, particularly when administered intravenously or intranasally. Individuals who inject high doses of bupropion may be at risk of tissue necrosis, seizures, or psychosis. Prescribers should be aware of uncontrolled medications with emerging potential for abuse and popularity among recreational drug users. We identify a need for policy on clinical strategies to minimize the abuse and diversion of bupropion and other uncontrolled prescription drugs.", "affiliations": "From the Department of Psychiatry (MS, SH), University of Ottawa, ON, Canada; and Department of Psychological Medicine (SH), University of Auckland, Auckland, New Zealand.", "authors": "Strike|Melanie|M|;Hatcher|Simon|S|", "chemical_list": "D018765:Dopamine Uptake Inhibitors; D016642:Bupropion", "country": "United States", "delete": false, "doi": "10.1097/ADM.0000000000000114", "fulltext": null, "fulltext_license": null, "issn_linking": "1932-0620", "issue": "9(3)", "journal": "Journal of addiction medicine", "keywords": null, "medline_ta": "J Addict Med", "mesh_terms": "D016642:Bupropion; D018765:Dopamine Uptake Inhibitors; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009336:Necrosis; D011605:Psychoses, Substance-Induced; D015819:Substance Abuse, Intravenous; D055815:Young Adult", "nlm_unique_id": "101306759", "other_id": null, "pages": "246-50", "pmc": null, "pmid": "25822212", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Bupropion injection resulting in tissue necrosis and psychosis: previously undocumented complications of intravenous bupropion use disorder.", "title_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder" }

[ { "companynumb": "PHHY2015CA134561", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "75932", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "EXTENDED RELEASE TABLET", "drugdosagetext": "300 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug administration error", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral swelling", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persecutory delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Injection site pain", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S.. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER.. J-ADDICT-MED. 2015?9(3):246-50.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151021", "receivedate": "20151021", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11649594, "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": "CA-TEVA-605130USA", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "045", "drugauthorizationnumb": "75310", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "75310", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG 4 TIMES DAILY AS REQUIRED FOR ANXIETY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "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": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG AT BEDTIME", "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": "QUETIAPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG AT BEDTIME", "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": "TRAZODONE" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Persecutory delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Injection site pain", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J-ADDICT-MED 2015? 9(3):246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151102", "receivedate": "20151102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11690644, "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" }, { "companynumb": "CA-IMPAX LABORATORIES, INC-2015-IPXL-01033", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "NICOTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICOTINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 3 /DAY (TAKING UP TO 10 MG DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "075913", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "300 MG, EVERY 1 TO 2 HOURS (1500 TO 3000 MG DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE SR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. INDICA TOP" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE ABUSE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANNABIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAFFEINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAFFEINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "075913", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "7 INJECTIONS OF 300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE SR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood pressure increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Heart rate increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arterial occlusive disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S.. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. JOURNAL OF ADDICTION MEDICINE. 2015?9:3:246-50", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151027", "receivedate": "20151027", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11668537, "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": "CA-WATSON-2016-10109", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, QHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "077715", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET (EXTENDED RELEASE)", "drugdosagetext": "4500 MG, DAILY( 30 TABLETS OVER 48 HOURS WITH AN AVERAGE OF 1 TABLET PER HOUR)", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE XL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "045", "drugauthorizationnumb": "077715", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET (EXTENDED RELEASE)", "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": "BUPROPION HYDROCHLORIDE XL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, QID, AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Injection site pain", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Substance-induced psychotic disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug diversion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED. 2015;9(3):246-50.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160516", "receivedate": "20160516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12372257, "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": "CA-EDGEMONT-2015EDG00043", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 4X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "022497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "4500 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE EXTENDED RELEASE (XL)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "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": "BUPROPION HYDROCHLORIDE EXTENDED RELEASE (XL)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" } ], "patientagegroup": "5", "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peripheral swelling", "reactionmeddraversionpt": "18.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED (DOI: 10.1097/ADM.0000000000000114). 2015?9(3):246-250", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11705977, "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": "CA-PRINSTON PHARMACEUTICAL INC.-2015PRN00101", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "202304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "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": "BUPROPION HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "202304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "4500 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 4X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED (DOI: 10.1097/ADM.0000000000000114). 2015?9(3):246-250", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151109", "receivedate": "20151109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11714448, "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": "CA-EDGEMONT-2015EDG00044", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 3X/DAY (UP TO 10 MG/DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAFFEINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "CAFFEINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "022497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "300 MG EVERY 1 TO 2 HOURS (1500 TO 3000 MG DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE EXTENDED RELEASE (XL)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NICOTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "NICOTINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, 1X/DAY", "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": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. INDICA TOP" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "CANNABIS" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Arterial occlusive disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2011" } }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED (DOI: 10.1097/ADM.0000000000000114). 2015?9(3):246-250", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11705988, "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" }, { "companynumb": "CA-TEVA-605131USA", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UP TO 10MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "75310", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 INJECTIONS AT RATE OF 300MG/H (TOTAL 2100MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1MG 3 TIMES DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "75310", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Arterial occlusive disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J-ADDICT-MED 2015? 9(3):246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151102", "receivedate": "20151102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11690648, "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" }, { "companynumb": "CA-BAUSCH-BL-2015-026277", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021515", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "USING ALTERNATING FOREARMS, CONSUMED AN AVERAGE OF 1 TABLET PER HOUR, INJECTED 30 TABLETS OVER 48 HO", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSIVE SYMPTOM", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION XL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIACETYLMORPHINE" }, "drugadditional": null, "drugadministrationroute": "042", "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": "HEROIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS REQUIRED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYCODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "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": "OXYCONTIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": null, "drugadministrationroute": "042", "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": "HYDROMORPHONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "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": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": 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": "COCAINE" }, "drugadditional": null, "drugadministrationroute": "042", "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": "COCAINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": null, "drugadministrationroute": "042", "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": "MORPHINE" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persecutory delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral swelling", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vascular wall hypertrophy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. JOURNAL OF ADDICTION MEDICINE. 2015?9:246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151111", "receivedate": "20151111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11723099, "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": "CA-WATSON-2016-10122", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET (EXTENDED RELEASE)", "drugdosagetext": "THE 7TH INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE SR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET (EXTENDED RELEASE)", "drugdosagetext": "1800 MG, TOTAL( 6 INJECTIONS AT A RATE OF 300 MG PER HOUR)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE SR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74869", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UP TO 10 MG DAILY", "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": "CLONAZEPAM (UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74869", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "1 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacillus infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug diversion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry gangrene", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED. 2015;9(3):246-50.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160516", "receivedate": "20160516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12372549, "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" }, { "companynumb": "CA-IMPAX LABORATORIES, INC-2015-IPXL-01032", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYCODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCONTIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "COCAINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COCAINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "4500 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION XL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION XL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIACETYLMORPHINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEROIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "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": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG 4 TIMES DAILY AS REQUIRED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Euphoric mood", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug tolerance increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persecutory delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S.. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. JOURNAL OF ADDICTION MEDICINE. 2015?9:3:246-50", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151026", "receivedate": "20151026", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11661182, "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" }, { "companynumb": "CA-MYLANLABS-2015M1036172", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "045", "drugauthorizationnumb": "075491", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG 4 TIMES DAILY AS REQUIRED FOR ANXIETY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "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": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG AT BEDTIME", "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": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "075491", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "30 TABLETS (4500MG DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG AT BEDTIME", "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": "QUETIAPINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral venous disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Injection site pain", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persecutory delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J-ADDICT-MED 2015? 9(3):246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151026", "receivedate": "20151026", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11662030, "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": "CA-PRINSTON PHARMACEUTICAL INC.-2015PRN00102", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "NICOTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "NICOTINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "202304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "300 MG EVERY 1 TO 2 HOURS (1500 TO 3000 MG DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. INDICA TOP" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "CANNABIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAFFEINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1X/DAY", "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": "CAFFEINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, 1X/DAY", "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": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 3X/DAY (UP TO 10 MG/DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacillus infection", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2011" } }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J ADDICT MED (DOI: 10.1097/ADM.0000000000000114). 2015?9(3):246-250", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151109", "receivedate": "20151109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11714450, "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" }, { "companynumb": "PHHY2015CA134563", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "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": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "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": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYMBALTA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPHENIDATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021278", "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": "METHYLPHENIDATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. INDICA TOP" }, "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": "CANNABIS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NICOTINE" }, "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": "NICOTINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALERT//CAFFEINE" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S.. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER.. J-ADDICT-MED. 2015?9(3):246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151020", "receivedate": "20151020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11645305, "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": "CA-MYLANLABS-2015M1036173", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "075491", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 INJECTIONS AT RATE OF 300MG/H (TOTAL 2100MG)", "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": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": 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"drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UP TO 10MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arterial occlusive disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER. J-ADDICT-MED 2015? 9(3):246-250.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151026", "receivedate": "20151026", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11662031, "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" }, { "companynumb": "PHHY2015CA134562", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "75932", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "EXTENDED RELEASE TABLET", "drugdosagetext": "300 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SMOKING CESSATION THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug administration error", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STRIKE M, HATCHER S.. BUPROPION INJECTION RESULTING IN TISSUE NECROSIS AND PSYCHOSIS: PREVIOUSLY UNDOCUMENTED COMPLICATIONS OF INTRAVENOUS BUPROPION USE DISORDER.. J-ADDICT-MED. 2015?9(3):246-50.", "literaturereference_normalized": "bupropion injection resulting in tissue necrosis and psychosis previously undocumented complications of intravenous bupropion use disorder", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151021", "receivedate": "20151021", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11649593, "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": "We describe a 51-year-old man who developed renal and neural toxicity after the administration of colistin. He developed respiratory apnoea, neuromuscular blockade and severe comatose encephalopathy with the lack of brainstem reflexes. After discontinuation of the antibiotic, he made a prompt recovery to his baseline neurological function. The case illustrates the importance of recognising the toxicities associated with colistin. Although recent literature details its nephrotoxicity, current data have been discordant with the rare cases of respiratory apnoea or neuromuscular blockade once cited over 30 years ago. Additionally, no cases have ever described the profound encephalopathy with lack of brainstem function described here. The awareness of colistin's potentially fatal effects must be kept in mind when administering this antibiotic. Vigilance of the encephalopathic picture can also facilitate the diagnosis of colistin-mediated neurotoxicity in a patient with altered mental status of otherwise unknown aetiology.", "affiliations": "Rush University Medical Center, Chicago, Illinois, USA.;Department of Pulmonary and Critical Care, Rush University Medical Center, Chicago, Illinois, USA.", "authors": "Wadia|Subeer|S|;Tran|Betty|B|", "chemical_list": "D000900:Anti-Bacterial Agents; D003091:Colistin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2014()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000900:Anti-Bacterial Agents; D001049:Apnea; D001933:Brain Stem; D003091:Colistin; D003128:Coma; D006801:Humans; D007674:Kidney Diseases; D008297:Male; D008875:Middle Aged; D009468:Neuromuscular Diseases; D020258:Neurotoxicity Syndromes", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "25199193", "pubdate": "2014-09-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "16507149;21906345;21906382;4306125", "title": "Colistin-mediated neurotoxicity.", "title_normalized": "colistin mediated neurotoxicity" }

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COLISTIN-MEDIATED NEUROTOXICITY. 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"actiondrug": null, "activesubstance": { "activesubstancename": "DORIPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACINETOBACTER INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DORIPENEM." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neuromuscular blockade", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal tubular necrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Apnoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WADIA S, TRAN B.. COLISTIN-MEDIATED NEUROTOXICITY.. BMJ CASE REP.. 2014?2014:PII: BCR-2014-205332", "literaturereference_normalized": "colistin mediated neurotoxicity", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200212", "receivedate": "20200212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17406116, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200409" } ]

{ "abstract": "Rivaroxaban is a factor-Xa-inhibitor which has been shown to be non-inferior to the vitamin-K-antagonist (VKA) warfarin in atrial fibrillation patients. In the manufacturer-sponsored trial, the rate of intracranial hemorrhage in rivaroxaban-treated patients was lower than in VKA-treated. It is unknown if this advantage of rivaroxaban is also present outside clinical trials. We report a patient with fatal cerebral bleeding 4months after initiation of rivaroxaban. Bleeding might be favored by hypertension, hypoalbuminemia, renal impairment, hepatopathy and drug-drug interactions of rivaroxaban with amiodarone and bisoprolol. Patients have to be monitored closely after initiation of rivaroxaban, especially if they are treated with possibly interacting drugs. Additionally, hepatic function, albumin level, and renal function have to be closely monitored. Therapy with VKA seems more convenient, safer and more favorable for the patient than rivaroxaban with its associated uncertainties concerning metabolization and drug-drug interactions and no possibility to reverse its activity in emergency situations.", "affiliations": "Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Austria. Electronic address: [email protected].;Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Austria. Electronic address: [email protected].;Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Austria. Electronic address: [email protected].", "authors": "Stöllberger|Claudia|C|;Bastovansky|Adam|A|;Finsterer|Josef|J|", "chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0167-5273", "issue": "201()", "journal": "International journal of cardiology", "keywords": "Atrial fibrillation; Cerebral bleeding; Rivaroxaban", "medline_ta": "Int J Cardiol", "mesh_terms": "D000368:Aged; D002543:Cerebral Hemorrhage; D065427:Factor Xa Inhibitors; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D000069552:Rivaroxaban", "nlm_unique_id": "8200291", "other_id": null, "pages": "110-2", "pmc": null, "pmid": "26296048", "pubdate": "2015-12-15", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Fatal intracerebral bleeding under rivaroxaban.", "title_normalized": "fatal intracerebral bleeding under rivaroxaban" }

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"drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "160", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALSARTAN." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STOLLBERGER, C.. FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. INTERNATIONAL JOURNAL OF CARDIOLOGY. 2015;201:110-112", "literaturereference_normalized": "fatal intracerebral bleeding under rivaroxaban", "qualification": "1", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20170801", "receivedate": "20151103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11693846, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "AT-FRESENIUS KABI-FK201505802", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIODARONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": 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"drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL" }, { "actiondrug": null, "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": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STOLLBERGER C,BASTOVANSKY A,FINSTERER J. FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. INTERNATIONAL JOURNAL OF CARDIOLOGY 2015 OCT 10?201:110-112.", "literaturereference_normalized": "fatal intracerebral bleeding under rivaroxaban", "qualification": "3", "reportercountry": "AT" }, "primarysourcecountry": "AT", "receiptdate": "20151116", "receivedate": "20151116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11744229, "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" }, { "companynumb": "PHHY2015AT142454", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": null, "drugadministrationroute": "065", 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FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. 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FATAL INTRACEREBRAL BLEEDING UNDER RIVAROXABAN. 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{ "abstract": "The long-term safety and efficacy of filgotinib (from phase II studies), with or without methotrexate (MTX), for the treatment of patients with rheumatoid arthritis was assessed in DARWIN 3, a long-term, open-label extension study (ClinicalTrials.gov: NCT02065700).\n\n\n\nEligible patients completing the 24-week DARWIN 1 (filgotinib + MTX) and DARWIN 2 (filgotinib monotherapy) studies entered DARWIN 3, where they received filgotinib 200 mg/day, except for 15 men who received filgotinib 100 mg/day. Safety analyses were performed using the safety analysis set and the exposure-adjusted incidence rate (EAIR) of treatment-emergent adverse events (TEAEs) was calculated. Efficacy was assessed from baseline in the parent studies.\n\n\n\nOf 790 patients completing the phase II parent studies, 739 enrolled in the study. Through April 2019, 59.5% of patients had received ≥ 4 years of the study drug. Mean (SD) exposure to filgotinib was 3.55 (1.57) years in the filgotinib + MTX group and 3.38 (1.59) years in the filgotinib monotherapy group. EAIR per 100 patient-years of exposure for TEAEs was 24.6 in the filgotinib + MTX group and 25.8 in the filgotinib monotherapy group, and for serious TEAEs, the EAIR was 3.1 and 4.3, respectively. American College of Rheumatology 20/50/70 responses among patients remaining in the study could be maintained through 4 years, with 89.3%/69.6%/49.1% of the filgotinib + MTX group and 91.8%/69.4%/44.4% of the monotherapy group maintaining ACR20/50/70 responses, respectively, based on observed data.\n\n\n\nFilgotinib was well tolerated with a 4-year safety profile comparable to that of the parent trials, both in patients receiving combination therapy with MTX or as monotherapy.", "affiliations": "A. Kavanaugh, MD, University of California San Diego, La Jolla, California, USA; [email protected].;R.R. Westhovens, MD, PhD, KU Leuven, Skeletal Biology and Engineering Research Center, Leuven, Belgium.;K.L. Winthrop, MD, MPH, Oregon Health and Science University, Portland, Oregon, USA.;S.J. Lee, MD, Y. Tan, PhD, D. An, PhD, L. Ye, PhD, J.S. Sundy, MD, PhD, Gilead Sciences Inc., Foster City, California, USA.;S.J. Lee, MD, Y. Tan, PhD, D. An, PhD, L. Ye, PhD, J.S. Sundy, MD, PhD, Gilead Sciences Inc., Foster City, California, USA.;S.J. Lee, MD, Y. Tan, PhD, D. An, PhD, L. Ye, PhD, J.S. Sundy, MD, PhD, Gilead Sciences Inc., Foster City, California, USA.;S.J. Lee, MD, Y. Tan, PhD, D. An, PhD, L. Ye, PhD, J.S. Sundy, MD, PhD, Gilead Sciences Inc., Foster City, California, USA.;S.J. Lee, MD, Y. Tan, PhD, D. An, PhD, L. Ye, PhD, J.S. Sundy, MD, PhD, Gilead Sciences Inc., Foster City, California, USA.;R. Besuyen, MD, L. Meuleners, MS, Galapagos NV, Mechelen, Belgium.;R. Besuyen, MD, L. Meuleners, MS, Galapagos NV, Mechelen, Belgium.;M. Stanislavchuk, MD, National Pirogov Memorial Medical University, Vinnytsya, Ukraine.;A.J. Spindler, MD, Centro Medico Privado de Reumatologia, San Miguel de Tucuman, Argentina.;M. Greenwald, MD, Desert Medical Advances, Palm Desert, California, USA.;R. Alten, MD, Schlosspark Klinik, University Medicine Berlin, Berlin, Germany.;M.C. Genovese, MD, Stanford University School of Medicine, Division of Immunology & Rheumatology, Stanford, and Gilead Sciences Inc., Foster City, California, USA.", "authors": "Kavanaugh|Arthur|A|;Westhovens|Rene R|RR|;Winthrop|Kevin L|KL|;Lee|Susan J|SJ|;Tan|YingMeei|Y|;An|Di|D|;Ye|Lei|L|;Sundy|John S|JS|;Besuyen|Robin|R|0000-0002-8699-4549;Meuleners|Luc|L|;Stanislavchuk|Mykola|M|;Spindler|Alberto J|AJ|;Greenwald|Maria|M|;Alten|Rieke|R|0000-0002-3395-4412;Genovese|Mark C|MC|0000-0001-5294-4503", "chemical_list": "D018501:Antirheumatic Agents; C584571:GLPG0634; D011725:Pyridines; D014230:Triazoles; D008727:Methotrexate", "country": "Canada", "delete": false, "doi": "10.3899/jrheum.201183", "fulltext": null, "fulltext_license": null, "issn_linking": "0315-162X", "issue": "48(8)", "journal": "The Journal of rheumatology", "keywords": "ACR improvement criteria; inflammation; methotrexate; rheumatoid arthritis", "medline_ta": "J Rheumatol", "mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008727:Methotrexate; D011725:Pyridines; D016896:Treatment Outcome; D014230:Triazoles", "nlm_unique_id": "7501984", "other_id": null, "pages": "1230-1238", "pmc": null, "pmid": "33526618", "pubdate": "2021-08", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Safety and Efficacy of Filgotinib: Up to 4-year Results From an Open-label Extension Study of Phase II Rheumatoid Arthritis Programs.", "title_normalized": "safety and efficacy of filgotinib up to 4 year results from an open label extension study of phase ii rheumatoid arthritis programs" }

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