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"abstract": "Previous studies of patients with cystic fibrosis (CF) treated with azole antifungals have shown altered pharmacokinetics relative to healthy patients. Data regarding the pharmacokinetic profile of isavuconazole in patients with CF undergoing lung transplantation are currently not available. Serum trough concentrations assessed in a single CF patient following transplant revealed significantly lower values relative to available literature. Larger studies are required to validate CF population pharmacokinetics of isavuconazole.",
"affiliations": "Department of Pharmacy Services, Medical University of South Carolina, Charleston, SC, USA.;Department of Pharmacy Services, Medical University of South Carolina, Charleston, SC, USA.",
"authors": "Kabulski|Galen M|GM|;MacVane|Shawn H|SH|http://orcid.org/0000-0002-8019-2270",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12878",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "cystic fibrosis; isavuconazole; lung transplant; mucormycosis; pharmacokinetics",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D003550:Cystic Fibrosis; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016040:Lung Transplantation; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12878",
"pmc": null,
"pmid": "29512930",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Isavuconazole pharmacokinetics in a patient with cystic fibrosis following bilateral orthotopic lung transplantation.",
"title_normalized": "isavuconazole pharmacokinetics in a patient with cystic fibrosis following bilateral orthotopic lung transplantation"
} | [
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"literaturereference_normalized": "isavuconazole pharmacokinetics in a patient with cystic fibrosis following bilateral orthotopic lung transplantation",
"qualification": "3",
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},
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"receiptdate": "20180803",
"receivedate": "20180801",
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},
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},
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] |
{
"abstract": "BACKGROUND\nIn May 2011, an outbreak of Shiga toxin-producing enterohaemorrhagic E coli O104:H4 in northern Germany led to a high proportion of patients developing post-enteritis haemolytic uraemic syndrome and thrombotic microangiopathy that were unresponsive to therapeutic plasma exchange or complement-blocking antibody (eculizumab). Some patients needed ventilatory support due to severe neurological complications, which arose 1 week after onset of enteritis, suggesting an antibody-mediated mechanism. Therefore, we aimed to assess immunoadsorption as rescue therapy.\n\n\nMETHODS\nIn our prospective non-controlled trial, we enrolled patients with severe neurological symptoms and confirmed recent E coli O104:H4 infection without other acute bacterial infection or raised procalcitonin concentrations. We did IgG immunoadsorption processing of 12 L plasma volumes on 2 consecutive days, followed by IgG replacement (0·5 g/kg intravenous IgG). We calculated a composite neurological symptom score (lowest score was best) every day and assessed changes before and after immunoadsorption.\n\n\nRESULTS\nWe enrolled 12 patients who initially presented with enteritis and subsequent renal failure; 10 (83%) of 12 patients needed renal replacement therapy by a median of 8·0 days (range 5-12). Neurological complications (delirium, stimulus sensitive myoclonus, aphasia, and epileptic seizures in 50% of patients) occurred at a median of 8·0 days (range 5-15) and mandated mechanical ventilation in nine patients. Composite neurological symptom scores increased in the 3 days before immunoadsorption to 3·0 (SD 1·1, p=0·038), and improved to 1·0 (1·2, p=0·0006) 3 days after immunoadsorption. In non-intubated patients, improvement was apparent during immunoadsorption (eg, disappearance of aphasia). Five patients who were intubated were weaned within 48 h, two within 4 days, and two patients needed continued ventilation for respiratory problems. All 12 patients survived and ten had complete neurological and renal function recovery.\n\n\nCONCLUSIONS\nAntibodies are probably involved in the pathogenesis of severe neurological symptoms in patients with E coli O104:H4-induced haemolytic uraemic syndrome. Immunoadsorption can safely be used to rapidly ameliorate these severe neurological complications.\n\n\nBACKGROUND\nGreifswald University and Hannover Medical School.",
"affiliations": "Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt-Universität, Greifswald, Germany. greinach@uni-greifswald.de",
"authors": "Greinacher|Andreas|A|;Friesecke|Sigrun|S|;Abel|Peter|P|;Dressel|Alexander|A|;Stracke|Sylvia|S|;Fiene|Michael|M|;Ernst|Friedlinde|F|;Selleng|Kathleen|K|;Weissenborn|Karin|K|;Schmidt|Bernhard M W|BM|;Schiffer|Mario|M|;Felix|Stephan B|SB|;Lerch|Markus M|MM|;Kielstein|Jan T|JT|;Mayerle|Julia|J|",
"chemical_list": "D007074:Immunoglobulin G",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(11)61253-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "378(9797)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000328:Adult; D054324:Enterohemorrhagic Escherichia coli; D004927:Escherichia coli Infections; D005260:Female; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D007074:Immunoglobulin G; D007163:Immunosorbent Techniques; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases; D054323:Shiga-Toxigenic Escherichia coli",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "1166-73",
"pmc": null,
"pmid": "21890192",
"pubdate": "2011-09-24",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial.",
"title_normalized": "treatment of severe neurological deficits with igg depletion through immunoadsorption in patients with escherichia coli o104 h4 associated haemolytic uraemic syndrome a prospective trial"
} | [
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},
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"drugdosageform": "UNK",
"drugdosagetext": "30 GRAM",
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"drugindication": "IMMUNODEFICIENCY COMMON VARIABLE",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "HUMAN NORMAL IMMUNOGLOBULIN"
}
],
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"reaction": [
{
"reactionmeddrapt": "No adverse event",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GREINACHER A, FRIESECKE S, ABEL P, DRESSEL A, STRACKE S, FIENE M ET AL. TREATMENT OF SEVERE NEUROLOGICAL DEFICITS WITH IGG DEPLETION THROUGH IMMUNOADSORPTION IN PATIENTS WITH ESCHERICHIA COLI O104:H4?ASSOCIATED HAEMOLYTIC URAEMIC SYNDROME: A PROSPECTIVE TRIAL. THE LANCET. 2011?378(9797):1166?73",
"literaturereference_normalized": "treatment of severe neurological deficits with igg depletion through immunoadsorption in patients with escherichia coli o104 h4 associated haemolytic uraemic syndrome a prospective trial",
"qualification": "3",
"reportercountry": "DE"
},
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"receiptdate": "20210324",
"receivedate": "20210324",
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},
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},
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210420"
}
] |
{
"abstract": "A 66-year-old multimorbid man with rheumatoid arthritis developed an infection after a steroid injection in the hand. Mycobacterium chelonae was cultured 1-month after presentation. In the mean time, his third finger had been amputated. Further treatment was based on preliminary susceptibility testing and the American Thoracic Society guidelines. No regression of the infection was observed before the addition of linezolid (600 mg×1/day) to a combination antimicrobial therapy also consisting of clarithromycin (500 mg×2/day) and moxifloxacin (400 mg×1/day), even though two methods of susceptibility testing, the E-test and broth microdilution, had shown susceptibility to other antimicrobial drugs. The healing was complete 12 months after presentation. There were no serious side effects observed with the use of linezolid in reduced dosage of 600 mg×1/day for a duration of 9 months.",
"affiliations": "Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark.;Department of Microbiology, Aarhus University Hospital, Aarhus N, Denmark.;Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark.",
"authors": "Olesen|Jens Steen|JS|;Wang|Mikala|M|;Wejse|Christian|C|http://orcid.org/0000-0002-2534-2942",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D017291:Clarithromycin; D000069349:Linezolid; D000077266:Moxifloxacin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-217257",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000671:Amputation; D000900:Anti-Bacterial Agents; D001172:Arthritis, Rheumatoid; D017291:Clarithromycin; D004359:Drug Therapy, Combination; D024841:Fluoroquinolones; D006225:Hand; D006801:Humans; D007267:Injections; D007270:Injections, Intra-Articular; D000069349:Linezolid; D008297:Male; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009165:Mycobacterium Infections, Nontuberculous; D016926:Mycobacterium chelonae; D013717:Tenosynovitis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28137898",
"pubdate": "2017-01-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11409581;11550122;12539076;1386098;1581184;16216196;16219512;1624823;16312965;16332331;16610256;17277290;17311842;17638751;18202441;18937568;19171799;19802419;20113563;21039785;21791449;22429487;22469352;22992056;23192911;23835173;24127799;24253248;24882980;25258544;25614735;26617105;2680056;5542366;8357113;9774549",
"title": "Mycobacterium chelonae hand infection after steroid injection in a patient with rheumatoid arthritis receiving long-term linezolid therapy.",
"title_normalized": "mycobacterium chelonae hand infection after steroid injection in a patient with rheumatoid arthritis receiving long term linezolid therapy"
} | [
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}
],
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"patientonsetage": "66",
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"reaction": [
{
"reactionmeddrapt": "Mycobacterium chelonae infection",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "OLESEN J, WANG M, WEJSE C. MYCOBACTERIUM CHELONAE HAND INFECTION AFTER STEROID INJECTION IN A PATIENT WITH RHEUMATOID ARTHRITIS RECEIVING LONG-TERM LINEZOLID THERAPY.. BMJ CASE REPORTS. 2017;.",
"literaturereference_normalized": "mycobacterium chelonae hand infection after steroid injection in a patient with rheumatoid arthritis receiving long term linezolid therapy",
"qualification": "1",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20170217",
"receivedate": "20170217",
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},
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"safetyreportversion": 1,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": 1,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170428"
},
{
"companynumb": "DK-EDENBRIDGE PHARMACEUTICALS, LLC-DK-2017EDE000013",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE SODIUM PHOSPHATE"
},
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"medicinalproduct": "METHOTREXATE."
}
],
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"reactionoutcome": "1"
}
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},
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"literaturereference": "OLESEN JS, WANG M, WEJSE C. MYCOBACTERIUM CHELONAE HAND INFECTION AFTER STEROID INJECTION IN A PATIENT WITH RHEUMATOID ARTHRITIS RECEIVING LONG-TERM LINEZOLID THERAPY. BMJ CASE REP. 2017",
"literaturereference_normalized": "mycobacterium chelonae hand infection after steroid injection in a patient with rheumatoid arthritis receiving long term linezolid therapy",
"qualification": "3",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20170410",
"receivedate": "20170410",
"receiver": {
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"receivertype": "6"
},
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"safetyreportid": 13422753,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
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}
] |
{
"abstract": "BACKGROUND\nTo establish the clinical use of bortezomib with fewer adverse events, we retrospectively analyzed the efficacy and safety of bortezomib plus dexamethasone (BD) therapy for relapsed or refractory multiple myeloma.\n\n\nMETHODS\nPatients received bortezomib (1.3 mg/m2) as an intravenous bolus on days 1, 4, 8 and 11 in a 3-week cycle (twice-weekly administration), or on days 1, 8, 15 and 22 in a 5-week cycle (once-weekly administration). Dexamethasone (20 mg) was given on the day of and day after bortezomib treatment.\n\n\nRESULTS\nFrom January 2007 to July 2010, 22 patients began to receive BD therapy. Initially, bortezomib was administered twice-weekly, but some severe adverse events developed; therefore, from January 2008, bortezomib was administered twice-weekly for the first two courses, followed by once-weekly for the subsequent courses. Patients who were expected to have severe adverse events beforehand were treated initially with once-weekly administration. Of the 22 patients, 14 were treated with twice-weekly followed by once-weekly administration, five with only twice-weekly administration and three with only once-weekly administration. Seventeen patients (77.3%) achieved at least partial response, including three with complete response and seven with very good partial response. The median progression-free survival and the median overall survival of 22 patients were 512 days and not reached, respectively. The median progression-free survival and the median overall survival of 17 patients who received at least one course of once-weekly administration were 615 days and not reached, respectively. The most frequent ≥grade 3 adverse events with twice-weekly administration were gastrointestinal, especially paralytic ileus and constipation. Among seven patients who developed ≥grade 3 gastrointestinal adverse events with twice-weekly administration, all four patients changed the schedule to once-weekly were able to continue BD therapy.\n\n\nCONCLUSIONS\nOnce-weekly administration of bortezomib in BD therapy may reduce the incidence of gastrointestinal adverse events without reducing the clinical efficacy of this therapy for refractory or relapsed multiple myeloma.",
"affiliations": "Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan. tfukus@kanazawa-med.ac.jp",
"authors": "Fukushima|Toshihiro|T|;Nakamura|Takuji|T|;Iwao|Haruka|H|;Nakajima|Akio|A|;Miki|Miyuki|M|;Sato|Tomomi|T|;Sakai|Tomoyuki|T|;Sawaki|Toshioki|T|;Fujita|Yoshimasa|Y|;Tanaka|Masao|M|;Masaki|Yasufumi|Y|;Nakajima|Hideo|H|;Motoo|Yoshiharu|Y|;Umehara|Hisanori|H|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "31(6)",
"journal": "Anticancer research",
"keywords": null,
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005767:Gastrointestinal Diseases; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D012189:Retrospective Studies",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "2297-302",
"pmc": null,
"pmid": "21737655",
"pubdate": "2011-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events.",
"title_normalized": "efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma once weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events"
} | [
{
"companynumb": "JP-TAKEDA-2017MPI007427",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Sepsis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Ileus paralytic",
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"reactionoutcome": "5"
}
],
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},
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"literaturereference": "FUKUSHIMA T, NAKAMURA T, IWAO H, NAKAJIMA A, MIKI M, SATO T, ET AL.. EFFICACY AND SAFETY OF BORTEZOMIB PLUS DEXAMETHASONE THERAPY FOR REFRACTORY OR RELAPSED MULTIPLE MYELOMA: ONCE-WEEKLY ADMINISTRATION OF BORTEZOMIB MAY REDUCE THE INCIDENCE OF GASTROINTESTINAL ADVERSE EVENTS.. ANTIRESEARCH CANCER. 2011;31:2297-2302",
"literaturereference_normalized": "efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma once weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events",
"qualification": "3",
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},
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"receivedate": "20170831",
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"transmissiondate": "20171127"
},
{
"companynumb": "JP-TAKEDA-2017MPI007530",
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"actiondrug": "1",
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},
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"drugintervaldosagedefinition": "803",
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{
"actiondrug": "1",
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"medicinalproduct": "DEXAMETHASONE."
},
{
"actiondrug": "6",
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"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},
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"drugindication": "PROPHYLAXIS",
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"medicinalproduct": "VALACICLOVIR"
},
{
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},
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"medicinalproduct": "VELCADE"
}
],
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"reaction": [
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Constipation",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Sepsis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Herpes zoster",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neuropathy peripheral",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Alanine aminotransferase increased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Ileus paralytic",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cytomegalovirus infection",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FUKUSHIMA T, NAKAMURA T, IWAO H, NAKAJIMA A, MIKI M, SATO T, ET AL. EFFICACY AND SAFETY OF BORTEZOMIB PLUS DEXAMETHASONE THERAPY FOR REFRACTORY OR RELAPSED MULTIPLE MYELOMA: ONCE-WEEKLY ADMINISTRATION OF BORTEZOMIB MAY REDUCE THE INCIDENCE OF GASTROINTESTINAL ADVERSE EVENTS. ANTIRESEARCH CANCER. 2011;31:2297-2302",
"literaturereference_normalized": "efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma once weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20170904",
"receivedate": "20170904",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13932417,
"safetyreportversion": 1,
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"sendertype": "2"
},
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"seriousnesscongenitalanomali": null,
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"transmissiondate": "20171127"
}
] |
{
"abstract": "BACKGROUND\nIdentifying the causes of acute liver failure (ALF) and predictors of death or liver transplantation (LTX) is crucial to decide its management. We aimed to describe features and outcome of ALF in Italian children.\n\n\nMETHODS\nRetrospective review of cases presenting between 1996-2012. ALF was defined by high transaminases, INR ≥2.0 regardless of hepatic encephalopathy (HE), no evidence of underlying chronic liver disease.\n\n\nRESULTS\n55 children (median age 2.6 years, range 0.1-15.1; M/F=31/24) had ALF due to autoimmune hepatitis (AIH) in 10 (18%), metabolic disorders in 9 (17%), paracetamol overdose in 6 (11%), mushroom poisoning in 3 (5%), viral infection in 1 (2%), indeterminate in 26 (47%); 25/55 recovered with supportive management (45%); 28/55 underwent LTX and 2 died on the waiting list (55%). On multivariate analysis severity of HE grade 3-4 and bilirubin ≥12mg/dl were independent predictors of death or LTX (p<0.05). After a median follow up of 4 years (range 2-15.0 years) the overall survival rate was 93%.\n\n\nCONCLUSIONS\nChildren with ALF can be managed successfully with combined medical treatment and transplantation, warranting a survival rate similar to children transplanted because of chronic conditions. In our cohort of patients severe HE and high bilirubin on admission were independent predictors of the need of LTX.",
"affiliations": "Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII Bergamo, Italy.;Liver and Transplant Pathology, Hospital Papa Giovanni XXIII Bergamo, Italy.;Hospital Management, Hospital Papa Giovanni XXIII Bergamo, Italy.;Laboratory Medicine, Hospital Papa Giovanni XXIII Bergamo, Italy.;Paediatric Intensive Care Unit, Hospital Papa Giovanni XXIII Bergamo, Italy.;General Surgery and Transplantation, Hospital Papa Giovanni XXIII Bergamo, Italy.;Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII Bergamo, Italy. Electronic address: ldantiga@asst-pg23.it.",
"authors": "Di Giorgio|A|A|;Sonzogni|A|A|;Piccichè|A|A|;Alessio|G|G|;Bonanomi|E|E|;Colledan|M|M|;D'Antiga|L|L|",
"chemical_list": "D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.dld.2017.05.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": "49(10)",
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "Acute liver failure; Children; Liver transplantation; Prognostic criteria",
"medline_ta": "Dig Liver Dis",
"mesh_terms": "D000293:Adolescent; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D001663:Bilirubin; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D019934:International Normalized Ratio; D007558:Italy; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015996:Survival Rate; D062606:Tertiary Care Centers",
"nlm_unique_id": "100958385",
"other_id": null,
"pages": "1139-1145",
"pmc": null,
"pmid": "28663066",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful management of acute liver failure in Italian children: A 16-year experience at a referral centre for paediatric liver transplantation.",
"title_normalized": "successful management of acute liver failure in italian children a 16 year experience at a referral centre for paediatric liver transplantation"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-147110",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
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"drugauthorizationnumb": "76200",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "PARACETAMOL"
}
],
"patientagegroup": "3",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Acute hepatic failure",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
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"abstract": "BACKGROUND Colorectal cancer is one of the most common cancers in men and women worldwide. There are several studies showing an association between chronic schistosomiasis infection and colorectal cancer. CASE REPORT A 53-year-old woman presented with recurrent metastatic colon cancer involving the peritoneum and bilateral adnexa. The patient then underwent exploratory laparotomy that involved abdominal wall deposit resection, omentectomy, redo left hemicolectomy, peritonectomy, diaphragmatic stripping, and total abdominal hysterectomy with bilateral salpingectomy-oophorectomy, as well as hyperthermic intraperitoneal chemotherapy (HIPEC). She also underwent adjuvant chemotherapy, but on her 6th cycle, the patient suffered intolerable anal pain, diarrhea, and rectal bleeding. Her colonoscopy showed extended circumferential inflammation with loses of vascular pattern and a few rectal ulcers going up to the anastomosis site. Biopsy revealed Schistosoma mansoni eggs and marked ischemic changes. She was then managed with a single dose of Praziquantel. CONCLUSIONS Colorectal schistosomiasis infection is a rare cause of such common presentations especially in postoperative settings in a patient with recurrent metastatic colon cancer. The use of multimodality investigations and high clinical suspicion were needed for the diagnosis and to exclude other common etiologies.",
"affiliations": "Department of Surgery, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.;Department of Surgery, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.;Department of Surgery, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.;Department of Surgery, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.;Department of Surgery, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.;Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.;Department of Surgery, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.",
"authors": "Alshammari|Sulaiman|S|;Almajed|Ashwaq|A|;Alkhawaja|Retaj|R|;Alshammari|Turki|T|;Hakami|Riyadh|R|;Husain|Sufia|S|;Bin Traiki|Thamer|T|",
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"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n33974618\n10.12659/AJCR.930439\n930439\nArticles\nColorectal Schistosomiasis Infection After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Metastatic Colon Adenocarcinoma: A Case Report\nAlShammari Sulaiman AD1\nAlmajed Ashwaq BC1\nAlkhawaja Retaj E1\nAlshammari Turki B1\nHakami Riyadh F1\nHusain Sufia BC2\nTraiki Thamer Bin F1\n1 Department of Surgery, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia\n2 Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia\nCorresponding Author: Sulaiman Alshammari, e-mail: dr.sulimaan@gmail.com\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nSource of support: Deanship of Scientific Research, King Saud University, through the Vice Deanship of Scientific Research Chairs\n\n2021\n11 5 2021\n22 e930439-1e930439-5\n12 12 2020\n05 3 2021\n11 4 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Female, 53-year-old\n\nFinal Diagnosis: Schistosomiasis colitis\n\nSymptoms: Intolerable anal pain • rectal bleeding\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Oncology • Surgery\n\nObjective:\n\nRare co-existance of disease or pathology\n\nBackground:\n\nColorectal cancer is one of the most common cancers in men and women worldwide. There are several studies showing an association between chronic schistosomiasis infection and colorectal cancer.\n\nCase Report:\n\nA 53-year-old woman presented with recurrent metastatic colon cancer involving the peritoneum and bilateral adnexa. The patient then underwent exploratory laparotomy that involved abdominal wall deposit resection, omentectomy, redo left hemicolectomy, peritonectomy, diaphragmatic stripping, and total abdominal hysterectomy with bilateral salpingectomy-oophorectomy, as well as hyperthermic intraperitoneal chemotherapy (HIPEC). She also underwent adjuvant chemotherapy, but on her 6th cycle, the patient suffered intolerable anal pain, diarrhea, and rectal bleeding. Her colonoscopy showed extended circumferential inflammation with loses of vascular pattern and a few rectal ulcers going up to the anastomosis site. Biopsy revealed Schistosoma mansoni eggs and marked ischemic changes. She was then managed with a single dose of Praziquantel.\n\nConclusions:\n\nColorectal schistosomiasis infection is a rare cause of such common presentations especially in postoperative settings in a patient with recurrent metastatic colon cancer. The use of multimodality investigations and high clinical suspicion were needed for the diagnosis and to exclude other common etiologies.\n\nKeywords:\n\nColonic Neoplasms\nSchistosomiasis\nSchistosomiasis mansoni\n==== Body\nBackground\n\nSchistosomiasis is a tropical parasitic disease affecting more than 240 million people globally, more endemic in tropical and subtropical areas with poor hygiene [1]. Schistosomiasis disease is more endemic in certain geographic areas depending on the species subtypes: the S. mansoni species is mainly found in the sub-Saharan African region and North America, the S. japonicum species is found in southeastern and eastern Asia including China, and the S. haematobium group is seen in Africa, Indian Ocean Islands, the Arabian Peninsula including Saudi Arabia, and Mediterranean regions [2]. There are several old studies suggesting that chronic intestinal schistosomiasis infection has etiological association with colorectal cancer [3]. However, different studies showed a lack of causal relationship between schistosomiasis infection and colorectal cancer [4]. In this case report, we present the first case of colorectal schistosomiasis infection in postoperative cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for a patient with recurrent colorectal adenocarcinoma.\n\nCase Report\n\nA 53-year-old woman presented with a history of sigmoid cancer, which was managed with surgical resection and adjuvant chemotherapy. One year later, she was referred to our hospital with findings of recurrence on computerized tomography (CT) scan.\n\nA full work-up was repeated for her, including tumor markers, colonoscopy, and CT chest, abdomen, and pelvis. Carcinoembryonic antigen (CEA) was high, with a level of 1225 ng/mL. Apart from internal hemorrhoids, colonoscopy reported unremarkable study with normal stapler line. CT abdomen showed bilateral adnexal masses inseparable from the uterus with multiple peritoneal soft tissue nodularities. CT chest reported unremarkable study. The case was discussed in the Tumor Board and the plan was to proceed with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).\n\nThe patient underwent exploration laparotomy, abdominal wall deposit resection, omentectomy, redo left hemicolectomy, peritonectomy, diaphragmatic stripping, and total abdominal hysterectomy with bilateral salpingectomy-oophorectomy. After completion of CRS, HIPEC with oxaliplatin-based protocol for 30 minutes was done. The postoperative course was smooth with no complications except for reactivation of herpes labialis in the left upper lip, managed conservatively. She was discharged on day 14 in a stable condition.\n\nThe surgical pathology report was positive for recurrence at sigmoid and anastomosis site with moderately differentiated invasive adenocarcinoma. The omentum was positive for multiple nodules showing metastases; the largest was 3 cm. The ovaries and fallopian tubes showed metastatic moderately differentiated adenocarcinoma of colonic origin. A diaphragm nodule was positive for metastatic adenocarcinoma. An abdominal wall lesion showed metastatic adenocarcinoma. A pyloric lesion was positive for metastatic adenocarcinoma with focal necrosis. The lesser curvature and portal hepatic lymph nodes were positive for metastatic adenocarcinoma.\n\nThe case was discussed in the Tumor Board with a plan to proceed with 8 cycles of oxaliplatin and capecitabin (XELOX) adjuvant chemotherapy. The patient was originally from a rural area in a southern province, with exposure to fresh water and soil. She came regularly for her chemotherapy sessions, but after the 6th cycle, she was very keen to stop because she started complaining of intolerable anal pain with defecation, diarrhea, and minimal amounts of bright red PR bleeding. On examination, there was an ulcerated left lateral pile. A full work-up was performed, including CEA, colonoscopy, and CT abdomen, with local conservative management of the anal fissure. CEA was unremarkable. CT abdomen showed interval decrease of the rectal wall diffuse mural thickening suggestive of infectious/inflammatory changes (Figure 1). Colonoscopy showed extended circumferential inflammation with loses of vascular pattern as well as a few rectal ulcers up to the anastomosis site. The proximal 10 cm of area of inflammation was significantly narrowed but not obstructed (Figure 2). Multiple biopsies were taken, which showed Schistosoma mansoni eggs and marked ischemic changes with regenerative atypia (Figure 3). These findings reflect schistosomiasis of the large intestine. In addition, the rectal mucosa showed features suggestive of mild chronic ischemic injury in the form of patchy mildly atrophic (“drop out”) glands, reduction in goblet cells, mild hyalinization of the lamina propria, minimal chronic inflammation, mild edema, and extravasated red blood cells. There was no dysplasia or invasive carcinoma seen. The patient was managed with a single dose of Praziquantel 600 mg with follow-up 1 week after. All her symptoms were completely resolved. She was arranged for a follow-up colonoscopy, which kept getting postponed until months after. Results revealed normal mucosa with no pathologies in the terminal ileum, anastomosis site, or rectum.\n\nDiscussion\n\nColorectal cancer is the third most common cancer in men and the second most common cancer in women worldwide [5]. According to the American Cancer Society, colorectal cancer is the third leading cause of cancer deaths in men and women in the United States [6]. In Saudi Arabia, colorectal cancer is the first most common cancer among men and the third most common cancer among women, with the estimated incidence of 12.2%, which represents 1465 newly diagnosed cases in the 2015 report by the Saudi Cancer Registry [7].\n\nSchistosomiasis is a parasitic disease caused by parasitic flatworms of the genus Schistosomes [8]. There are 3 major schistosomes infecting humans: Schistosoma mansoni and S. japonicum, primarily affecting the intestine and liver, and S. haematobium, which affects the bladder and urogenital system [8.] Many studies reported a possible link between colonic schistosomiasis and colorectal cancer, and a study in China showed that out of 179 schistosomiasis infection patients, 32 had colorectal cancer [9]. Moreover, many studies reported a link between Schistosoma japonicum in developing colorectal cancer more than for S. mansoni [10,11]. A few cases were reported of colorectal cancer with S. mansoni, but a clear link was not yet established, and they reported that more studies are needed [3,12]. A study investigating the pathogenesis in developing colorectal cancer in patients with schistosomiasis infection showed that the chronic inflammation, immunomodulation, Schistosoma toxins, and bacterial coinfection may have a major role in the pathogenesis [10].\n\nAcute schistosomiasis typically presents with a sudden onset of fever, malaise, myalgia, headache, eosinophilia, fatigue, and abdominal pain lasting 2–10 weeks [8]. Over time the granulomatous response to eggs is downregulated through several mechanisms, leading to the chronic intestinal manifestation, which includes intermittent abdominal pain, diarrhea, and rectal bleeding [8]. The frequency of these symptoms depends on the intensity of infection. These gastrointestinal features are often present with focal isolated mucosal hyperplasia, pseudopolyposis, and polyposis [8]. More severe forms of intestinal schistosomiasis present extensive fibrosis and subsequent hepatosplenic disease with periportal fibrosis [8]. Clinical features include upper-abdominal discomfort with palpable nodular and hepatosplenomegaly [8]. As a consequence, severe cases might present with the complication of portal hypertension, which can include ascites and hematemesis from esophageal varices, which can rapidly lead to death [8].\n\nSchistosomiasis infection can be difficult to diagnose, as previous studies showed that many cases were misdiagnosed as ulcerative colitis, Crohn’s disease, ischemic colitis, and irritable bowel syndrome [13,14]. Many studies concluded that clinical manifestations and endoscopy are insufficient for the diagnosis for schistosomiasis infection, as it shows non-specific features, and multiple biopsies are needed to confirm the diagnosis by the pathological features. Furthermore, they emphasized the importance of follow-up by colonoscopy, as they are at high risk of developing colorectal cancer [9,13,14]. The endoscopic features of schistosomes that were reported in the literature were divided into acute colitis, chronic colitis, and mixed type. In the acute colitis type the mucosa is congested and edematous, while in chronic colitis type the mucosa is hypertrophied with scarring [9,13,14]. Regarding the pathological features, all cases had schistosome ovum deposited in the lamina propria; the ova nodules of acute colitis consisted of one or multiple central ova surrounded by eosinocytes, in contrast to chronic colitis, where the ova are ruptured, calcified, and surrounded by lymphocytes [13,14].\n\nThe challenge in our case was the wide differential diagnosis, including postoperative complications, recurrence of primary disease, and adverse effects of chemotherapy, which are more common than schistosomiasis infection. Therefore, colonoscopy and biopsy were crucial to reach the diagnosis. Schistosomiasis infection is mainly treated medically by Praziquantel, which is the drug of choice for all Schistosoma species [8]. However, some severe cases need to be treated surgically, including extreme degrees of portal hypertension, which needs shunting, esophageal varices bleeding, and urinary tract or intestinal obstruction [15].\n\nThere were many cases reported in the literature of schistosomiasis infection found in patients with colorectal cancer at the time of diagnosis [9,13,14]. However, in our case schistosomiasis infection was found postoperatively after CRS and HIPEC, which was more challenging to diagnose. Moreover, being immune-compromised, especially after chemotherapy, as in our case, might have a role in making her more susceptible to schistosomiasis infection. The patient was managed medically with a single dose of Praziquantel 600 mg.\n\nConclusions\n\nColorectal schistosomiasis infection is a rare cause of such a common presentation. Although there are many cases published with patients having the parasitic infection at the time of diagnosis, schistosomiasis infection can occur postoperatively, as in our case. The high clinical suspicion of parasitic infection and the use of multimodality investigations is needed for the diagnosis in the presence of other common differential etiologies for postoperative patients.\n\nFigure 1. CT scan showed rectum is slightly collapsed with interval decrease of the rectal wall diffuse mural thickening suggestive of infectious/inflammatory changes. (A) Axial view and (B) sagittal view.\n\nFigure 2. Colonoscopy findings showed (A) circumferential inflammation with loses of vascular pattern (B) significant narrowing with few rectal ulcers.\n\nFigure 3. (A–D) Photomicrographs from a colonoscopic rectal biopsy shows several Schistosoma eggs (arrows) embedded in the lamina propria of the rectal mucosa. The Schistosoma eggs are yellowish brown, elongated to ovoid with a refractile shell. The large eccentric lateral spine projecting near one end (arrowhead) is a characteristic feature of a Schistosoma mansoni eggs. In addition, the rectal mucosa shows mild hyalinization of the lamina propria with mild chronic inflammation, edema, and extravasated red blood cells. There is no dysplasia or invasive carcinoma seen. This biopsy was diagnosed as schistosomiasis of the large intestine in which the location and histomorphology of the eggs are consistent with Schistosoma mansoni infection (hematoxylin and eosin stain, original magnification ×100, ×200, ×400, and ×600, respectively).\n==== Refs\nReferences:\n\n1. Schistosomiasis (Bilharzia) [Internet] Who.int 2020 [cited 4 December 2020]. https://www.who.int/health-topics/schistosomiasis#tab=tab_3\n2. Jamieson BGM Schistosoma: Biology, pathology and control CRC Press Boca Raton, FL 2017\n3. H Salim OE Hamid HK Mekki SO Colorectal carcinoma associated with schistosomiasis: A possible causal relationship World J Surg Oncol 2010 8 68 20704754\n4. Darre T Djiwa T Dare S Difficult causality relationship between colorectal cancer and schistosomiasis Pathol Oncol Res 2020 26 1 597 98 30604273\n5. Colorectal cancer statistics [Internet] World Cancer Research Fund 2018 [cited 4 December 2020]. https://www.wcrf.org/dietandcancer/cancer-trends/colorectal-cancer-statistics\n6. Colorectal Cancer Statistics | How Common Is Colorectal Cancer? [Internet] Cancer.org 2020 [cited 4 December 2020]. https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html\n7. Cancer Incidence Report Saudi Arabia 2015 [Internet] Nhic.gov.sa 2018 [cited 4 December 2020]. https://nhic.gov.sa/eServices/Documents/E%20SCR%20final%206%20NOV.pdf\n8. Colley DG Bustinduy AL Secor WE King CH Human schistosomiasis Lancet 2014 383 9936 2253 64 24698483\n9. Liu W Zeng HZ Wang QM Schistosomiasis combined with colorectal carcinoma diagnosed based on endoscopic findings and clinicopathological characteristics: A report on 32 cases Asian Pac J Cancer Prev 2013 14 8 4839 42 24083755\n10. Hamid HKS Schistosoma japonicum – associated colorectal cancer: A review Am J Trop Med Hyg 2019 100 3 501 5 30560774\n11. Matsuda K Masaki T Ishii S Possible associations of rectal carcinoma with Schistosoma japonicum infection and membranous nephropathy: A case report with a review Jpn J Clin Oncol 1999 29 11 576 81 10678562\n12. Herman AM Kishe A Babu H Colorectal cancer in a patient with intestinal schistosomiasis: A case report from Kilimanjaro Christian Medical Center Northern Zone Tanzania World J Surg Oncol 2017 15 1 146 28768520\n13. Cao J Liu WJ Xu XY Zou XP Endoscopic findings and clinicopathologic characteristics of colonic schistosomiasis: A report of 46 cases World J Gastroenterol 2010 16 6 723 27 20135720\n14. Ye C Tan S Jiang L Endoscopic characteristics and causes of misdiagnosis of intestinal schistosomiasis Mol Med Rep 2013 8 4 1089 93 23969514\n15. Barsoum RS Esmat G El-Baz T Human schistosomiasis: clinical perspective: Review J Adv Res 2013 4 5 433 44 25685450\n\n",
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"abstract": "Statin treatment has been associated with necrotizing autoimmune myopathy and has been linked to myasthenia gravis. We present an unprecedented clinical challenge with both disorders occurring in a patient treated with statins few months earlier.",
"affiliations": "Department of Neurology AULSS 6 Euganea Cittadella Hospital Padua Italy.;Department of Neurology AULSS 6 Euganea Cittadella Hospital Padua Italy.;Section of Clinical Neurology Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy.;Department of Neurology AULSS 6 Euganea Cittadella Hospital Padua Italy.;Department of Neurology AULSS 6 Euganea Cittadella Hospital Padua Italy.;Department of Neurology AULSS 6 Euganea Cittadella Hospital Padua Italy.;Department of Neurology AULSS 6 Euganea Cittadella Hospital Padua Italy.;Department of Neurology AULSS 6 Euganea Cittadella Hospital Padua Italy.;Section of Clinical Neurology Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy.",
"authors": "Frasson|Emma|E|https://orcid.org/0000-0002-0134-1144;Simonetto|Marco|M|;Bertolasi|Laura|L|;Caneve|Giorgio|G|;Vilotti|Cristina|C|;Ruzza|Giampietro|G|;Perelli|Anna|A|;Piccinno|Maria Grazia|MG|;Monaco|Salvatore|S|",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.3925\nCCR33925\nCase Report\nCase Reports\nStatin‐associated necrotizing autoimmune myopathy with concurrent myasthenia gravis\nFRASSON et al.\nFrasson Emma https://orcid.org/0000-0002-0134-1144\n1 emma.frasson@aulss6.veneto.it\n\nSimonetto Marco 1\nBertolasi Laura 2\nCaneve Giorgio 1\nVilotti Cristina 1\nRuzza Giampietro 1\nPerelli Anna 1\nPiccinno Maria Grazia 1\nMonaco Salvatore 2\n1 Department of Neurology AULSS 6 Euganea Cittadella Hospital Padua Italy\n2 Section of Clinical Neurology Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy\n* Correspondence\nEmma Frasson, Department of Neurology, AULSS 6 Euganea, Via Casa di Ricovero, 40, 35013 Cittadella, Padua, Italy.\nEmail: emma.frasson@aulss6.veneto.it\n\n28 3 2021\n5 2021\n9 5 10.1002/ccr3.v9.5 e0392526 12 2020\n01 10 2020\n17 1 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nStatin treatment has been associated with necrotizing autoimmune myopathy and has been linked to myasthenia gravis. We present an unprecedented clinical challenge with both disorders occurring in a patient treated with statins few months earlier.\n\nStatin treatment has been associated with necrotizing autoimmune myopathy and has been linked to myasthenia gravis. We present an unprecedented clinical challenge with both disorders occurring in a patient treated with statins few months earlier.\n\nautoimmune disease\nmyasthenia gravis\nnecrotizing autoimmune myopathy\nstatins\nsource-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:13.05.2021\nFrasson E , Simonetto M , Bertolasi L , et al. Statin‐associated necrotizing autoimmune myopathy with concurrent myasthenia gravis. Clin Case Rep. 2021;9 :e03925. 10.1002/ccr3.3925\n==== Body\n1 INTRODUCTION\n\nStatins are commonly prescribed for atherosclerotic disease, and although generally safe, their use has been associated with serious muscular involvement. 1 The spectrum of statin‐associated neuromuscular involvement ranges from myalgia with increase of creatine kinase (CK), to severe conditions including necrotizing autoimmune myopathy (NAM), and less commonly, myasthenia gravis (MG). 1 , 2 , 3\n\nSerum myositis‐specific autoantibodies associated with NAM include anti‐3‐hydroxy‐3‐methylglutarylcoenzyme‐A reductase (HMGCR) and antisignal recognition particle (SRP). 4 Anti‐HMGCR myopathy is characterized by severe, rapidly progressive proximal muscle weakness along with dysphagia in 16%‐30% of the patients, and elevated serum CK levels. 5 , 6 Muscle biopsy shows necrosis with scarce or no inflammation. In most patients with a history of statin exposure, symptoms do not resolve after withdrawing the drug, and only a prompt immunosuppressive treatment leads to clinical improvement. 4 , 7\n\nWhile lines of evidences suggest a causal relationship between NAM and statin intake, MG is not currently included among adverse drug reactions to statins and in a disproportionality analysis of nearly 4,000 reports mentioning MG, a weak potential signal was found linking statins and MG. 8 On the other hand, there have been a number of literature and postmarketing pharmacovigilance reports suggesting that statins may induce, unmask or exacerbate ocular or generalized MG, either seropositive or seronegative for antibodies against acetylcholine receptors (AchR). 3 , 9 , 10 , 11 , 12 , 13 , 14\n\nWe report on a patient treated with statin and ezetimibe who developed NAM and generalized MG which responded favorably to immunosuppressive therapy.\n\n2 CASE REPORT\n\nA 65‐year‐old male complained of progressive lower limb weakness and calf muscle pain. No autoimmune or hereditary neuromuscular diseases were referred. His medical history was remarkable for arterial hypertension, mild carotid atherosclerosis, subclinical hypothyroidism, and hyperlipidemia. Eight months before admission the patient had an acute myocardial infarct for which percutaneous transluminal coronary angioplasty with placement of two stents in main coronary arteries was performed. Medical therapy at discharge included ramipril, bisoprolol, ticagrelor, aspirin, and high‐intensity statin treatment with 80 mg atorvastatin. Six months later atorvastatin was switched to rosuvastatin/ezetimibe 20 mg/10 mg combination therapy because the patient reported mild weakness and fatigue. The treatment with rosuvastatin/ezetimibe was discontinued 2 weeks prior to admission because of worsening weakness and increased serum CK level (12 309 IU/L; reference range <223 IU/L).\n\nOn admission, 3 months after the onset of symptoms, the patient complained of easy fatigability and difficulties in getting up from a chair and walking; his muscle strength was symmetrically reduced at proximal (3/5 by MRC) and distal (4/5 by MRC) segments of all limbs; arm and thigh muscles were hypotrophic. The patient had mild facial and palatal weakness, severe dysphonia, and dysphagia. Sensation and deep tendon reflexes were normal. Severity of weakness fluctuated during the day being worse at evening. During hospitalization, the patient developed dyspnea at rest with decreased oxygen saturation values of 90% in room air.\n\nSerum CK was 32 000 IU/L, AST 950 IU/L (reference range: 5‐38 IU/L), ALT 655 IU/L (reference range 5‐41 IU/L), LDH 1100 (reference: <248 IU/L). Anti‐AchR turned out to be increased to 8.9 nmol/L (NV < 0.5), and anti‐HMGCR antibody titer was 255.2 IU/mL (reference range, <19 IU/mL). ANA, anti‐ds‐DNA, anti‐SSA, and anti‐SSB were negative. Among myositis‐associated autoantibodies, a moderate positivity for anti‐Ro‐52 was detected by immunoblotting. Extensive electrodiagnostic investigations, including bilateral median, ulnar, radial, peroneal, and tibial motor‐conduction studies and median, ulnar, radial, and sural sensory‐conduction studies, were normal. Needle electromyography (EMG) studies showed a myopathic pattern on voluntary recruitment with abnormal spontaneous activity in proximal limb muscles, including trapezius, deltoid, biceps, and vastus lateralis. Single‐fiber EMG (SF‐EMG) performed during voluntary contraction of the extensor digitorum communis at 20 recording sites showed a mean jitter of 65.5 ± 40.2 µs (range 39.7‐196 µs), in the presence of blockings.\n\nA lower limb MRI revealed asymmetric edema and atrophy of proximal and distal thigh muscles (Figure 1). A left vastus lateralis muscle biopsy showed slight variation in fiber caliber, with few atrophic fibers, randomly distributed necrotic myofibers, either hyalinized or myophagocytic, and rare basophilic fibers, but not inflammatory infiltrates. Echocardiogram and total body CT scan were normal.\n\nFIGURE 1 Muscle MRI of lower limbs. Coronal T1‐weighted images (A) reveal muscle atrophy and hyperintensity reflecting connective tissue and fatty replacement (arrows). Coronal short‐tau inversion recovery (STIR) sequences (B) show edema and asymmetrically increased signals in muscle compartments (arrows). Axial T2‐weighted sequences show atrophy in proximal (C) and in the distal (D) thigh muscles. (semimembranosus = SM). PEC, denotes pectineus, PSOAS, ileopsoas, ADB, adductor brevis, OE, obturator externus, and OI, obturator internus\n\nThe patient was treated with IVIg (0.4 g/kg die) for 5 days, prednisone 1 mg/kg, and azathioprine 100 mg/die. After 8 days, azathioprine was discontinued because the patient had a diffuse rash, and intramuscular injections of methotrexate 15 mg/week were given; in addition, piridostigmine at a dose of 30 mg three times a day was started.\n\nThe patient gradually improved and after 4 months of treatment, he could walk and feed unaided. CK was 241 IU/L, anti‐HMGCR 25 IU/mL, and anti‐AchR 9.3 nmol/L. A repeated EMG recorded a myopathic pattern without denervation. Six months later, prednisone was tapered to 15 mg/die and methotrexate to 10 mg/week because of persistent improvement of symptoms.\n\n3 DISCUSSION\n\nTo our knowledge, this is the first reported patient with statin‐associated NAM with anti‐HMGCR IgG occurring concomitantly with anti‐AchR seropositive MG.\n\nAs reported in previous cases, the duration of statin exposure before the onset of NAM ranges from few months to 2 years, and the course of the disease is remarkably varied, usually within months and years. 15 In addition, while the majority of patients with NAM require immunosuppressive and/or immunomodulatory medications, subjects with mild weakness may have spontaneous remission. The latter evolution is at variance with the disappearance of minor symptoms, such as myalgias and cramps, which cease a few weeks after discontinuation of statins. 15\n\nThe variability in clinical presentation and outcome suggests that immune‐mediated muscle injury and reversible statin myotoxicity might contribute to varying degrees of perceived and objective weakness in a given patient, and also provides an explanation for the persistence of muscular involvement months after statin withdrawal. In the present case, all clinical and paraclinical features observed at disease onset and evolution are consistent with statin‐associated NAM, but not myotoxicity.\n\nHowever, in our patient distinctive clinical features, such as fatigable and fluctuating muscle weakness, dysphonia, facial and palatal weakness, dysphagia, and respiratory distress, suggested a coexistent dysfunction of the neuromuscular junction. Indeed, beside the occurrence of dysphagia occurring in 16%‐30% of patients with NAM, 4 only one patient with facial weakness has been reported in revised case series, while there is no consistent evidence of respiratory involvement. 16 The clinical suspicion of MG was further supported by neurophysiological and serological findings. In our case, the possibility of a subclinical form of MG exacerbated by statin treatment is not consistent with previous observations reporting MG worsening within 1‐16 weeks of statin treatment. 17 On the contrary, in statin‐associated MG the time interval from the initiation of statins to the onset of MG ranges from 6 months to 6 years. 13 The most likely hypothesis to account for the coexistence of both NAM and MG in our patient is based on the immunomodulatory effects of statins, 5 , 18 which may trigger an increased immunogenicity to neuromuscular peptides in subjects with distinctive HLA haplotypes. These drugs are recognized to induce other autoimmune disorders such as a lupus‐like syndrome, myositis, and immune hepatitis. 19 The mechanisms underlying the production of antibodies to HMGCR and AchR, in addition to anti‐Ro‐52, are unknown, although autoimmunity could be driven by drug‐induced loss of immune tolerance.\n\nTimely immunosuppressive treatment in statin‐exposed patients usually leads to muscle strength improvement and decrease in anti‐HMGCR and CK levels, as we observed in our patient. 1 This is keeping with previous observations showing a strict correlation among anti‐HMGCR titer, CK level, and muscle weakness. 4 Notably, in refractory cases or in patients receiving delayed treatment, accelerated muscle atrophy represents the major contributor to long‐term disability. 7\n\nIn conclusion, clinicians should be alerted to the possible association between statin exposure and incident NAM/MG in order to discontinue the drug and promptly begin an immunosuppressive treatment.\n\nCONFLICT OF INTEREST\n\nNone of the authors has potential conflicts of interest to be disclosed.\n\nAUTHOR CONTRIBUTIONS\n\nEF: collected the information and drafted the manuscript. MS: contributed in writing the paper and preparing images. LB: contributed in designing the paper. GC: was in charge of the patient's treatment plan. CV, GR, AP, and MGP: involved in responsible for the treatment of the patient and reviewed the case. SM: contributed in writing and designing the paper and approved the final version of the manuscript.\n\nETHICAL APPROVAL\n\nWe all authors confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Patient's written informed consent to publication was obtained.\n\nACKNOWLEDGMENTS\n\nThe authors thank Dr Paola Tonin for helpful suggestions.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to their containing information that could compromise the privacy of the patient.\n==== Refs\nREFERENCES\n\n1 Mammen AL . Statin‐Associated Autoimmune Myopathy. N Engl J Med. 2016;374 :664‐669.26886523\n2 Du Souich P , Roederer G , Dufour B . Myotoxicity of statins: Mechanism of action. Pharmacol Ther. 2017;175 :1‐16.28223230\n3 Khalid R , Ibad A , Thompson PD . Statins and myasthenia gravis. Muscle Nerve. 2016;54 :509.\n4 Mohassel P , Mammen AL . Anti‐HMGCR myopathy. J Neuromuscul Dis. 2018;5 :11‐20.29480216\n5 Yongchairat K , Tanboon J , Waisayarat J , et al. Clinical spectrums and outcomes of necrotizing autoimmune myopathy versus other idiopathic inflammatory myopathies: a multicenter case‐control study. Clin Rheumatol. 2019;38 :3459‐3469.31446540\n6 Allenbach Y , Mammen AL , Benveniste O , Stenzel W , Immune‐Mediated Necrotizing Myopathies Working Group . 224th ENMC International Workshop: Clinico‐sero‐pathological classification of immune‐mediated necrotizing myopathies. Zandvoort, The Netherlands, 14‐16 October 2016. Neuromuscul Disord. 2018;28 :87‐99.29221629\n7 Rudski L , Rabinovitch MA , Danoff D . Systemic immune reactions to HMG‐CoA reductase inhibitors. Report of 4 cases and review of the literature. Medicine (Baltimore). 1998;77 :378‐383.9854600\n8 Gras‐Champel V , Batteux B , Masmoudi K , Liabeuf S . Statin‐induced myasthenia: a disproportionality analysis of the WHO's VigiBase pharmacovigilance database. Muscle Nerve. 2019;60 :382‐386.31298743\n9 Parmar B , Francis PJ , Ragge NK . Statins, fibrates, and ocular myasthenia. Lancet. 2002;360 :717.\n10 Cartwright MS , Jeffery DR , Nuss GR , Donofrio PD . Statin‐associated exacerbation of myasthenia gravis. Neurology. 2004;63 :2188.\n11 Keogh MJ , Findlay JM , Leach S , Bowen J . Statin‐associated weakness in myasthenia gravis: a case report. J Med Case Rep. 2010;4 :61.20170525\n12 Gale J , Danesh‐Meyer HV . Statins can induce myasthenia gravis. J Clin Neurosci. 2014;21 :195‐197.24433954\n13 Purvin V , Kawasaki A , Smith KH , Kesler A . Statin‐associated myasthenia gravis: report of 4 cases and review of the literature. Medicine (Baltimore). 2006;85 :82‐85.16609346\n14 Negevesky GJ , Kolsky MP , Laureno R , Yau TH . Reversible atorvastatin‐associated external ophthalmoplegia, anti‐acetylcholinereceptor antibodies, and ataxia. Arch Ophthalmol. 2000;118 :427‐428.10721974\n15 Ramanathan S , Langguth D , Hardy TA , et al. Clinical course and treatment of anti‐HMGCR antibody‐associated necrotizing autoimmune myopathy. Neurol Neuroimmunol Neuroinflamm. 2015;2 (3 ):e96.25866831\n16 Watanabe Y , Uruha A , Suzuki S , et al. Clinical features and prognosis in anti SRP andanti‐HMGCR necrotising myopathy. J Neurol Neurosur Psychiatry. 2016;87 :1038‐1044.\n17 Oh SJ , Dhall R , Young A , Morgan MB , Lu L , Claussen GC . Statins may aggravate myasthenia gravis. Muscle Nerve. 2008;38 :1101‐1107.18720508\n18 Loganathan P , Oddis CV , Aggarwal R . Immune‐mediated statin myopathy. Expert Rev Clin Immunol. 2016;12 :33‐38.26515829\n19 Dehnavi S , Sohrabi N , Sadeghi M , et al. Statins and autoimmunity: State‐of‐the‐art. Pharmacol Ther. 2020;214 :1076.\n\n",
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{
"abstract": "Incidents of new-onset vitiligo attributed to infliximab therapy for rheumatoid arthritis and ulcerative colitis have been reported. Reported cases share a common theme in that symptoms manifested in close proximity to the initiation or significant dose increase of the medication. This case describes the presentation of infliximab-induced vitiligo in a patient using it for long-term treatment of stable pityriasis rubra pilaris. The patient was initiated and titrated to a stable dose of infliximab totaling 27 months' duration. He was able to achieve near-complete resolution of symptoms before developing depigmented patches consistent with vitiligo. Infliximab was discontinued. Tacrolimus 0.1% ointment and narrow-band ultraviolet B light successfully repigmented the patches. The association of discontinuing infliximab and resolution of vitiligo suggests infliximab had a role in this case. Though the mechanism of involvement is undetermined, infliximab may have induced an autoimmune process by paradoxically activating lymphocytes. Alternatively, infliximab antibodies may have led to the process by disrupting the normal balance of cytokines.",
"affiliations": "Department of Dermatology, Saint Louis University School of Medicine, St. Louis, MO, USA. amattox@slu.edu",
"authors": "Mattox|Adam R|AR|;Chappell|Jeaneen A|JA|;Hurley|M Yadira|MY|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D000069285:Infliximab; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "1545-9616",
"issue": "12(2)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D003924:Diabetes Mellitus, Type 2; D006073:Gout; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D010916:Pityriasis Rubra Pilaris; D016559:Tacrolimus; D014467:Ultraviolet Therapy; D014820:Vitiligo",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "217-9",
"pmc": null,
"pmid": "23377397",
"pubdate": "2013-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "New-onset vitiligo during long-term, stable infliximab treatment of pityriasis rubra pilaris.",
"title_normalized": "new onset vitiligo during long term stable infliximab treatment of pityriasis rubra pilaris"
} | [
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "50 TO 1000 MG",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "METFORMIN AND SITAGLIPTIN"
}
],
"patientagegroup": "5",
"patientonsetage": "60",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective for unapproved indication",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MATTOX AR, CHAPPELL JA, HURLEY MY. NEW-ONSET VITILIGO DURING LONG-TERM, STABLE INFLIXIMAB TREATMENT OF PITYRIASIS RUBRA PILARIS. JOURNAL OF DRUGS IN DERMATOLOGY FEB-2013;12/2:217-219.",
"literaturereference_normalized": "new onset vitiligo during long term stable infliximab treatment of pityriasis rubra pilaris",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150525",
"receivedate": "20150321",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10947212,
"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": "OBJECTIVE\nTo investigate the effect of the addition of bone morphogenetic protein 2 (BMP-2) to leukocyte-rich and platelet-rich fibrin (L-PRF) on the treatment of medication-related osteonecrosis of the jaws (MRONJ), this study compared the healing outcome of combined use of BMP-2 and L-PRF with single use of L-PRF.\n\n\nMETHODS\nOf 55 patients who were diagnosed with MRONJ, 25 were treated with L-PRF alone and 30 were treated with L-PRF and recombinant human BMP-2. For each patient, surgical sites were evaluated postoperatively at 4 and 16 weeks. Associations between the treatment method and the resolution of MRONJ were analyzed with the adjustment of patient-specific factors that may influence the treatment outcome.\n\n\nRESULTS\nAt 4 and 16 weeks postoperatively, patients with MRONJ who were treated with both L-PRF and BMP-2 showed favorable outcomes with complete resolution of the lesions, which was statistically significant compared with that of the therapy using L-PRF alone (P = .028). Therefore, the additional use of BMP-2 considerably improved MRONJ healing. Among patient-specific factors, the existence of a bacterial colony in the biopsy specimen was a significant factor that negatively affected disease resolution (P = .017).\n\n\nCONCLUSIONS\nThe combined use of BMP-2 and L-PRF leads to the early resolution of MRONJ; thus patients who need to continue antiresorptive therapy may benefit from the combined regimen.",
"affiliations": "Clinical Assistant Professor, Department of Oral and Maxillofacial Surgery, Ewha Womans University, Seoul, Republic of Korea.;Clinical Assistant Professor, Department of Oral and Maxillofacial Surgery, Ewha Womans University, Seoul, Republic of Korea.;Professor, Department of Oral and Maxillofacial Surgery, Ewha Womans University, Seoul, Republic of Korea. Electronic address: oralsurgeonsj@gmail.com.",
"authors": "Park|Jung-Hyun|JH|;Kim|Jin-Woo|JW|;Kim|Sun-Jong|SJ|",
"chemical_list": "D055396:Bone Morphogenetic Protein 2; D005337:Fibrin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.joms.2016.12.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "75(6)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D019072:Antibiotic Prophylaxis; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D001792:Blood Platelets; D055396:Bone Morphogenetic Protein 2; D003131:Combined Modality Therapy; D003777:Dental Prophylaxis; D005260:Female; D005337:Fibrin; D006801:Humans; D007962:Leukocytes; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D014945:Wound Healing",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "1176-1184",
"pmc": null,
"pmid": "28042979",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Does the Addition of Bone Morphogenetic Protein 2 to Platelet-Rich Fibrin Improve Healing After Treatment for Medication-Related Osteonecrosis of the Jaw?",
"title_normalized": "does the addition of bone morphogenetic protein 2 to platelet rich fibrin improve healing after treatment for medication related osteonecrosis of the jaw"
} | [
{
"companynumb": "PHHY2017KR017433",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "021817",
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"drugindication": "OSTEOPOROSIS",
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"medicinalproduct": "ZOLEDRONATE"
}
],
"patientagegroup": null,
"patientonsetage": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Osteonecrosis of jaw",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PARK JH, KIM JW, KIM SJ. DOES THE ADDITION OF BONE MORPHOGENETIC PROTEIN 2 TO PLATELET-RICH FIBRIN IMPROVE HEALING AFTER TREATMENT FOR MEDICATION-RELATED OSTEONECROSIS OF THE JAW?. JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY. 2017;1-9",
"literaturereference_normalized": "does the addition of bone morphogenetic protein 2 to platelet rich fibrin improve healing after treatment for medication related osteonecrosis of the jaw",
"qualification": "3",
"reportercountry": "KR"
},
"primarysourcecountry": "KR",
"receiptdate": "20170207",
"receivedate": "20170207",
"receiver": {
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},
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},
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}
] |
{
"abstract": "Drug re-exposure resulting in Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is a rare phenomenon and has scarcely been reported. With an aging population, polypharmacy, and a lack of a unified electronic medical record, standard recommendations to prevent or minimize the risk of re-exposure are necessary. We identified five patients, with diagnosis confirmed SJS/TEN, and determined the clinical characteristics and contributing risk factors leading to re-exposure. Polypharmacy, multiple prescribers, advanced age, medical illiteracy, retention of discontinued medications and self-prescribing all contributed to re-exposure in this cohort of patients. This case series demonstrates the potentially deadly effect of drug re-exposure, and the need for both streamlined and integrated medication allergy documentation systems.\n\nJ Drugs Dermatol. 2019;18(10):1049-1052.",
"affiliations": null,
"authors": "O’Brien|Kathleen F.|KF|;Saardi|Karl M.|KM|;Johnson|Laura S.|LS|;Shupp|Jeffrey W.|JW|;Rodic|Nemanja|N|;Pasieka|Helena B.|HB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1545-9616",
"issue": "18(10)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008487:Medical History Taking; D059065:Medication Reconciliation; D008875:Middle Aged; D019233:Retreatment; D012307:Risk Factors; D012720:Severity of Illness Index; D013262:Stevens-Johnson Syndrome; D055815:Young Adult",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "1049-1052",
"pmc": null,
"pmid": "31603634",
"pubdate": "2019-10-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Recommendations for Prevention of Drug Re-Exposure in Toxic Epidermal Necrolysis",
"title_normalized": "recommendations for prevention of drug re exposure in toxic epidermal necrolysis"
} | [
{
"companynumb": "US-TEVA-2019-US-1153132",
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"medicinalproduct": "COTRIMOXAZOLE"
},
{
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},
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"drugdosagetext": "SINGLE DOSE UPON RE-EXPOSURE",
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"medicinalproduct": "COTRIMOXAZOLE"
}
],
"patientagegroup": null,
"patientonsetage": "100",
"patientonsetageunit": "801",
"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Pain of skin",
"reactionmeddraversionpt": "22.1",
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},
{
"reactionmeddrapt": "Toxic epidermal necrolysis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash erythematous",
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}
],
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},
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"literaturereference": "O^BRIEN KF, SAARDI KM, JOHNSON LS, SHUPP JW, RODIC N, PASIEKA HB. RECOMMENDATIONS FOR PREVENTION OF DRUG RE-EXPOSURE IN TOXIC EPIDERMAL NECROLYSIS. J-DRUGS-DERMATOL 2019?18(10):1049-1052.",
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"qualification": "3",
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},
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"medicinalproduct": "ARIPIPRAZOLE."
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{
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"medicinalproduct": "CARBAMAZEPINE."
},
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},
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"medicinalproduct": "ARIPIPRAZOLE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXCARBAZEPINE"
},
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"medicinalproduct": "OXCARBAMAZEPINE"
}
],
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"patientonsetage": "21",
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"reaction": [
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stevens-Johnson syndrome",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Toxic epidermal necrolysis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Swelling face",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
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},
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"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
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},
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},
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},
"drugadditional": "3",
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"drugcharacterization": "1",
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"drugdosagetext": "SINGLE DOSE UPON RE-EXPOSURE",
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"medicinalproduct": "COTRIMOXAZOLE"
},
{
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"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
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"drugdosagetext": null,
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"drugindication": "URINARY TRACT INFECTION",
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"medicinalproduct": "COTRIMOXAZOLE"
}
],
"patientagegroup": null,
"patientonsetage": "63",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Toxic epidermal necrolysis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Skin burning sensation",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
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},
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},
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"drugdosagetext": "UNK (2 MONTHS LATER SINGLE DOSE)",
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{
"abstract": "People with schizophrenia and medical comorbidities are often on multiple medications to manage their symptoms. Herein we present a case of drug-drug interaction (meloxicam and desmopressin), in a patient also on clozapine, that ultimately resulted in hyponatremia and seizure.\n\n\n\nThe patient provided consent to have his case published. We searched PubMed and after reviewing 321 articles, 11 were chosen for relevance.\n\n\n\nMeloxicam enhanced the adverse effect (hyponatremia) of desmopressin and was the likely culprit.\n\n\n\nIn a patient with higher ADH levels, as in our patient taking desmopressin, the addition of an NSAID could further increase water retention and worsen hyponatremia; indeed, meloxicam was the only new medication added to the patient's regimen, and a drug interaction calculator supports the desmopressin-meloxicam drug-drug interaction as the culprit. We urge clinicians to avoid the use of desmopressin in patients with schizophrenia as this can lead to water intoxication. As meloxicam may worsen desmopressin-induced hyponatremia and could result in seizure, one should avoid using NSAIDs in patients with schizophrenia whom are also prescribed vasopressin/desmopressin. Serum sodium levels should be closely monitored in patients with schizophrenia whose regimen includes desmopressin.",
"affiliations": "Harvard South Shore Psychiatry Residency Training Program, Brockton, MA, United States; VA Boston Healthcare System, Brockton, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States. Electronic address: Ermal.Bojdani2@va.gov.;Harvard South Shore Psychiatry Residency Training Program, Brockton, MA, United States; VA Boston Healthcare System, Brockton, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States.;Harvard South Shore Psychiatry Residency Training Program, Brockton, MA, United States; VA Boston Healthcare System, Brockton, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States.;Harvard South Shore Psychiatry Residency Training Program, Brockton, MA, United States; VA Boston Healthcare System, Brockton, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States.;VA Boston Healthcare System, Brockton, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States.",
"authors": "Bojdani|Ermal|E|;Chen|Anderson|A|;Buonocore|Stefania|S|;Li|Kevin J|KJ|;Gurrera|Ronald|R|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D050034:Antidiuretic Agents; D003894:Deamino Arginine Vasopressin; D000077239:Meloxicam",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.psychres.2019.05.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-1781",
"issue": "279()",
"journal": "Psychiatry research",
"keywords": null,
"medline_ta": "Psychiatry Res",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D050034:Antidiuretic Agents; D003894:Deamino Arginine Vasopressin; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007010:Hyponatremia; D008297:Male; D000077239:Meloxicam; D008875:Middle Aged",
"nlm_unique_id": "7911385",
"other_id": null,
"pages": "284-286",
"pmc": null,
"pmid": "31084937",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Meloxicam-desmopressin drug-drug interaction producing hyponatremia.",
"title_normalized": "meloxicam desmopressin drug drug interaction producing hyponatremia"
} | [
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"abstract": "Since coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state, especially in critical patients, anticoagulation is used for thromboprophylaxis. Hemorrhagic complications, even uncommon ones such as retroperitoneal hemorrhage, can occur following anticoagulant administration. We present 5 patients with COVID-19 whose clinical course was complicated by spontaneous retroperitoneal hemorrhage. The patients were initially presented with respiratory manifestations of the infection. There was no history or evidence suggestive for traumatic injury. After hospitalization, the patients received supplemental oxygen, antibiotics, enoxaparin or heparin, interferon beta-1b (in three patients), and anticoagulation with subcutaneous injection of enoxaparin (three patients) or heparin (two patients). During the course of hospitalization, the patients showed sudden-onset abdominal pain (three cases), hypotension (three cases), and an acute drop in hemoglobin level. CT scan of the abdomen and pelvis revealed retroperitoneal hemorrhage. For one patient, owing to unstable vital signs and an expanding hematoma, surgical intervention was performed. Others were managed conservatively with discontinuation of anticoagulants, intravenous (IV) fluid resuscitation, and packed red blood cells transfusion. Three patients died due to worsening of the infection and respiratory failure. Retroperitoneal hemorrhage could be a potential complication in COVID-19 patients receiving anticoagulation. Careful monitoring of the vital signs and blood tests like hemoglobin level of such patients is essential.",
"affiliations": "Department of Radiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Radiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Radiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Internal Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Internal Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Radiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Radiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.",
"authors": "Mahboubi-Fooladi|Zahra|Z|https://orcid.org/0000-0002-2489-9263;Pourkarim Arabi|Kowsar|K|https://orcid.org/0000-0002-4248-6163;Khazaei|Mehdi|M|https://orcid.org/0000-0001-7852-7951;Nekooghadam|Sayyedmojtaba|S|;Shadbakht|Bita|B|https://orcid.org/0000-0002-4774-5013;Moharamzad|Yashar|Y|https://orcid.org/0000-0002-5986-3754;Sanei Taheri|Morteza|M|0000-0002-8881-9058",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s42399-021-01006-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2523-8973",
"issue": null,
"journal": "SN comprehensive clinical medicine",
"keywords": "COVID-19; Hemorrhage; Retroperitoneal space; SARS-CoV-2",
"medline_ta": "SN Compr Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101740833",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "34222798",
"pubdate": "2021-06-26",
"publication_types": "D016428:Journal Article",
"references": "32239799;32809158;32915717;32561464;32953290;32838153;32502594;32600997;32655742;33861553;33520659;33353545;32651579;32220112",
"title": "Parenteral Anticoagulation and Retroperitoneal Hemorrhage in COVID-19: Case Report of Five Patients.",
"title_normalized": "parenteral anticoagulation and retroperitoneal hemorrhage in covid 19 case report of five patients"
} | [
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{
"abstract": "This is the first case report of infection with the environmental bacterium Pseudomonas citronellolis, presented here as a urinary tract and bloodstream infection that occurred shortly after a transrectal ultrasound-guided prostate biopsy.",
"affiliations": "Pathology and Laboratory Medicine Service, VA Central Western Massachusetts, Leeds, MA 01053, USA.",
"authors": "Williams|G|G|",
"chemical_list": null,
"country": "England",
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"doi": "10.1016/j.nmni.2019.100531",
"fulltext": "\n==== Front\nNew Microbes New InfectNew Microbes New InfectNew Microbes and New Infections2052-2975Elsevier S2052-2975(19)30027-710.1016/j.nmni.2019.100531100531New Microbes in HumanFirst report of infection with Pseudomonas citronellolis: a case of urosepsis Williams G. glynne.williams@va.gov∗Pathology and Laboratory Medicine Service, VA Central Western Massachusetts, Leeds, MA 01053, USA∗ Corresponding author: G. Williams, Pathology and Laboratory Medicine Service, Veterans Affairs Medical Center, Central Western Massachusetts, 421 North Main Street, Leeds, MA 01053, USA. glynne.williams@va.gov20 3 2019 7 2019 20 3 2019 30 10053120 12 2018 8 3 2019 12 3 2019 © 2019 Published by Elsevier Ltd.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).This is the first case report of infection with the environmental bacterium Pseudomonas citronellolis, presented here as a urinary tract and bloodstream infection that occurred shortly after a transrectal ultrasound-guided prostate biopsy.\n\nKeywords\nBacterial identification methodsciprofloxacin resistantenvironmental bacteriumprostate biopsyPseudomonas citronellolisurosepsis\n==== Body\nCase report\nA 71-year-old male presented to the urgent care clinic at the Veterans Affairs Central Western Massachusetts Medical Center with complaints of dysuria, intermittent bloody urine, lower abdominal pain and chills for 4 days. His temperature was measured at 39.6°C. The patient had a history that included kidney stones, horseshoe kidney, nephrolithiasis, diabetes mellitus, and elevated prostate-specific antigen levels. He had undergone a transrectal ultrasound-guided prostate biopsy 12 days earlier. Symptoms had started 8 days after the biopsy. He had been given perioperative prophylaxis with ciprofloxacin 500 mg tablets twice daily for 3 days. The biopsy had proved negative for malignancy.\n\nClean-catch urine and blood specimens were collected, including two sets of blood cultures. Laboratory results were notable for a complete blood count that included a white blood cell count of 20.6 x 103/μL (normal 4.5–11 x 103/μL) and an absolute neutrophil count of 17.7 x 103/μL (normal 1.8–6.5 x 103/μL). The urinalysis was positive for leukocyte esterase and blood. Microscopic examination showed >50 white and red blood cells/high-power field (HPF) (normal 0–5 cells/HPF).\n\nIt was decided to transfer the patient to a larger Veterans Affairs facility for treatment. In preparation for transport he received a ciprofloxacin/dextrose solution (400 mg intravenously). Upon arrival at the receiving hospital the patient was started empirically on piperacillin–tazobactam and ciprofloxacin IV.\n\nAt our laboratory the urine was inoculated using a 1-μL loop onto sheep-blood and MacConkey agars (BD, Sparks, MD, USA) and incubated in ambient air at 35°C. The blood cultures were analysed in a BacT/Alert instrument (BioMérieux, Durham, NC, USA). After overnight incubation, oxidase-positive colonies grew on plates in numbers that indicated >105 colony-forming units (CFU)/mL urine. The blood cultures were positive for Gram-negative rods in the aerobic bottles of both sets. Upon subculture on sheep blood and MacConkey agars, the colonies had the same morphology as those on the urine culture plates, as expected. The oxidase-positive colonies were large, flat with irregular edges, light grey, and at first appeared to be Pseudomonas aeruginosa.\n\nThe urine isolate was designated NH-138 and the blood isolates NH-125 and NH-126. The three isolates were tested for identification and antibiotic susceptibility with the MicroScan AutoSCAN System (Beckman Coulter, Brea, CA, USA). The results came back as Pseudomonas ‘fluorescens/putida’ with a 95.8% probability. The MicroScan AutoSCAN does not differentiate between Pseudomonas fluorescens and Pseudomonas putida. Along with the identification, the isolates showed susceptibility to piperacillin–tazobactam, ceftriaxone, ceftazidimine, tobramycin, gentamicin, amikacin and tetracycline. The isolates were resistant to aztreonam, ciprofloxacin and trimethoprim–sulfamethoxazole.\n\nThe Clinical and Laboratory Standards Institute (CLSI) document M100 under the section “Minimum Inhibitory Concentration Interpretative Standards (μg/mL) for Other Non-Enterobacteriaceae” was used for antibiotic reporting purposes [1]. When the results were released, the patient's treatment was changed to ceftazidime 1 g intravenously every 8 h. After 14 days of treatment he was discharged from the hospital.\n\nTo help verify the MicroScan AutoSCAN results, NH-126 was sent to a large commercial reference laboratory where it was identified biochemically as Pseudomonas fluorescens. NH-126 was also sent to a nearby community hospital laboratory where it was identified as Pseudomonas fluorescens using a Vitek 2 system. Their report also showed ciprofloxacin resistance.\n\nFurther investigation was warranted because the MicroScan identification included a positive nitrite reaction. Only 5% of Pseudomonas ‘fluorescens/putida’ strains are positive for nitrite in the MicroScan system (personal communication, Beckman Coulter). NH-126 was tested for growth at 42°C on trypticase soy agar slant along with strains of Pseudomonas aeruginosa, Pseudomonas putida and Pseudomonas fluorescens derived from the American Type Culture Collection (ATCC). The clinical isolate grew readily at 42°C, as did Pseudomonas aeruginosa. Pseudomonas putida and Pseudomonas fluorescens did not grow, suggesting that the earlier identifications had been erroneous [2].\n\nIsolate NH-126 was sent for identification to reference labs: MIDI Labs in Newark, Delaware, USA, for matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), and the Culture Collection, University of Göteborg, Sweden (CCUG).\n\nThe CCUG reported an identification of Pseudomonas citronellolis. NH-126 was assigned number CCUG 59066. The identification was reported after extensive phenotypic testing that included cellular fatty acid methyl ester (CFA-FAME) analysis and comparison to their collection of non-fermenters followed by CCUG software analysis.\n\nAt MIDI Labs the isolate was analysed by MALDI-TOF MS (Bruker Biotyper Microflex LT Bruker Daltronics, Billerica, MA, USA). Both Bruker and MIDI libraries were searched. The isolate was identified as P. citronellolis with a score of 2.423 (>2.0 species level). The source of the entry was DSM 50332 THAM, the type strain for Pseudomonas citronellolis. The next closest match was Pseudomonas citronellolis 993700254 LBK, with a score of 2.079. The next result was Pseudomonas jinjuensis with score of 1.841.\n\nFor final confirmation full 16s rRNA gene sequencing was performed at MIDI Labs followed by Sherlock DNA (MIDI) analysis. The closest match of the 1498 base pairs was the Pseudomonas citronellolis type strain with 99.7% sequence homology (Sherlock DNA software (MIDI), www.midi-inc.com). The sequence was submitted to GenBank and was assigned accession number MK404228.\n\nFor comparison, the type strain of Pseudomonas citronellolis was obtained. ATCC 13674T and isolate NH-126 were tested using the MicroScan, and both were identified as Pseudomonas ‘fluorescens/putida’ with essentially the same probabilities and susceptibilities, with one noticeable difference: ATCC 13674T was ciprofloxacin-susceptible. It was resistant to aztreonam and trimethoprim-sulfamethoxazole, as was NH-126.\n\nATCC 13674T (DSM50332) originated from soil under pine trees in northern Virginia, USA, when research was being done concerning the degradation of isoprenoid compounds, such as citronellol, by bacteria. The new species in the genus Pseudomonas was proposed in 1960 [3]. There was a later emended description of Pseudomonas citronellolis\n[4].\n\nA literature search did not reveal any published reports of human infection. Isolates from human sources can be found on the CCUG website (www.ccug.se, 2018) and include one isolate from a human appendix, two from human blood, and one from a rectal sample. Previous reports of Pseudomonas citronellolis susceptibilities were not found for comparison. There have been publications presenting Pseudomonas citronellolis as a possible agent for bioremediation [5], [6].\n\nDiscussion\nIt is unusual for an environmental bacterium such as Pseudomonas citronellolis to cause an infection, in this case involving a prostate biopsy. The CCUG collection contains a rectal isolate. Possibly in this instance the patient's rectum became colonized by Pseudomonas citronellolis due to some contact with soil.\n\nP. citronellolis has likely been overlooked in the past due to its identification as P. putida or P. fluorescens by systems that use phenotypic methods, such as Vitek or MicroScan. With the rapidly expanding use of MALDI-TOF MS in clinical microbiology laboratories it is possible that more human isolates of P. citronellolis will be detected.\n\nIn conclusion, a case of P. citronellolis infection has been presented here. Its presence in both urine and blood suggests it can act as a pathogen.\n\nTransparency declaration\nThe author declares no conflict of interest.\n==== Refs\nReferences\n1 Clinical and Laboratory Standards Institute Performance standards for antimicrobial susceptibility testing. CLSI M100 29th ed. 2018 Clinical Laboratory Standards Institute Wayne ,PA, USA p54 p56 \n2 Henry D.A. Speert D.P. Pseudomonas Jorgensen J.H. Pfaller M.A. Carrol K.C. Funke G. Landry M.L. Richter S.S. Manual of clinical microbiology 11th ed. 2011 ASM Washington, DC 68 \n3 Seubert W. Degradation of isoprenoid compounds by microorganisms I. Pseudomonas citronellolis n. sp. Isolation and characterization of an isoprenoid-degrading bacterium J Bacteriol 79 1960 426 434 14445211 \n4 Lang E. Griese B. Sprӧer C. Schumann P. Steffen M. Verbarg S. Characterization of ‘Pseudomonas azelaica ’ DSM 9128, leading to emended descriptions of Pseudomonas citronellolis Seubert 1960 (Approved Lists 1980) and Pseudomonas nitroreducens lizuka and Komagata 1964 (Approved Lists 1980), including Pseudomonas multiresinivorans as its later heterotypic synonym Int J Syst Evol Microbiol 57 2007 878 882 17392224 \n5 Remus-Emsermann M.N. Schmid M. Gekenidis M.-T. Pelludat C. Frey J.E. Ahrens C.H. Complete genome sequence of Pseudomonas citronellolis P3B5, a candidate for microbial phyllo-remediation of hydrocarbon-contaminated sites Stand Genomic Sci 11 2016 75 28300228 \n6 Zheng D. Wang X. Wang P. Peng W. Ji N. Liang R. Genome Sequence of Pseudomonas citronellolis SJTE-3, an estrogen- and polycyclic aromatic hydrocarbon-degrading bacterium Genome Announc 4 2016 16\n\n",
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"abstract": "BACKGROUND\nCOVID-19 disease may be associated with a wide range of bacterial and fungal infections. We report a patient with COVID-19 infection who developed rhino-facial mucormycosis during treatment with corticosteroids.\n\n\nMETHODS\nA 59-year-old non-diabetic male patient was admitted with a diagnosis of COVID-19 based on positive RT-PCR and CT of the lungs. Due to sever lung involvement, he was treated with methylprednisolone. The patient was re-admitted to hospital, due to nasal obstruction and left side facial and orbital swelling, several days after discharge. In sinus endoscopic surgery, debridement was performed and the specimens were sent to pathology and mycology laboratories. A nasal biopsy showed wide hyphae without septa. The sequenced PCR product revealed Rhizopus oryzae. Despite all medical and surgical treatment, the patient died. In addition, the characteristics of patients with COVID-19-associated mucormycosis were reviewed in 44 available literatures. In most studies, diabetes mellitus was the most common predisposing factor for mucormycosis.\n\n\nCONCLUSIONS\nOur report highlights the need for assessing the presence of mucormycosis in patients with COVID-19 and also it shows that physicians should consider the potential for secondary invasive fungal infections in COVID-19 cases.",
"affiliations": "Department of Medical Parasitology and Mycology, School of Medicine, Qazvin University of Medical Sciences, Shahid Bahonar Blvd, PO Box: 34199-15315, Qazvin, Iran. Faezehmohamadi119@yahoo.com.;Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.;Department of Otolaryngologist, Fellowship of Rhinology, Razi Hospital, Qazvin, Iran.;Department of Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.",
"authors": "Mohammadi|Faezeh|F|http://orcid.org/0000-0002-9822-2626;Badri|Milad|M|http://orcid.org/0000-0002-1860-326X;Safari|Shapoor|S|;Hemmat|Nima|N|",
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"country": "England",
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"doi": "10.1186/s12879-021-06625-3",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334\nBioMed Central London\n\n6625\n10.1186/s12879-021-06625-3\nCase Report\nA case report of rhino-facial mucormycosis in a non-diabetic patient with COVID-19: a systematic review of literature and current update\nhttp://orcid.org/0000-0002-9822-2626\nMohammadi Faezeh Faezehmohamadi119@yahoo.com\n\n1\nhttp://orcid.org/0000-0002-1860-326X\nBadri Milad 25\nSafari Shapoor 3\nHemmat Nima 4\n1 grid.412606.7 0000 0004 0405 433X Department of Medical Parasitology and Mycology, School of Medicine, Qazvin University of Medical Sciences, Shahid Bahonar Blvd, PO Box: 34199-15315, Qazvin, Iran\n2 grid.412606.7 0000 0004 0405 433X Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran\n3 grid.415733.7 Department of Otolaryngologist, Fellowship of Rhinology, Razi Hospital, Qazvin, Iran\n4 grid.412606.7 0000 0004 0405 433X Department of Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran\n5 grid.412606.7 0000 0004 0405 433X Metabolic Diseases Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran\n3 9 2021\n3 9 2021\n2021\n21 9069 3 2021\n27 8 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open 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.\nBackground\n\nCOVID-19 disease may be associated with a wide range of bacterial and fungal infections. We report a patient with COVID-19 infection who developed rhino-facial mucormycosis during treatment with corticosteroids.\n\nCase presentation\n\nA 59-year-old non-diabetic male patient was admitted with a diagnosis of COVID-19 based on positive RT-PCR and CT of the lungs. Due to sever lung involvement, he was treated with methylprednisolone. The patient was re-admitted to hospital, due to nasal obstruction and left side facial and orbital swelling, several days after discharge. In sinus endoscopic surgery, debridement was performed and the specimens were sent to pathology and mycology laboratories. A nasal biopsy showed wide hyphae without septa. The sequenced PCR product revealed Rhizopus oryzae. Despite all medical and surgical treatment, the patient died. In addition, the characteristics of patients with COVID-19-associated mucormycosis were reviewed in 44 available literatures. In most studies, diabetes mellitus was the most common predisposing factor for mucormycosis.\n\nConclusion\n\nOur report highlights the need for assessing the presence of mucormycosis in patients with COVID-19 and also it shows that physicians should consider the potential for secondary invasive fungal infections in COVID-19 cases.\n\nKeywords\n\nCOVID-19\nMucormycosis\nRhizopus oryzae\nhttp://dx.doi.org/10.13039/501100006396 Qazvin University of Medical Sciences IR.QUMS.REC.1399.357 Mohammadi Faezeh issue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nCOVID-19 is a viral disease of the respiratory tract that continues to be a major health issue worldwide. The disease is associated with common symptoms such as fever, dry cough, fatigue, and shortness of breath and sometimes in severe cases, leads to acute respiratory distress syndrome (ARDS) [1]. On the other hand, the use of corticosteroids to modulating lung injury and reduce mortality in COVID-19 patients may be exposes the patient to opportunistic bacterial and fungal infections [2].\n\nInvasive pulmonary aspergillosis is one of the fungal diseases that complicates COVID-19 manifestations [3]. Moreover, mucormycosis as an opportunistic fungal infection can progress rapidly in immunocompromised patients. The most common clinical form of this fungal infection is rhino-cerebral mucormycosis [4]. We reported a case of rhino facial mucormycosis in a 59-year-old non-diabetic male patient with COVID-19 following corticosteroid treatment, which eventually resulted in death.\n\nCase presentation\n\nA 59-year-old non-diabetic male patient without any underlying disease with clinical symptoms of cough, shortness of breath, and oxygen saturation of 76% was admitted to Razi Hospital, Qazvin, Iran. His vital signs included body temperature of 37.6 °C, blood pressure value of 140/85 (mm Hg) and oxygen saturation of 76%. Positive results of chest X-ray test (CXR), computed tomography (CT) scan of lungs and positive reverse transcriptase polymerase chain reaction (RT-PCR) showed a definite diagnosis of COVID-19 (Fig. 1).Fig. 1 Computed tomography (CT) scan of the chest of a patient with COVID-19 shows multiple patchy ground-glass opacities\n\nHe was treated with remdesivir injection at a dose of 250 mg stat and then 100 mg daily. The patient was under supportive care for six days, and thereafter methylprednisolone was administered at a dose of 250 mg stat and then 125 mg for 3 days. After 10 days, the patient was discharged while he was relatively in good general condition. Four days after his discharge, the patient was re-admitted to hospital because of nasal obstruction and left side facial and orbital swelling. Table 1 shows the laboratory findings of the patient during both COVID-19 and mucormycosis. Subsequently, the patient visited by an infectious disease specialist and due to the involvement of the left ethmoid, sphenoid, and maxillary sinuses, a CT scan was performed (Fig. 2). In sinus endoscopic surgery, by Rhinologist, severe involvement and necrosis of the left side lateral nasal wall, floor, and septum as well as left ethmoid and sphenoid sinuses were observed and also destruction of the left orbital floor and medial wall were observed. Since clinical results confirmed the possibility of mucormycosis in the patient, treatment with IV liposomal amphotericin B (3 mg/kg/day, according to local guidelines [5]) was started. In addition, the patient underwent daily paranasal sinuses debridement and irrigation with diluted amphotericin B. Biopsy of sinonasal area was made and the specimens were sent to both pathology and mycology laboratories. Examination of the results with haematoxylin and eosin (H&E) staining and direct experiment with 10% potassium hydroxide (KOH) showed irregular hyphae, wide and aseptate (Fig. 3).Table 1 The measured hematological biomarkers in blood of the patient\n\nCategorization of hematological factor\tAt the time of admission to\t\nCovid-19\tMucormycosis\t\nWhite Blood Cell (WBC) Count, µL\t10,400\t18,100\t\nRed Blood Cell Count (RBC),million/µL\t5.1\t4.5\t\nHemoglobin (Hb), mg/dL\t15.8\t14.1\t\nPlatelets, µL\t136,000\t137,000\t\nNeutrophil count, %\t88.1\t94.7\t\nLymphocyte count, %\t7.7\t1.8\t\nC-Reactive Protein (CRP)\t48.1\t55.8\t\nBlood urea nitrogen (BUN), mg/dL\t25.2\t28.4\t\nSerum creatinine, mg/dL\t1.59\t1.24\t\nSodium Blood, mEq/L\t146\t144\t\nPotassium Blood,mEq/L\t4\t4.6\t\n\nFig. 2 CT scan shows involvement of the left ethmoid, sphenoid, maxillary and paranasal sinuses in a patient with mucormycosis\n\nFig. 3 a Presence of irregular and non-septate hyphae in H&E staining of pathology. b Observation of broad aseptate hyphae in surgical debridement in direct examination (10% KOH). c and d Lactophenol cotton blue (LCB) mount showed nonseptate hyphae, rhizoids and spore-filled sporangiophores\n\nIn addition, the sample was inoculated on PDA (Sigma-Aldrich,UK) and was incubated for 4–5 days at 37 °C. After colony growth, non- septate hyphae, rhizoids and spore-filled sporangiophores were observed in slides prepared with LCB (Fig. 3). The antifungal susceptibility testing was performed in 96-well plates by following the M38-A2 guidelines of the CLSI for in vitro testing. MIC values against AMB, ITC and VRC were 0.5 mg/mL, 16 mg/mL and 32 mg/mL, respectively. In the next step, DNA extraction was carried out using the glass beads and phenol:chloroform:isoamyl alcohol (25:24:1) method, previously described [6]. The fungal isolate was identified by molecular analysis of ITS1-5.8S-ITS2 region using the primers for ITS1 (5′-TCCGTAGGTGAACCTGCGG-3′) and ITS4 (5′-TCCTCCGCTTATTGATATGC-3′). The sequenced PCR product showed 100% sequence identity with R. oryzae and it was registered in the GenBank database under the assigned accession number MW317184. Sequence was aligned with using the ClustalW algorithm as implemented in Bioedit version 7 (http://www.mbio.ncsu.edu/BioEdit/bioedit.html). The molecular diversity of the sample was estimated by phylogenetic analysis via MEGA7 software. In order to compare the sequences with available DNA sequences in GenBank, the nucleotide BLAST with the BLASTn algorithm was applied through CLUSTAL omega (https://www.ebi.ac.uk/Tools/msa/clustalo/). The protocols were conducted based on the ML method using the Tamura-Nei model. The number of bootstrap replications was considered to be 1000 (Fig. 4). Because of the progression of the disease and the involvement of the cheeks and orbit, necrotic tissues were removed. Despite all measures, the patient unfortunately expired on the seventh day of his admission due to loss of consciousness and involvement of central nervous system.Fig. 4 The phylogenetic tree of isolates of Rhizopus oryzae. Based on ITS sequence from a patient with mucormycosis and GenBank sequences of some related species were estimated in MEGA7 using the ML analyses based on 1,000 bootstrap replications\n\nDiscussion and conclusions\n\nCOVID-19 disease has a rapid and widespread distribution with mild to severe symptoms. Supportive care, corticosteroids and remedial drugs are good treatment options in COVID-19. On the other hand, due to the use of steroids, these patients may be susceptible to invasive mould infections. Furthermore, diabetes mellitus complicates the management of Covid-19 infection.\n\nMucormycosis is an acute fungal infection caused by the members of mucoraceae family. Mucormycosis in uncontrolled diabetic patients and immunocompromised is an opportunistic and fatal fungal disease [7]. The most common clinical manifestation of mucormycosis in immunocompromised patients is the rhino-orbito-cerebral form [8]. Infection begins in the nasal cavities and paranasal sinuses. The symptoms of mucormycosis include one-sided facial swelling, headache, fever, inflammation, eyelid drooping and black lesions on nasal that the disease spreads rapidly [9]. Infarction and necrosis of host tissues occur due to invasion of non-septate hyphae [10]. Methods for diagnosing mycromycosis include histopathology, direct testing, and culture of clinical specimens [11]. The first line of management of mucormycosis is recommended injection of liposomal amphotericin B. In case of intolerance of the treatment regimen or general weakness of the patient, azole compounds such as Posaconazole and Isavuconazole can be used [5].\n\nThe database search using the terms ‘‘COVID’’ OR ‘‘SARS-CoV2’’ OR ‘‘Coronavirus’’ AND \"Mucor\" OR ‘‘Zygomycosis’’ revealed a total of 44 articles. The characteristics of patients with COVID-19-associated mucormycosis were shown in Table 2.Table 2 Characteristics of patients with mucormycosis and COVID-19 reported in the literature\n\nCountry (case)\tMean age\tSex\tUnderlying conditions\tType of Mucormycosis\tOutcome\t\nIndia (n = 110)\t53.5\tM:86,F:24\tDM:88,DKA:9\n\nCKD:9, RT:2 SOT:1,CGD:1 DCLD:1,TB:1\n\n\tRhino-Facial: Majority\n\nPulmonary:2.7%\n\n\tDied:27,Alive:74\n\nLFU:4, Unchanged:4\n\nLAMA:5\n\n\t\nIran (n = 20)\t51.6\tM:11,F:9\tDM:15,HM:2\tRhino-Facial\tDied:8, Alive:12\t\nTurkey (n = 12)\t64.5\tM:9,F:3\tDM:9\tROM, ROCM\tDied:8,Alive:4\t\nEgypt (n = 11)\t53\tM:7,F:4\tDM:7\tROCM\tDied:5,Alive:6\t\nUSA (n = 10)\t51.4\tM:8,F:2\tDM:7\tROCM:3,ROM:3\n\nPulmonary:4\n\n\tDied:8, Alive:2\t\nThe Netherlands (n = 4)\t60\tM:4\tDM:2, CLL:1\tROCM, Pulmonary Disseminated\tDied:3, Alive:1\t\nUK (n = 2)\t22\tM:2\tHypothyroidism:1\n\nObesity:1\n\n\tDisseminated\tDied:2\t\nSpain (n = 2)\t55\tM:2\tDM:1, RT:2\tRhino-Facial, Musculoskeletal\tAlive:2\t\nAustralia (n = 1)\t53\tM:1\tMDS, AML\tPulmonary\tDied\t\nBrazil (n = 1)\t86\tM:1\tHTN\tGIM\tDied\t\nFrance (n = 1)\t55\tM:1\tFL, HCT\tPulmonary\tDied\t\nMexico (n = 1)\t24\tF:1\tDKA\tROM\tDied\t\nItaly (n = 1)\t66\tM:1\tHTN\tPulmonary\tDied\t\nIraq (n = 1)\t53\tM:1\tDM\tROCM\tDied\t\nF female; M male; DM diabetes mellitus; HTN hypertension; CKD chronic kidney disease; SOT solid organ transplant; DCLD Decompensated chronic liver disease; AML Acute myeloid leukemia; MDS Myelodysplastic syndrome; DKA Diabetic ketoacidosis; RT Renal transplant; FL Follicular lymphoma; HCT Hematopoietic cell transplantation; TB Tuberculosis; ROM rhino-orbital mucormycosis; ROCM rhino-orbito-cerebral mucormycosis; GIM gastrointestinal mucormycosis\n\nReview of literature published till June 2021 shows that the most cases are related to mucormycosis in COVID-19 patients was in India with 110 cases [12–25], followed by Iran (20 cases) [26–30], Turkey (12 cases) [31, 32], Egypt (11 cases) [33, 34], the United States and (10 cases) [35–43], the Netherlands (4 cases) [44], UK and Spain (2 cases) [45–47]. Furthermore, a case of mucormycosis in COVID-19 patients has been published from Brazil [48], Australia [49], France [50], Mexico [51], Italy [52] and Iraq [53]. Studies show that the median age of the patients was 53.4 years (range 22–86) with a higher prevalence of mucormycosis in men (75.7%). The association of mucormycosis with uncontrollable diabetes has been proven [54]. Diabetes mellitus was the most common predisposing factor (73.4%) for mucormycosis in COVID-19 patients [14, 15, 27, 32, 35, 44]. In 5 cases (2.8%), no risk factors for mucormycosis were reported [14, 21, 29, 37]. In our reported case, corticosteroid-related hyperglycemia was observed in a patient with no history of diabetes. Predisposing factors for mucormycosis include diabetes mellitus, neutropenia, corticosteroid use, and immunodeficiency, among which diabetes is the most common risk factor linked with mucormycosis [55]. The severity of COVID-19 infection and its dangerous consequences are higher in individuals with diabetes. Glucocorticoids reduce mortality in patients with COVID-19 by reducing cytokine storm. Nevertheless, corticosteroids can increase the risk of fungal and bacterial secondary infections [56]. Therefore, use of steroids should be avoided in mild to moderate COVID-19 cases as they lead to dangerous results. Reports indicate that 82% of patients received corticosteroids.\n\nThe mean duration from between diagnosis of COVID-19 and the onset of symptoms of mucormycosis was 15 days [15, 18]. Studies show that the most common clinical manifestation of mucormycosis is rhino-facial, followed by pulmonary and disseminated form. Herein, we report a case of mucormycosis in a 59-year-old male non-diabetic with COVID-19. The patient developed rhino-facial mucormycosis after the initiation of corticosteroid. The mean duration between diagnosis of COVID-19 infection and the onset of symptoms of mucormycosis was 15 days [13, 15, 57]. The present case indicates that in the presence of COVID-19, even short-term treatment with corticosteroids may be a predisposing factor in leading the patient to rhino-orbital mucormycosis. Studies show that glucose control, timely treatment with liposomal amphotericin B, and surgical debridement are effective in the management of mucormycosis. The prognosis of the disease depends on factors such as early diagnosis and management to limit the spread of infection into the intracranial space [5, 58]. This study, in line with the results of other studies, reveals that the possible occurrence of secondary invasive fungal infections in patients with COVID-19 infection should not be neglected. Effort to maintain blood sugar and the rational use of corticosteroids in COVID-19 patients is recommended to reduce the risk of mucormycosis.\n\nAbbreviations\n\nCOVID-19 Coronavirus disease 2019\n\nARDS Acute respiratory distress syndrome\n\nH&E Hematoxylin and eosin\n\nPDA Potato dextrose agar\n\nCLSI Clinical and Laboratory Standards Institute\n\nMIC Minimum inhibitory concentration\n\nR. oryzae Rhizopus oryzae\n\nML Maximum-likelihood\n\nAcknowledgements\n\nThe authors would like to thank the medical staff of the Razi Hospital in Qazvin, Iran.\n\nAuthors' contributions\n\nFM responsible for designing the manuscript and mycological analysis. MB and NH collaboration in mycological experiments. SS general ENT surgeon. All authors contributed to writing of the final version of the paper.\n\nFunding\n\nThis study was financially supported by the Research Deputy of Qazvin University of Medical Sciences and the ethics approval code of this research is IR.QUMS.REC.1399.357.\n\nAvailability of data and materials\n\nAll data analyzed during this study are included in this published article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe ethical approval was required and provided for this study, as stated by our institutional review board.\n\nConsent for publication\n\nThe consent form has been signed by the family members of the patient.\n\nCompeting interests\n\nThe authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "21(1)",
"journal": "BMC infectious diseases",
"keywords": "COVID-19; Mucormycosis; Rhizopus oryzae",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000086382:COVID-19; D003920:Diabetes Mellitus; D006801:Humans; D000072742:Invasive Fungal Infections; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis; D000086402:SARS-CoV-2",
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"pmid": "34479495",
"pubdate": "2021-09-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": "34052046;33513875;33145132;34057620;32983308;22386924;33842203;22247442;34096653;33544266;33590551;32972795;34237015;33575155;12161726;33331988;33713565;33716414;33229953;34124087;32844161;33463566;30181998;10736409;33527098;33906877;33964720;34038014;31811914;33984095;34075329;34011758;32979569;33207116;32768493;32572965;33752571;33653643;33727483;31699664;34114540;22684277;33827722;34081817;33670842;33903850;34087330;33147877;33857916;33843287",
"title": "A case report of rhino-facial mucormycosis in a non-diabetic patient with COVID-19: a systematic review of literature and current update.",
"title_normalized": "a case report of rhino facial mucormycosis in a non diabetic patient with covid 19 a systematic review of literature and current update"
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"literaturereference": "Mohammadi F., Badri M., Safari S., Hemmat N. A case report of rhino-facial mucormycosis in a non-diabetic patient with COVID-19: a systematic review of literature and current update.. BMC Infectious Diseases. 2021;21(906):UNK",
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"literaturereference": "Mohammadi F, Badri M, Safari S, Hemmat N. A case report of rhino-facial mucormycosis in a non-diabetic patient with COVID-19: a systematic review of literature and current update. BMC Infect Dis. 2021;21(1)",
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},
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"activesubstancename": "REMDESIVIR"
},
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"drugauthorizationnumb": null,
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"drugdosagetext": "250 MILLIGRAM, SINGLE (AT A DOSE OF 250 MG STAT AND THEN 100 MG DAILY)",
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"drugindication": "COVID-19",
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"medicinalproduct": "REMDESIVIR"
},
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"activesubstancename": "REMDESIVIR"
},
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"drugdosagetext": "100 MILLIGRAM, QD (AT A DOSE OF 250 MG STAT AND THEN 100 MG DAILY)",
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"drugintervaldosagedefinition": "804",
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"drugstructuredosagenumb": "100",
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"medicinalproduct": "REMDESIVIR"
}
],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Mucormycosis",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Loss of consciousness",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Central nervous system infection",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Hyperglycaemia",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
}
],
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"literaturereference": "Mohammadi F, Badri M, Safari S, Hemmat N. A case report of rhino-facial mucormycosis in a non-diabetic patient with COVID-19: a systematic review of literature and current update. BioMed Central Infectious Diseases. 2021;21(1):906:1-7",
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},
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},
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}
] |
{
"abstract": "BACKGROUND\nSupraventricular tachycardia is the most common fetal tachyarrhythmia and if persistent often associated with fetal hydrops which can cause intrauterine and neonatal death.\n\n\nMETHODS\nWe present a case of early second trimester supraventricular tachycardia in a hydropic fetus, initially refractory to transplacental treatment.\n\n\nCONCLUSIONS\nThe supraventricular tachycardia was successfully treated when supplemented with intraperitoneal flecainide in the fetus.",
"affiliations": "Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, cathrinevedel@gmail.com.;Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.;Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.;Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.;Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.;Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.;Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.;Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.;Department of Obstetrics and Prenatal Medicine, University of Bonn, Bonn, Germany.;Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.",
"authors": "Vedel|Cathrine|C|;Vejlstrup|Niels|N|;Jensen|Lisa Neerup|LN|;Ekelund|Charlotte Kvist|CK|;Nørgaard|Lone Nikoline|LN|;Harmsen|Lotte|L|;Petersen|Olav Bjørn|OB|;Jaeggi|Edgar|E|;Gembruch|Ulrich|U|;Sundberg|Karin|K|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D005424:Flecainide",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000508811",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1015-3837",
"issue": "47(9)",
"journal": "Fetal diagnosis and therapy",
"keywords": "Fetal intervention; Intraperitoneal flecainide; Refractory fetal supraventricular tachycardia",
"medline_ta": "Fetal Diagn Ther",
"mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D005260:Female; D046128:Fetal Therapies; D005424:Flecainide; D006801:Humans; D015160:Hydrops Fetalis; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D013617:Tachycardia, Supraventricular; D016896:Treatment Outcome",
"nlm_unique_id": "9107463",
"other_id": null,
"pages": "717-720",
"pmc": null,
"pmid": "32570238",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Refractory Fetal Supraventricular Tachycardia with Hydrops Successfully Converted by Intraperitoneal Flecainide in the Fetus: A Case Report.",
"title_normalized": "refractory fetal supraventricular tachycardia with hydrops successfully converted by intraperitoneal flecainide in the fetus a case report"
} | [
{
"companynumb": "DK-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-303118",
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"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"drugadditional": "3",
"drugadministrationroute": "064",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "150 MILLIGRAM, BID",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FOETAL EXPOSURE TIMING UNSPECIFIED",
"drugintervaldosagedefinition": "805",
"drugintervaldosageunitnumb": "12",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"drugstartdateformat": null,
"drugstructuredosagenumb": "150",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FLECAINIDE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": "3",
"drugadministrationroute": "064",
"drugauthorizationnumb": "76363",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "250 MICROGRAM, DAILY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FOETAL EXPOSURE TIMING UNSPECIFIED",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "250",
"drugstructuredosageunit": "004",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DIGOXIN."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pericardial effusion",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Skin oedema",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Ascites",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "VEDEL C, VEJLSTRUP N, JENSEN LN, EKELUND CK, NORGAARD LN, HARMSEN L, ET AL. REFRACTORY FETAL SUPRAVENTRICULAR TACHYCARDIA WITH HYDROPS SUCCESSFULLY CONVERTED BY INTRAPERITONEAL FLECAINIDE IN THE FETUS: A CASE REPORT. FETAL DIAGN THER. 2020?47(9):717?720",
"literaturereference_normalized": "refractory fetal supraventricular tachycardia with hydrops successfully converted by intraperitoneal flecainide in the fetus a case report",
"qualification": "5",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20210721",
"receivedate": "20210721",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19585145,
"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": "OBJECTIVE\nThe aim of this study was to determine the prevalence, safety (as measured by the incidence of adverse events), and effectiveness (as measured by the incidence of intubations) of ketamine sedation in patients with acute behavioral disturbance (ABD) during air medical retrieval.\n\n\nMETHODS\nThis was a retrospective observational study. Eligible patients were identified by searching the electronic databases of 2 air medical retrieval services in Queensland, Australia, for adult patients with ABD transported between January 1, 2015, and June 30, 2016. Data abstraction was performed as per standard chart review criteria. The incidences of intubations and adverse reactions were the main outcomes.\n\n\nRESULTS\nOne hundred twenty-two patients met the inclusion criteria. Thirty-one (25.4%) patients were intubated, 21 (17.2%) for airway protection/respiratory depression and 10 (8.1%) for persistent ABD. Twenty-one (17.2%) patients received ketamine, 3 of whom (14.3%) were intubated for persistent ABD. Nine (42.9%) patients developed hypertension after ketamine, 2 of whom needed intervention. One patient developed hypoxia after ketamine that resolved without intervention, and 1 patient developed increased secretions. No patients developed nausea, vomiting, emergence phenomena, apnea, or laryngospasm.\n\n\nCONCLUSIONS\nOur study suggests that ketamine is a safe and effective agent for sedating patients with ABD during air medical retrieval.",
"affiliations": "LifeFlight Retrieval Medicine, Queensland, Australia. Electronic address: Vinay.Gangathimmaiah@lifeflight.org.au.;Royal Flying Doctor Service, Queensland, Australia.;LifeFlight Retrieval Medicine, Queensland, Australia.;LifeFlight Retrieval Medicine, Queensland, Australia.;LifeFlight Retrieval Medicine, Queensland, Australia.;LifeFlight Retrieval Medicine, Queensland, Australia.;School of Health, Medical & Applied Sciences, CQUniversity, Queensland, Australia.;School of Health, Medical & Applied Sciences, CQUniversity, Queensland, Australia.",
"authors": "Gangathimmaiah|Vinay|V|;Le Cong|Minh|M|;Wilson|Mike|M|;Hooper|Kate|K|;Perry|Andrew|A|;Burman|Luke|L|;Puckeridge|Nathan|N|;Maguire|Brian J|BJ|",
"chemical_list": "D000778:Anesthetics, Dissociative; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amj.2017.06.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1067-991X",
"issue": "36(6)",
"journal": "Air medical journal",
"keywords": null,
"medline_ta": "Air Med J",
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"abstract": "Checkpoint inhibitors have improved the survival of patients with advanced tumors and show a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery, external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment with methylprednisolone 2 mg/kg was initiated which led to a decrease in the number of stools to grade 1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient experienced a major partial response and, following the resolution of diarrhea, she was re-challenged again with immunotherapy, with the reappearance of grade 2 diarrhea, leading to permanent immunotherapy interruption. We conclude and propose that performing random colonic biopsies should be considered in cases of immune checkpoint-associated unexplained diarrhea, even when colonoscopy shows macroscopically normal colonic mucosa inflammatory lesions.",
"affiliations": "Department of Pathology, Clinica Universidad de Navarra (CUN), Pamplona, Spain.;Department of Oncology, Clinica Universidad de Navarra (CUN), Pamplona, Spain.;Department of Oncology, Clinica Universidad de Navarra (CUN), Pamplona, Spain.;Department of Oncology, Clinica Universidad de Navarra (CUN), Pamplona, Spain.;Department of Pathology, Clinica Universidad de Navarra (CUN), Pamplona, Spain.;Department of Immunology, Clinica Universidad de Navarra (CUN), Pamplona, Spain.;Department of Oncology, Clinica Universidad de Navarra (CUN), Pamplona, Spain.;Department of Oncology, Clinica Universidad de Navarra (CUN), Pamplona, Spain.",
"authors": "de Andrea|Carlos Eduardo|CE|;Perez-Gracia|Jose Luis|JL|;Castanon|Eduardo|E|;Ponz-Sarvise|Mariano|M|;Echeveste|Jose I|JI|;Melero|Ignacio|I|;Sanmamed|Miguel F|MF|;Rodriguez-Ruiz|Maria Esperanza|ME|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors; D000074324:Ipilimumab; D000077594:Nivolumab",
"country": "United States",
"delete": false,
"doi": "10.1080/2162402X.2020.1760676",
"fulltext": "\n==== Front\nOncoimmunology\nOncoimmunology\nOncoimmunology\n2162-4011\n2162-402X\nTaylor & Francis\n\n32934876\n10.1080/2162402X.2020.1760676\n1760676\nVersion of Record\nBrief Report\nBrief Report\nEndoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors\nC. E. DE ANDREA ET AL.\nONCOIMMUNOLOGY\nde Andrea Carlos Eduardo a\nPerez-Gracia Jose Luis b\nCastanon Eduardo b\nPonz-Sarvise Mariano b\nEcheveste Jose I. a\nMelero Ignacio c\nSanmamed Miguel F. b\nRodriguez-Ruiz Maria Esperanza b\na Department of Pathology, Clinica Universidad de Navarra (CUN) , Pamplona, Spain\nb Department of Oncology, Clinica Universidad de Navarra (CUN) , Pamplona, Spain\nc Department of Immunology, Clinica Universidad de Navarra (CUN) , Pamplona, Spain\nCONTACT Maria Esperanza Rodriguez-Ruiz mrruiz@unav.es Department of Oncology, Clinica Universidad de Navarra (CUN) , Pamplona, Spain\n13 5 2020\n2020\n13 5 2020\n9 1 1760676© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.\n2020\nThe Author(s)\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nABSTRACT\n\nCheckpoint inhibitors have improved the survival of patients with advanced tumors and show a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery, external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment with methylprednisolone 2 mg/kg was initiated which led to a decrease in the number of stools to grade 1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient experienced a major partial response and, following the resolution of diarrhea, she was re-challenged again with immunotherapy, with the reappearance of grade 2 diarrhea, leading to permanent immunotherapy interruption. We conclude and propose that performing random colonic biopsies should be considered in cases of immune checkpoint-associated unexplained diarrhea, even when colonoscopy shows macroscopically normal colonic mucosa inflammatory lesions.\n\nKEYWORDS\n\ncolitis\nimmune-related adverse event\nNivolumab\nIpilimumab\nEuropean Union's Horizon 2020 research and innovation programme 635122 CRIS/FEOR Foundation Against Cancer 2017-2018 This project has received funding from the European Union's Horizon 2020 research and innovation programme (grant agreement n° 635122 - PROCROP). M.E.R.R. is supported by a fellowship from CRIS/FEOR Foundation Against Cancer 2017-2018.\n==== Body\nIntroduction\n\nRecurrent metastatic cervical cancer has a poor prognosis, with a 5-year survival rate of 17%.1 Recently, immune-checkpoint inhibitors (ICPI) have emerged as an active treatment option for a variety of human malignant diseases,2,3 including metastatic cervical cancer.4,5 Several studies are currently being conducted in this tumor type with promising results.6–9\n\nImmune-related adverse events (irAEs) have been extensively reported during treatment with immune-checkpoint inhibitors10,11 and include, among others, dermatitis, thyroiditis, pneumonitis, colitis, myocarditis and hypophysitis.12,13 Although there is not a clear relation between the type of checkpoint inhibitor and the induction of irAEs, some toxicities, such as hypophysitis and colitis, are found with a higher prevalence among patients receiving anti-CTLA-4 mAb agents, either as single agents or in combination with anti PD1/PDL1 inhibitors.14,15\n\nAs described in the literature, diarrhea associated with anti-CTLA-4 therapy usually appears after 7–8 weeks from the first infusion, while anti-PD1 associated diarrhea usually onsets as late as 12–24 weeks following treatment initiation.14,15 These diarrheas have been linked to macroscopic and microscopic alterations similar to the ones found on immune-mediated colitis.16 In general terms, drug-induced microscopic colitis (MC) can be grouped into two main categories, known as microscopic colitis: collagenous and lymphocytic colitis, both of which have a grossly normal endoscopic appearance and are differentiated by histology.17 Both patterns are reported in patients receiving immune-checkpoint inhibitors. Interestingly, lymphocytic colitis has been related to other autoimmune disorders, such as type I diabetes, thyroid alterations or polyarthritis.18 Importantly, in the context of microscopic colitis, the presence of diarrhea with the absence of macroscopic signs of inflammation should not discard a microscopic immune infiltration pattern. Microscopic colitis is not usually associated with endoscopic or radiological alterations.\n\nHere we report the case of a patient diagnosed with metastatic cervical carcinoma treated with a combination of Ipilimumab and Nivolumab who presented different irAEs, including thyroiditis and pneumonitis. Interestingly, several weeks after withholding Ipilimumab and switching to Nivolumab monotherapy per protocol, while receiving Nivolumab, the patient presented grade 3 diarrhea with microscopic colitis, despite showing a normal-appearing colonic mucosa in the colonoscopy.\n\nCase presentation\n\nA 50-year-old woman without the previous medical history of gastrointestinal pathology was diagnosed with cervical carcinoma (T2N1M0) in April 2015. Radical surgery was performed in June 2015 and subsequently she received adjuvant radiotherapy using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) followed by brachytherapy. Between August 17 and September 24, 2015, a total dose of 50.4 Gy (1.8 Gy/fraction) to the pelvic lymph node chains and 58.8 Gy (2.10 Gy/fraction) to the postsurgical high-risk area were administered. In addition, a total dose of 12 Gy (6 Gy/2fractions) was delivered using intracavitary high-dose-rate brachytherapy. Simultaneously, six cycles of cisplatin 40 mg/m2/week were administered. Radiation therapy ended in October 2015 and she started follow-up. In May 2016, a pelvic MRI and whole-body CT showed recurrence in the vulva and multiple lymph nodes. She was then treated with Paclitaxel 60 mg/m2 and Carboplatin AUC 1.5, showing clear disease progression at the first evaluation performed 4 weeks later.\n\nIn March 2017, she was enrolled in a phase I–II clinical trial19 and she received Nivolumab 1 mg/kg plus Ipilimumab 3 mg/kg every 3 weeks for four doses, followed by Nivolumab 240 mg every 2 weeks until progression or unacceptable toxicity. After the first cycle (3 weeks), she developed grade 2 symptomatic thyroiditis, which required Methylprednisolone 2 mg/kg, Metamizole/acetaminophen for pain and beta-blockers to control hyperthyroidism-associated signs. After cycle 2 (9 weeks), she presented symptomatic grade2 pneumonitis. Methylprednisolone 2 mg/kg was started based on the clinical trial protocol. The pneumonitis resolved and Nivolumab was re-introduced 14 weeks after completed the steroid tapering.\n\nIn the CT-SCAN performed 19 weeks after treatment onset, the patient showed a partial response (80% decrease) by RECIST 1.1 criteria, and she remained on treatment. Following cycle 10 (29 weeks), she presented grade-2 colitis due to grade-3 diarrhea (seven non-bloody stools per day over baseline), abdominal pain and a total weight loss of 4 kg during the diarrhea (31 weeks). Nivolumab was interrupted and infectious colitis was ruled out after bacteriological, virological and parasitological analyses of stools, including testing for Clostridium difficile toxin. Upper digestive tract endoscopy did not show any endoscopic abnormalities. However, a colonoscopy showed macroscopically normal-appearing mucosa in the whole length of the colon (Figure 1a and b). Interestingly, severe lymphocytic colitis was observed in multiple colonic biopsies. Hematoxylin-eosin staining and immunohistochemical staining showed an increased intraepithelial infiltration of CD8+ lymphocytes (>10/100 enterocytes) with a severe CD4+ and CD8+ lymphocytic infiltration in the lamina propria (Figure 1c–e).Figure 1. (a and b) Endoscopic revealed grossly normal mucosa in patients treated with anti-PD-1 and anti-CTLA-4 combination mAbs. (c) Hematoxylin and Eosin (H&E)-stained section of the colonic biopsy shows diffuse colitis with crypt atrophy and loss of crypts with residual inflamed lamina propria. A severe lymphoplasmacytic infiltration of the lamina propria with increased intraepithelial lymphocytes and crypt epithelial cell apoptosis is seen. (d and e) A severe CD4+ and CD8+ lymphocytic infiltration is seen in lamina propria. (e) Increased intraepithelial CD8+ lymphocytes (>10/100 enterocytes) and lymphocytic cryptitis are observed.\n\nAs severe diarrhea persisted despite full-dose loperamide and diet, methylprednisolone 2 mg/kg/day was started, leading to a decrease in the number of stools to grade 1 and resolution of the colitis. After careful consideration of the risks and benefits, and following thorough discussion with the patient, Nivolumab was restarted after tapering steroids. Grade 2 diarrhea recurred after 2 weeks and Nivolumab was permanently discontinued (35 weeks) (Figure 2). The patient remains in partial response (80% decrease) after 153 weeks (3 years) of treatment initiation and is completely asymptomatic.Figure 2. Treatment schema and AEs during the clinical trial. Week of cycle administration (upper line) and week at the moment of toxicity (lower line). EOT: end of treatment; FUP: follow up; G: grade; W:week; (*) Metilprednisolone.\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images, in addition to the explicit permission from the Ethics Committee of Clínica Universidad de Navarra and the sponsor of the clinical trial (Bristol Myers Squibb).\n\nDiscussion\n\nAuto-immune colitis is a well-described complication of treatment with immune-checkpoint inhibitors, and grades 3–4 episodes have been reported in up to 15.81%.19–21 Here, we report a case of a patient presenting with an adenocarcinoma of the cervix that relapsed following standard treatment with radical surgery, external radiation, brachytherapy and chemotherapy with carboplatin and paclitaxel. She started treatment combination with Nivolumab and Ipilimumab and developed grade 2 thyroiditis and pneumonitis, which required treatment with steroids (metilprednisolone 1 mg/kg weeks 3 to 6 and 9 to 13). After 19 weeks of treatment, a major partial response was observed, but on week 31 she progressed with diarrhea displaying a normal-appearing colonic mucosa, with no signs of inflammation, in the colonoscopy and a microscopic grade2 lymphocytic colitis. Lymphocytic colitis was observed on all random distal colonic biopsies. Treatment with steroids improved the diarrhea, which relapsed following rechallenge with Nivolumab, leading to permanent Nivolumab treatment discontinuation. The patient remains in a major partial response after 3 years.\n\nEven though this patient progressed with lymphocytic colitis upon treatment with immune-checkpoint inhibitors, other possible causes of colitis should be considered as the role of previous surgery, external radiation, brachytherapy and chemotherapy. Nevertheless, severe and even fatal cases of acute and late-onset colitis associated with immune-checkpoint inhibitor treatment have been reported in the literature.22–24 The clinical course of the patient, with improvement after steroids and relapse upon rechallenge with Nivolumab, and the histological finding of lymphocytic colitis support the association between colitis and immune-checkpoint inhibitor treatment, but nevertheless the impact of previous therapy, either as a primary cause or as an associated risk factor, cannot be ruled out.\n\nEndoscopy and microscopic examination poignantly rendered dissociated results in this case. This suggests that infiltrating immune cells are capable of functionally damaging the intestinal inner lining, causing diarrhea without obvious ulcers or even milder signs of inflammation. We interpret this dissociation as a result of different timing of cellular changes and the translation to pathological impact in the tissue architecture. The microstructural changes likely precede the macroscopic alterations. It remains to be seen what would have been the natural course of the lesions if left untreated. Perhaps, macroscopic lesions denoting inflammation would have appeared at a later point. Also, there is a possibility that previous treatment of the thyroiditis and pneumonitis with methylprednisolone 18 weeks before the diarrhea contributed to decrease the inflammation, masking the presence of macroscopical lesions. Despite some histopathological similarities between microscopic colitis with and without prior exposure to ICPIs, differences have been demonstrated in clinical presentations, disease courses and treatments between non-ICPI-induced MC and ICPI-induced MC. ICPI-induced MC has greater symptom severity and a more aggressive disease course that requires more potent immunosuppressive treatment regimens.25\n\nThis case highlights the potential for the development of immune-related toxicity in patients treated with immunotherapy combinations,10,11 including multiple irAEs affecting several organs in a single patient. An important unresolved question is which factors render certain patients more susceptible to irAEs. Probably, several factors underlie this increased risk, including genetic predisposition, microbiome22-24 and perhaps subclinical pretreatment inflammation of the target organ. Conversely, the correlation of irAE and clinical benefit is weak at best26 and cannot be used as a predictor, even if in this case our patient experienced a major and sustained response. Another relevant observation confirmed by this case is that treatment cessation and steroid treatment do not seem to spoil clinical benefit.26,27\n\nThe most important message for clinical practice from this case is that autoimmune colitis would have remained undiagnosed unless random biopsies would have been obtained from apparently healthy mucosa. Therefore, random obtention of colonic biopsies should be considered in cases of unexplained diarrhea in patients treated with immune checkpoint-inhibitors, even if an experienced endoscopist fails to identify alterations on a macroscopically normal-appearing mucosal tissue, and especially in patients that have received previous steroids, that may have contributed to mask macroscopic inflammation.\n\nAcknowledgments\n\nWe are grateful for Scientific discussion and excellent endoscopic image by Dr. Subtil. Excellent work by personnel at the Unidad Central de Ensayos Clinicos of CUN (UCEC) is acknowledged.\n\nAbbreviations\n\nirAEs\tImmune related adverse events\t\nmAb\tMonoclonal antibodies.\t\nSIB-IMRT\tsimultaneous integrated boost intensity-modulated radiotherapy\t\nGy\tgray\t\nMRI\tMagnetic resonance image\t\nCT\tcomputer tomography\t\nRECIST\tResponse evaluation criteria in solid tumors\t\nCTLA-4\tCytotoxic T-lymphocyte antigen-4\t\nPD-1\tProgrammed cell death protein-1\t\nPD-L1\tProgrammed cell death ligand-1\t\n\nAvailability of data and materials\n\nNot applicable\n\nAuthors’ contributions\n\nAll authors contributed to their order in writing the manuscript. All authors read and approved the final manuscript.\n\nConsent for publication\n\nInformed consent by the patient.\n\nCompeting interests\n\nM consultant for BMS, Roche, Seattle Genetics, Tusk, Genmab, Alligator, Merck-Serono, Bioncotech, Molecular Partners; receives Grants from Alligator, Roche, BMS. JL Research funding, travel grants and speaker honoraria from BMS.\n\nEthics approval and consent to participate\n\nNot applicable.\n==== Refs\nReferences\n\n1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136 (5 ):E359–5. doi:10.1002/ijc.29210.25220842\n2. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359 (6382 ):1350–1355. doi:10.1126/science.aar4060.29567705\n3. Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer. 2007;7 (2 ):95–106. doi:10.1038/nrc2051.17251916\n4. Borcoman E, Le Tourneau C. Pembrolizumab in cervical cancer: latest evidence and clinical usefulness. Ther Adv Med Oncol. 2017;9 (6 ):431–439. doi:10.1177/1758834017708742.28607581\n5. 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Sci Transl Med. 2018;10 (459 ):459. doi:10.1126/scitranslmed.aat7807.\n10. Guillermo De Velasco, Youjin Je, Dominick Bosse, Mark M. Awad, Patrick A. Ott, Raphael B. Moreira, Fabio Schutz, Joaquim Bellmunt, Guru P. Sonpavde, F. Stephen Hodi, et al. comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Cancer Immunol Res. 2018;6 (4 ):498–499. doi:10.1158/2326-6066.CIR-18-0078.29559478\n11. De Velasco G, Je Y, Bosse D, Awad MM, Ott PA, Moreira RB, Schutz F, Bellmunt J, Sonpavde GP, Hodi FS, Choueiri TK Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Cancer Immunol Res. 2017;5 (4 ):312–318. doi:10.1158/2326-6066.CIR-16-0237.28246107\n12. Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS One. 2016;11 (7 ):e0160221. doi:10.1371/journal.pone.0160221.27472273\n13. Vanpouille-Box C, Lhuillier C, Bezu L, Aranda F, Yamazaki T, Kepp O, Fucikova J, Spisek R, Demaria S, Formenti SC, et al. Trial watch: immune checkpoint blockers for cancer therapy. Oncoimmunology. 2017;6 (11 ):e1373237. doi:10.1080/2162402X.2017.1373237.29147629\n14. Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol. 2017;8 :49. doi:10.3389/fphar.2017.00049.28228726\n15. Wang DY, Mooradian MJ, Kim D, Shah NJ, Fenton SE, Conry RM, Mehta R, Silk AW, Zhou A, Compton ML, et al. Clinical characterization of colitis arising from anti-PD-1 based therapy. Oncoimmunology. 2019;8 (1 ):e1524695. doi:10.1080/2162402X.2018.1524695.30546965\n16. Garcia-Varona A, Odze RD, Makrauer F. Lymphocytic colitis secondary to ipilimumab treatment. Inflamm Bowel Dis. 2013;19 (2 ):E15–6. doi:10.1002/ibd.22846.22114048\n17. Pisani LF, Tontini GE, Vecchi M, Pastorelli L. Microscopic colitis: what do we know about pathogenesis? Inflamm Bowel Dis. 2016;22 (2 ):450–458. doi:10.1097/MIB.0000000000000628.26529562\n18. Parfitt JR, Driman DK. Pathological effects of drugs on the gastrointestinal tract: a review. Hum Pathol. 2007;38 (4 ):527–536. doi:10.1016/j.humpath.2007.01.014.17367604\n19. Naumann RW, Hollebecque A, Meyer T, Devlin MJ, Oaknin A, Kerger J, López-Picazo JM, Machiels J-P, Delord J-P, Evans TRJ, et al. Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II checkmate 358 trial. J Clin Oncol. 2019;37 (31 ):2825–2834. doi:10.1200/JCO.19.00739.31487218\n20. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, et al.. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;JCO2017776385.\n21. Abdel-Rahman O, ElHalawani H, Fouad M. Risk of gastrointestinal complications in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Immunotherapy. 2015;7 (11 ):1213–1227. doi:10.2217/imt.15.87.26513491\n22. Kountouras J, Zavos C. Recent advances in the management of radiation colitis. World J Gastroenterol. 2008;14 (48 ):7289–7301. doi:10.3748/wjg.14.7289.19109862\n23. Kennedy GD, Heise CP. Radiation colitis and proctitis. Clin Colon Rectal Surg. 2007;20 (1 ):64–72. doi:10.1055/s-2007-970202.20011363\n24. Andreyev J. Gastrointestinal complications of pelvic radiotherapy: are they of any importance? Gut. 2005;54 (8 ):1051–1054. doi:10.1136/gut.2004.062596.16009675\n25. Choi K, Abu-Sbeih H, Samdani R, Nogueras Gonzalez G, Raju GS, Richards DM, Can immune checkpoint inhibitors induce microscopic colitis or a brand new entity? Inflamm Bowel Dis. 2019;25 (2 ):385–393. doi:10.1093/ibd/izy240.30169584\n26. Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, Carvajal RD, Dickson MA, D'Angelo SP, Woo KM, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33 (28 ):3193–3198. doi:10.1200/JCO.2015.60.8448.26282644\n27. Aston WJ, Hope DE, Cook AM, Boon L, Dick I, Nowak AK, Lake RA, Lesterhuis WJ. Dexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment. Oncoimmunology. 2019;8 (11 ):e1641390. doi:10.1080/2162402X.2019.1641390.31646089\n\n",
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"issn_linking": "2162-4011",
"issue": "9(1)",
"journal": "Oncoimmunology",
"keywords": "Ipilimumab; Nivolumab; immune-related adverse event; colitis",
"medline_ta": "Oncoimmunology",
"mesh_terms": "D003092:Colitis; D004213:Dissociative Disorders; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D000074324:Ipilimumab; D008875:Middle Aged; D000077594:Nivolumab",
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"pmid": "32934876",
"pubdate": "2020-05-13",
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"references": "29095678;31646089;16009675;27472273;2257528;22114048;19109862;28607581;1711515;28228726;28246107;30546965;17367604;29567705;30232229;31487218;25220842;26282644;17251916;26529562;26513491;29147629;29442540;2054806;20011363;30169584",
"title": "Endoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors.",
"title_normalized": "endoscopical and pathological dissociation in severe colitis induced by immune checkpoint inhibitors"
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] |
{
"abstract": "Flecainide acetate is an antiarrhythmic agent commonly used in clinical practice, in particular, for the treatment of supraventricular tachycardias. We report a rare case of voluntary poisoning by flecainide. The patient was successfully resuscitated.A review of the literature related to this type of intoxication is presented.",
"affiliations": null,
"authors": "Benoit|A|A|;Paolucci|M|M|;Stefan|L|L|;Vanderperren|O|O|;Hoffer|E|E|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D005424:Flecainide",
"country": "Belgium",
"delete": false,
"doi": null,
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"issn_linking": "0370-629X",
"issue": "70(9)",
"journal": "Revue medicale de Liege",
"keywords": null,
"medline_ta": "Rev Med Liege",
"mesh_terms": "D000889:Anti-Arrhythmia Agents; D016887:Cardiopulmonary Resuscitation; D005260:Female; D005424:Flecainide; D006801:Humans",
"nlm_unique_id": "0404317",
"other_id": null,
"pages": "442-5",
"pmc": null,
"pmid": "26638444",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A CASE OF FLECAINIDE INTOXICATION.",
"title_normalized": "a case of flecainide intoxication"
} | [
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"companynumb": "BE-ROXANE LABORATORIES, INC.-2016-RO-00363RO",
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{
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},
{
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},
{
"reactionmeddrapt": "Electrocardiogram QRS complex prolonged",
"reactionmeddraversionpt": "19.0",
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}
],
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},
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"literaturereference": "BENOIT A,PAOLUCCI M,STEFAN L,VANDERPERREN O,HOFFER E. A CASE OF FLECAINIDE INTOXICATION. REVUE MEDICALE DE LIEGE 2015?70:9:442-445.",
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},
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] |
{
"abstract": "Nutritional protein may decrease levodopa absorption and has resulted in withdrawal and neuroleptic malignant-like syndromes in critically ill patients. A 72-year-old male was admitted with shortness of breath. His medical history included Parkinson's disease for over 30 years for which he took carbidopa/levodopa 5 times daily. The patient's home medications were continued. On day 2, he was intubated and transferred to the intensive care unit (ICU). He was extubated the next day and reintubated on day 4. Enteral nutrition was initiated at 85 mL/h overnight. The patient's carbidopa/levodopa was administered to limit coadministration with nutrition. Throughout his ICU stay, the patient did not demonstrate changes in mental status. Despite resolution of his pneumonia, he developed fever after administration of one dose overlapping with nutrition, with defervescence throughout the rest of the day. On hospital day 10, that dose was empirically increased. After this dosing change, the patient failed to develop fever during the rest of his hospital stay. On day 16, the patient was discharged to a long-term care facility without any other complications. Our case highlights the interaction between levodopa and enteral nutrition and the potential of fever as the sole sign of withdrawal.",
"affiliations": "Department of Pharmacy Practice, Temple University School of Pharmacy, Philadelphia, PA, USA craig.whitman@temple.edu.;Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA.;Department of Food and Nutrition, Barnes-Jewish Hospital, St Louis, MO, USA.",
"authors": "Whitman|Craig B|CB|;Ablordeppey|Enyo|E|;Taylor|Beth|B|",
"chemical_list": "D007980:Levodopa",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190015627530",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "29(6)",
"journal": "Journal of pharmacy practice",
"keywords": "carbidopa/levodopa; critically ill; fever; withdrawal",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000368:Aged; D003131:Combined Modality Therapy; D004750:Enteral Nutrition; D005334:Fever; D018565:Food-Drug Interactions; D006801:Humans; D007980:Levodopa; D008297:Male; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "574-578",
"pmc": null,
"pmid": "26801658",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Levodopa Withdrawal Presenting as Fever in a Critically Ill Patient Receiving Concomitant Enteral Nutrition.",
"title_normalized": "levodopa withdrawal presenting as fever in a critically ill patient receiving concomitant enteral nutrition"
} | [
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"abstract": "Pseudomelanosis of the gastrointestinal (GI) tract is a rare condition used to describe the accumulation of pigment deposits in the intestinal mucosa. Its underlying cause is not well understood. It has been described in association with gastrointestinal hemorrhage, chronic kidney disease, hypertension, diabetes mellitus, and medications such as hydralazine, ferrous sulfate, and furosemide. Melanosis coli is a well-known condition associated with the use of anthranoid laxatives; however, pseudomelanosis of the small intestine is extremely rare and most commonly described in the duodenum, with few cases in the gastric mucosa and even more rare in the jejunum. Herein, we report a case of pseudomelanosis intestini involving the pylorus, duodenum, and proximal jejunum in a patient presented with GI bleeding. The clinical significance of this condition is unknown; however, gastroenterologists should be aware of its existence.",
"affiliations": "Department of Gastroenterology, Providence-Providence Park Hospital, Michigan State University College of Human Medicine, Southfield, Michigan, USA.;Department of Internal Medicine, Providence-Providence Park Hospital, Michigan State University College of Human Medicine, Southfield, Michigan, USA.;Department of Internal Medicine, Providence-Providence Park Hospital, Michigan State University College of Human Medicine, Southfield, Michigan, USA.;Department of Gastroenterology, Providence-Providence Park Hospital, Michigan State University College of Human Medicine, Southfield, Michigan, USA.;Department of Gastroenterology, Providence-Providence Park Hospital, Michigan State University College of Human Medicine, Southfield, Michigan, USA.",
"authors": "Zakaria|Ali|A|;Abdu|Backer|B|;Al Share|Bayan|B|;Manabat|Mia|M|;Ngo|Kha|K|",
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"country": "India",
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"fulltext": "\n==== Front\nJ Family Med Prim CareJ Family Med Prim CareJFMPCJournal of Family Medicine and Primary Care2249-48632278-7135Medknow Publications & Media Pvt Ltd India JFMPC-7-112010.4103/jfmpc.jfmpc_53_18Case ReportPseudomelanosis intestini “from pylorus to jejunum:” A rare endoscopic finding in a patient with GI bleeding Zakaria Ali 1Abdu Backer 2Al Share Bayan 2Manabat Mia 1Ngo Kha 11 Department of Gastroenterology, Providence-Providence Park Hospital, Michigan State University College of Human Medicine, Southfield, Michigan, USA2 Department of Internal Medicine, Providence-Providence Park Hospital, Michigan State University College of Human Medicine, Southfield, Michigan, USAAddress for correspondence: Dr. Ali Zakaria, Department of Internal Medicine, Southfield, Michigan, USA. E-mail: Alizakaria86@hotmail.comSep-Oct 2018 7 5 1120 1122 Copyright: © 2018 Journal of Family Medicine and Primary Care2018This 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.Pseudomelanosis of the gastrointestinal (GI) tract is a rare condition used to describe the accumulation of pigment deposits in the intestinal mucosa. Its underlying cause is not well understood. It has been described in association with gastrointestinal hemorrhage, chronic kidney disease, hypertension, diabetes mellitus, and medications such as hydralazine, ferrous sulfate, and furosemide. Melanosis coli is a well-known condition associated with the use of anthranoid laxatives; however, pseudomelanosis of the small intestine is extremely rare and most commonly described in the duodenum, with few cases in the gastric mucosa and even more rare in the jejunum. Herein, we report a case of pseudomelanosis intestini involving the pylorus, duodenum, and proximal jejunum in a patient presented with GI bleeding. The clinical significance of this condition is unknown; however, gastroenterologists should be aware of its existence.\n\nGastro-duodeno-jejunumgastrointestinal pigmentationpseudomelanosis\n==== Body\nIntroduction\nGastrointestinal melanosis is a rare condition described first by Bosordi and Kleinman in 1976 in reference to the endoscopic appearance of black speckled pigmentation of the mucosa.[1] It has been described in association with gastrointestinal hemorrhage, chronic kidney disease, hypertension, diabetes mellitus, and medications such as hydralazine, ferrous sulfate, and furosemide.[2345] Melanosis coli is a well-known condition associated with the use of anthranoid laxatives; however, pseudomelanosis of the small intestine is extremely rare.[67] The underlying cause and the clinical significance of this condition is unknown; however, gastroenterologists should be aware of its existence. Here, we report a case of pseudomelanosis inestini involving the pylorus, duodenum, and proximal jejunum in a patient presented with recurrent GI bleeding.\n\nCase History\nA 70-year-old African–American female with past medical history significant for hypertension, chronic obstructive pulmonary disease, chronic kidney disease stage-IIIb, and permanent atrial fibrillation on anticoagulation with warfarin. She presented to the emergency department complaining of recurrent melena. Her home medications included aspirin, clopidogrel, warfarin, hydralazine, bumetanide, metformin, metoprolol, and albuterol inhaler.\n\nOn physical examination she was alert, oriented, and not in acute distress. Her vital signs were: Temp 97.8°F; pulse 70 bpm; blood pressure 113/69; and respiratory rate 14 bpm. The abdomen was soft and lax without tenderness, rebound, or organomegally, auscultation revealed normal bowel sounds, and point of care fecal occult blood test was positive.\n\nHer initial blood workup revealed normocytic hypochromic anemia with a hemoglobin of 6.9 gm/dl (9.2 gm/dL two weeks prior to this admission), platelets 229 × 103/mcl, and prothrombin time/INR 19.8 seconds/1.8. Serum iron studies revealed a ferritin level of 1704 ng/mL, iron of 74 mcg/dL, total iron binding capacity (TIBC) 183 mcg/dL, unsaturated iron binding capacity (UIBC) 109 mcg/dL, and iron saturation of 15%.\n\nShe underwent esophagogastroduodenoscopy (EGD) which revealed one non-bleeding superficial gastric ulcer with a clean base (Forrest class III) on the lesser curvature of the gastric antrum and diffuse duodenal melanosis. She was discharged home after stabilization and packed red blood cells transfusion. She presented again two weeks later with the same complaint of melena, a repeat EGD showed a healed gastric ulcer with no stigmata of bleeding, and diffuse pseudomelanosis of the gastric antrum, pylorus [Figure 1], duodenum and proximal jejunum [Figure 2]. Histopathology of the gastric antrum and duodenum revealed macrophages containing dark pigmented granules within the lamina propria [Figure 3a and b], nonreactive to Perl's iron stain [Figure 3c], a picture consistent with pseudomelanosis mucosal changes.\n\nFigure 1 EGD images reveal hyperpigmented pyloric mucosa\n\nFigure 2 EGD images reveal hyperpigmented mucosa of duodenum and proximal jejunum\n\nFigure 3 Histopathology revealed pigment-laden macrophages [arrows] within the lamina propria of the (a) pyloric and (b) duodenal mucosa [H&E stain]. The pigment deposits are non-reactive to Perl's iron stain (c)\n\nShe was readmitted three weeks later with similar complaints. An upper and lower device-assisted enteroscopy with fluoroscopy was performed which revealed pseudomelanosis extending throughout the gastric antrum, duodenum, and jejunum (280 cm distal to the pylorus). A 5 mm polyp in the cecum was removed and revealed tubular adenoma, the remaining parts of the colon and terminal ileum were normal with no evidence of melanosis.\n\nDiscussion\nPseudomelanosis intestini is a benign condition that refers to the rare endoscopic appearance of dark pigment deposits in the intestinal mucosa. The condition has a female predominance and is most commonly found in the 6th and 7th decade of life.[2] It is characterized by the accumulation of pigment-laden macrophages in the lamina propria, and is thought to be secondary to iron sulfide, hemosiderin, or lipomelanin deposition within the lysosomes as suggested by histochemical analysis and electron microscopy.[8]\n\nPseudomelanosis is generally recognized on endoscopy; however, the appearance of pigmented gastrointestinal mucosa makes this a challenging dilemma as the differential diagnosis includes clinically significant conditions such as metastatic malignant melanoma, brown bowel syndrome, hemosiderosis, and hemochromatosis.[9] True melanosis associated with malignant melanoma does not stain with Prussian blue, but rather would be highlighted with the Masson-Fontana stain, revealing the melanin pigments.[10] However, this stain is not specific for melanin, and other immunohistochemical stains would benefit in the differentiation of malignant melanoma from pseudomelanosis. Brown bowel syndrome involves the deposition of lipofuscin in the intestinal tunica muscularis and usually spares the actual mucosal lining.[11] It is usually seen with certain vitamin deficiencies but it may also be secondary to an underlying intestinal malignancy.[12] The differentiation between brown bowel syndrome and pseudomelanosis is crucial for identifying the etiology and management of each condition. In hemosiderosis, diffuse strong iron staining of all pigments would be present with the Prussian blue iron stain, in contrast to pseudomelanosis, where there is partial and relatively weak iron positivity.[13] Although pseudomelanosis contains iron components, some biopsies will not stain positive with the Prussian blue iron stain.[14] This discrepancy is thought to be due to iron in the pigments occurring in the iron sulfide form rather than in the iron oxide form, which is not highlighted with the Prussian blue or Perls iron stain.[1314] This is evident in our patient, in which there was a recent history of gastrointestinal hemorrhage yet biopsy specimens resulted in negative Perl's iron stain. This finding suggests that the pigmented mucosa is most likely not a result of hemosiderin deposition from the gastrointestinal hemorrhage.\n\nIt has been proposed that pseudomelanosis is associated with impaired luminal absorption of iron, as it is most commonly seen in the proximal duodenum, the site of maximal iron absorption.[15] This has been hypothesized to be secondary to coupling of iron with sulfur or cyclic compounds, leading to the accumulation of the pigment within the mucosa, the source of sulfate is unclear; however, antihypertensive drugs such as hydralazine and foods that contain sulfate are thought to be the culprit.[16] Nonetheless, this does not explain the extra-duodenal sites of pigments or the association where sulfur containing ingestions are not found. This case is also unique because the pseudomelanosis pigmentation is not confined to areas in the GI tract with known iron absorption, and the distribution of pigmentation is much greater than most cases reported in the literature.\n\nAnother contributing factor that has been hypothesized is a defect in macrophage metabolism that leads to the accumulation of the iron-containing pigments.[17] It has been suggested that this defect is acquired rather than congenital, which is consistent with the chronological appearance of new pigmented mucosa as seen in this patient.\n\nThis case illustrates the importance of identifying the etiology of pigmented mucosa in the gastrointestinal tract and the importance of excluding other causes of the pigmentation. Furthermore, the correlation between the site of pigmentation, the extent of involvement, the clinical significance and long-term sequelae have yet to be fully established.\n\nConclusion\nThe etiologic mechanism, clinical significance, and prognostic and long-term impact of pseudomelanosis intestini remains unknown. Also, there is no established recommendation regarding the need for therapeutic interventions or regular upper endoscopy surveillance.\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\n1 Bisordi WM Kleinman MS Melanosis duodeni Gastrointest Endosc 1976 23 37 8 964586 \n2 Giusto D Jakate S Pseudomelanosis duodeni : Associated with multiple clinical conditions and unpredictable iron stainability – A case series Endoscopy 2008 40 165 7 18253910 \n3 Cantu J Adler D Pseudomelanosis Duodeni Endoscopy 2005 37 789 9 16032511 \n4 De Magalha˜es Costa MH Fernandes Pegado Mda G Vargas C Castro MEC Madi K Nunes T Pseudomelanosis duodeni associated with chronic renal failure World J Gastroenterol 2012 18 1414e6 22493558 \n5 Gupta TP Weinstock JV Duodenal pseudomelanosis associated with chronic renal failure Gastrointest Endosc 1986 32 358 60 3770391 \n6 Kibria R Barde CJ Pseudomelanosis of the stomach Endoscopy 2010 42 E60 20157892 \n7 Weinstock LB Katzman D Wang HL Pseudomelanosis of stomach, duodenum and jejunum Gastrointest Endosc 2003 58 578 14520298 \n8 Ghadially F Walley V Pigments of the gastrointestinal tract: A comparison of light microscopic and electron microscopic findings Ultrastruct Pathol 1995 19 213 9 7571080 \n9 Abumoawad A Venu M Huang L Ding X Pseudomelanosis duodeni: A short review Am J Digest Dis 2015 2 41 5 \n10 Kaplan MR Knittel DR Lawson P Schafer TW Panenteric melanosis: An ominous endoscopic finding Gastrointest Endosc 2005 61 762 5 15855990 \n11 Connolly CE Kennedy M Stevens FM McCarthy CF Brown bowel syndrome occurring in coeliac disease in the west of Ireland Scand J Gastroenterol 1994 29 91 4 8128183 \n12 Horn T Svendsen LB Nielsen R Brown-bowel syndrome. Review of the literature and presentation of cases Scand J Gastroenterol 1990 25 66 72 2406889 \n13 Pounder DJ Ghadially FN Mukherjee TM Hecker R Rowland R Dixon B Ultrastructure and electron-probe x-ray analysis of the pigment in melanosis duodeni J Submicroscopic Cytol Pathol 1982 14 389 400 \n14 Fernando S Pseudomelanosis duodeni: A case report with electron-probe X-ray analysis Pathology 1990 22 169 72 1700852 \n15 Wang K Lin HJ Perng CL Chiang HU Lee CT Chang FY Pseudomelanosis duodeni: Report of eight cases J Formosan Med Assoc 1995 94 632 4 8527967 \n16 Samiullah S Bhurgri H Babar A Samad F Choudhary MM Demyen M Peppered and rare – Gastric and Duodenal Pseudomelanosis: A case series Pak J Med Sci 2017 33 757 60 28811809 \n17 Rex DK Jersild RA Further characterization of the pigment in pseudomelanosis duodeni in three patients Gastroenterology 1988 95 177e82 3371613\n\n",
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"issn_linking": "2249-4863",
"issue": "7(5)",
"journal": "Journal of family medicine and primary care",
"keywords": "Gastro-duodeno-jejunum; gastrointestinal pigmentation; pseudomelanosis",
"medline_ta": "J Family Med Prim Care",
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"nlm_unique_id": "101610082",
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"pages": "1120-1122",
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"references": "14520298;15855990;16032511;1700852;18253910;20157892;22493558;2406889;28811809;3371613;3770391;7077717;7571080;8128183;8527967;964586",
"title": "Pseudomelanosis intestini \"from pylorus to jejunum:\" A rare endoscopic finding in a patient with GI bleeding.",
"title_normalized": "pseudomelanosis intestini from pylorus to jejunum a rare endoscopic finding in a patient with gi bleeding"
} | [
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"abstract": "Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by rapidly progressing necrolytic ulceration of the skin. Proper treatment is crucial since it can result in devastating consequences. First-line treatments include systemic corticosteroids or cyclosporine. However, no standardized treatment regimens for refractory cases exist and treatment outcomes are affected by underlying conditions. PG after cesarean section, which is believed to occur in association with underlying pregnancy- and parturition-related immune changes, is extremely rare, and all reported cases in the literature have been successfully treated with systemic or topical corticosteroids. We report a case of a 32-year-old patient with severe PG occurring on her cesarean scar 3 days after the cesarean delivery. Treatment with systemic corticosteroids and first-line immunomodulatory agents resulted in insufficient response and serious complications. Intravenous immunoglobulin (IVIG) was then initiated, and a rapid clinical response was seen. Corticosteroid dose was gradually decreased and ceased. IVIG infusion was continued for 3 months until complete recovery. Reactivation was not observed in a 1-year follow-up period. Due to its cost, IVIG infusion is less suitable as a first-line agent. However, IVIG may be an important therapeutic option in resistant postpartum PG, in which first-line agents have failed or led to complications.",
"affiliations": "Medical Faculty, Department of Dermatology, Celal Bayar University, Manisa, Turkey.;Medical Faculty, Department of Dermatology, Celal Bayar University, Manisa, Turkey.;Medical Faculty, Department of Obstetrics and Gynecology, Celal Bayar University, Manisa, Turkey.;Medical Faculty, Department of Pathology, Celal Bayar University, Manisa, Turkey.;Medical Faculty, Department of Dermatology, Celal Bayar University, Manisa, Turkey.",
"authors": "Gündüz|Kamer|K|;Gülbaşaran|Fatmagül|F|0000-0002-7550-6052;Hasdemir|Pınar Solmaz|PS|;Temiz|Peyker|P|;Inanır|Işıl|I|",
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"keywords": "cesarean section; intravenous immunoglobulin; postpartum; pyoderma gangrenosum",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D002585:Cesarean Section; D016572:Cyclosporine; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D011247:Pregnancy; D017511:Pyoderma Gangrenosum",
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"pmid": "32743854",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of severe refractory post-cesarean pyoderma gangrenosum with intravenous immunoglobulin.",
"title_normalized": "successful treatment of severe refractory post cesarean pyoderma gangrenosum with intravenous immunoglobulin"
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"literaturereference": "GUNDUZ K, GULBASARAN F, HASDEMIR PS, TEMIZ P, INANIR I. SUCCESSFUL TREATMENT OF SEVERE REFRACTORY POST?CESAREAN PYODERMA GANGRENOSUM WITH INTRAVENOUS IMMUNOGLOBULIN. DERMATOLOGIC THERAPY. 2020?33(6):1?4",
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{
"abstract": "We report two patients with chronic hyperglycaemia secondary to type 2 diabetes who developed severe vomiting on d. The first patient was diagnosed with a mixed picture of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS) and the second, with DKA. They were on insulin therapy which was discontinued on commencing d because of inefficacy and weight gain. The HHS patient developed dehydration secondary to vomiting and had lactic acidosis but no other precipitant could be found in either case. It appears that the abrupt insulin discontinuation coupled with vomiting and dehydration led to the metabolic derangements. Subsequent C-peptide levels were found to be low in both patients. In view of the predisposition of patients with chronic hyperglycaemia to glucagon-like peptide 1 receptor (GLP-1R) downregulation and the lag time to optimal efficacy of GLP-1R agonists, we propose that patients should have C-peptide levels measured to determine the risk of ketosis and whether insulin should be continued with dose adjustments when starting a GLP-1R agonist.",
"affiliations": "Sligo University Hospital, Sligo, Ireland.;Department of Medicine, Sligo University Hospital, Sligo, Ireland.;Department of Endocrinology, Sligo General Hospital, Sligo, Ireland.",
"authors": "Okiro|Julie Omolola|JO|;Mc Hugh|Catherine|C|;Abdalla|Abuelmagd|A|",
"chemical_list": "D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D007328:Insulin; D011993:Recombinant Fusion Proteins; D004763:Glucagon-Like Peptides; C555680:dulaglutide",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220437",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Diabetes; Drugs: endocrine system",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D003924:Diabetes Mellitus, Type 2; D003937:Diagnosis, Differential; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides; D006801:Humans; D006943:Hyperglycemia; D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D007328:Insulin; D008297:Male; D011993:Recombinant Fusion Proteins",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28710307",
"pubdate": "2017-07-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17360984;19037628;22863615;23413806;23869296;25830090;25980647;26213556",
"title": "Is it safe to acutely discontinue insulin therapy in patients with chronic hyperglycaemia starting GLP-1R agonists?",
"title_normalized": "is it safe to acutely discontinue insulin therapy in patients with chronic hyperglycaemia starting glp 1r agonists"
} | [
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}
},
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"drugdosagetext": "25 UNITS IN THE MORNING AND 20 UNITS IN THE EVENING",
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},
{
"reactionmeddrapt": "Lactic acidosis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
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},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
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"literaturereference": "OKIRO J. IS IT SAFE TO ACUTELY DISCONTINUE INSULIN THERAPY IN PATIENTS WITH CHRONIC HYPERGLYCAEMIA STARTING GLP-1R AGONISTS?. BMJ-CASE-REP 2017. 2017 JAN 01;.",
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"qualification": "3",
"reportercountry": "IE"
},
"primarysourcecountry": "IE",
"receiptdate": "20170928",
"receivedate": "20170928",
"receiver": {
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},
"reporttype": "1",
"safetyreportid": 14020341,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
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}
] |
{
"abstract": "Studies have suggested that the incidence of multiple sclerosis (MS) in HIV-infected (HIV+) patients is lower than that of the general population. Here, we present a case of MS in an HIV+ patient with a relatively suppressed CD4 cell count who developed clinical and radiographic disease worsening in the setting of antiretroviral therapy (ART) initiation. A 47-year-old HIV+ woman (CD4 cell count 216 cells/µl) presented with decreased vision in her right eye. Magnetic resonance imaging (MRI) revealed optic nerve enhancement and open ring-enhancing lesions in the brain concerning for demyelinating disease. Cerebrospinal fluid was tested extensively for infection and malignancy with no abnormal findings. She received five days of intravenous methylprednisolone. Nine days later, she was restarted on ART. Three weeks later, she was readmitted with left eye vision loss and left hemiplegia (CD4 cell count 342 cells/µl). Repeat imaging showed multiple new enhancing lesions. Several cases have described severe MS relapses and unusually widespread demyelinating lesions on MRI after withdrawal of immunosuppressive drugs. We posit that the clinical and radiographic progression that occurred in our patient after initiation of ART represented an immune reconstitution response to ART. Caution may be warranted when initiating ART in HIV+ patients with suppressed CD4 cell count and active MS.",
"affiliations": "Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.",
"authors": "Anand|Pria|P|0000-0002-7421-7750;Saylor|Deanna|D|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "England",
"delete": false,
"doi": "10.1177/0956462418754972",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "29(9)",
"journal": "International journal of STD & AIDS",
"keywords": "HIV; antiretroviral therapy; immune reconstitution; multiple sclerosis",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009103:Multiple Sclerosis",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "929-932",
"pmc": null,
"pmid": "29466918",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple sclerosis and HIV: a case of multiple sclerosis-immune reconstitution inflammatory syndrome associated with antiretroviral therapy initiation.",
"title_normalized": "multiple sclerosis and hiv a case of multiple sclerosis immune reconstitution inflammatory syndrome associated with antiretroviral therapy initiation"
} | [
{
"companynumb": "US-MYLANLABS-2018M1060136",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE"
},
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"drugauthorizationnumb": "206436",
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"drugindication": "HIV INFECTION",
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"medicinalproduct": "EMTRICITABINE/TENOFOVIR DISOPROXIL FUMARATE"
},
{
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"activesubstance": {
"activesubstancename": "DOLUTEGRAVIR"
},
"drugadditional": "3",
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"drugenddateformat": null,
"drugindication": "HIV INFECTION",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
"drugrecurrence": null,
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"medicinalproduct": "DOLUTEGRAVIR"
}
],
"patientagegroup": null,
"patientonsetage": "47",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Multiple sclerosis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Immune reconstitution inflammatory syndrome",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ANAND P, SAYLOR D. MULTIPLE SCLEROSIS AND HIV: A CASE OF MULTIPLE SCLEROSIS-IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME ASSOCIATED WITH ANTIRETROVIRAL THERAPY INITIATION. INT-J-STD-AIDS 2018?29(9):929-932.",
"literaturereference_normalized": "multiple sclerosis and hiv a case of multiple sclerosis immune reconstitution inflammatory syndrome associated with antiretroviral therapy initiation",
"qualification": "3",
"reportercountry": "US"
},
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"receiptdate": "20180808",
"receivedate": "20180808",
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},
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190204"
}
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{
"abstract": "Saprochaete capitata (S. capitata) is a very rare fungal pathogen that causes disseminated opportunistic infections in patients with hematologic malignancies. Fever resistant to broad-spectrum antibiotic and antifungal treatment is common in the presence of fungemia during the period of profound neutropenia. We describe three cases of leukemic children who died from S. capitata fungemia following a first febrile neutropenic episode after the induction of chemotherapy. S. capitata fungemia is an emergent infection associated with high mortality and low susceptibility to fluconazole and echinocandins. Awareness of this emergent infection is needed to ensure that it can be properly treated.",
"affiliations": "a Division of Pediatric Hematology/Oncology, Faculty of Medicine , Eskişehir Osmangazi University , Eskişehir , Turkey.;b Divison of Pediatric Hematology/Oncology , İstanbul Medeniyet University Göztepe Traininig and Research Hospital , İstanbul , Turkey.;a Division of Pediatric Hematology/Oncology, Faculty of Medicine , Eskişehir Osmangazi University , Eskişehir , Turkey.;c Division of Pediatric Intensive Care Unit, Faculty of Medicine , Eskişehir Osmangazi University , Eskişehir , Turkey.;d Department of Pediatrics, Faculty of Medicine , Eskişehir Osmangazi University , Eskişehir , Turkey.",
"authors": "Özdemir|Zeynep Canan|ZC|;Bozkurt Turhan|Ayşe|A|;Düzenli Kar|Yeter|Y|;Dinleyici|Çağrı Ener|ÇE|;Bör|Özcan|Ö|",
"chemical_list": "D054714:Echinocandins; D015725:Fluconazole",
"country": "England",
"delete": false,
"doi": "10.1080/08880018.2017.1316808",
"fulltext": null,
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"issn_linking": "0888-0018",
"issue": "34(2)",
"journal": "Pediatric hematology and oncology",
"keywords": null,
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D054714:Echinocandins; D017809:Fatal Outcome; D005260:Female; D015725:Fluconazole; D016469:Fungemia; D006801:Humans; D060828:Induction Chemotherapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D004718:Saccharomycetales",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "66-72",
"pmc": null,
"pmid": "28574735",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal course of Saprochaete capitata fungemia in children with acute lymphoblastic leukemia.",
"title_normalized": "fatal course of saprochaete capitata fungemia in children with acute lymphoblastic leukemia"
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"abstract": "BACKGROUND\nImmune-related adverse events (ir-AEs) are increasingly becoming a concern, as immune checkpoint inhibitors (ICIs) are used more frequently. Herein, we present a case of fulminant cytokine release syndrome (CRS) complicated by dermatomyositis after the combination therapy with ICIs.\nA 70-year-old male developed dermatomyositis during the course of treatment with two ICIs, nivolumab and ipilimumab. He was treated by steroid pulse therapy, but the effect was limited. Afterwards, he had acute-onset high fever, hypotension, respiratory failure, impaired consciousness, renal failure, and coagulation abnormality at the same time. C reactive protein (CRP), creatinine kinase (CK), D-dimer, and ferritin levels were considerably elevated: CRP, 24 mg/dL; CK, 40,500 U/L; D-dimer, 290 μg/mL; ferritin, 329,000 ng/mL.\n\n\nMETHODS\nCRS induced by ICI combination therapy.\n\n\nMETHODS\nGiven that high fever and elevated CRP level indicated potential sepsis, an antibiotic was used until the confirmation of negative blood cultures. All the simultaneous acute symptoms were supposed to be CRS. He was admitted to the intensive care unit (ICU), and temporary intubation and hemodialysis were needed. Immunosuppressive therapy was reinforced by mycophenolate mofetil together with steroid, and plasma exchange was performed for the elimination of abnormal proteins.\n\n\nRESULTS\nThe patient's clinical symptoms and laboratory parameters gradually improved and he was discharged from the ICU in a month.\n\n\nCONCLUSIONS\nFulminant CRS can be induced by ICI combination therapy. As the initial symptoms of CRS resemble sepsis, it is important to consider CRS as a differential diagnosis and to initiate immunosuppressive therapy early when needed. In steroid-resistant cases, early introduction of other immunosuppressive therapy and plasma exchange can be effective.",
"affiliations": "Department of Neurology, Kobe City Medical Center General Hospital, 650-0047, 2-1-1 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo.;Department of Neurology, Kobe City Medical Center General Hospital, 650-0047, 2-1-1 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo.;Department of Urology, Kobe City Medical Center General Hospital, 650-0047, 2-1-1 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo, Japan.;Department of Neurology, Kobe City Medical Center General Hospital, 650-0047, 2-1-1 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo.",
"authors": "Ohira|Junichiro|J|;Kawamoto|Michi|M|;Sugino|Yoshio|Y|;Kohara|Nobuo|N|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D007155:Immunologic Factors; D000074324:Ipilimumab; D000077594:Nivolumab; D009173:Mycophenolic Acid",
"country": "United States",
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"doi": "10.1097/MD.0000000000019741",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32282733\nMD-D-19-06050\n10.1097/MD.0000000000019741\n19741\n3600\nResearch Article\nClinical Case Report\nA case report of fulminant cytokine release syndrome complicated by dermatomyositis after the combination therapy with immune checkpoint inhibitors\nOhira Junichiro MDab∗ Kawamoto Michi MDa Sugino Yoshio MD, PhDc Kohara Nobuo MD, PhDa NA. \na Department of Neurology, Kobe City Medical Center General Hospital, 650-0047, 2-1-1 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo\n\nb Department of Neurology, Kyoto University Hospital, 606-8507, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto\n\nc Department of Urology, Kobe City Medical Center General Hospital, 650-0047, 2-1-1 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo, Japan.\n∗ Correspondence: Junichiro Ohira, Department of Neurology, Kobe City Medical Center General Hospital, 650-0047, 2-1-1 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo, Japan (e-mail: j.ohira0614@gmail.com).\n4 2020 \n10 4 2020 \n99 15 e1974102 8 2019 07 1 2020 04 3 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This 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\nIntroduction:\nImmune-related adverse events (ir-AEs) are increasingly becoming a concern, as immune checkpoint inhibitors (ICIs) are used more frequently. Herein, we present a case of fulminant cytokine release syndrome (CRS) complicated by dermatomyositis after the combination therapy with ICIs.\n\nPatient concerns:\nA 70-year-old male developed dermatomyositis during the course of treatment with two ICIs, nivolumab and ipilimumab. He was treated by steroid pulse therapy, but the effect was limited. Afterwards, he had acute-onset high fever, hypotension, respiratory failure, impaired consciousness, renal failure, and coagulation abnormality at the same time. C reactive protein (CRP), creatinine kinase (CK), D-dimer, and ferritin levels were considerably elevated: CRP, 24 mg/dL; CK, 40,500 U/L; D-dimer, 290 μg/mL; ferritin, 329,000 ng/mL.\n\nDiagnosis:\nCRS induced by ICI combination therapy.\n\nInterventions:\nGiven that high fever and elevated CRP level indicated potential sepsis, an antibiotic was used until the confirmation of negative blood cultures. All the simultaneous acute symptoms were supposed to be CRS. He was admitted to the intensive care unit (ICU), and temporary intubation and hemodialysis were needed. Immunosuppressive therapy was reinforced by mycophenolate mofetil together with steroid, and plasma exchange was performed for the elimination of abnormal proteins.\n\nOutcomes:\nThe patient's clinical symptoms and laboratory parameters gradually improved and he was discharged from the ICU in a month.\n\nConclusion:\nFulminant CRS can be induced by ICI combination therapy. As the initial symptoms of CRS resemble sepsis, it is important to consider CRS as a differential diagnosis and to initiate immunosuppressive therapy early when needed. In steroid-resistant cases, early introduction of other immunosuppressive therapy and plasma exchange can be effective.\n\nKeywords\ncytokine release syndromedermatomyositisimmune checkpoint inhibitorsimmune-related adverse eventsOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nImmune checkpoint inhibitors (ICIs) have emerged as a novel class of anti-cancer agents. ICIs include the programmed cell death protein 1 (PD-1), its ligand (PD-L1), and the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors. The basic mechanism of action of these drugs is to release the brakes of immune regulation and to restore anti-cancer immune response.12 It has been recently demonstrated that combination therapy with nivolumab (a PD-1 inhibitor) and ipilimumab (a CTLA-4 inhibitor) prolonged survival better than standard chemotherapy for the treatment of metastatic renal cell carcinoma.[3] However, various immune-related adverse events (ir-AEs) have been reported to occur during such treatment.[2] The incidence of ir-AEs in melanoma patients was higher during combination therapy than during monotherapy with either nivolumab or ipilimumab[4], and thus ir-AEs are of greater concern in the combination use of ICIs. Neuromuscular ir-AEs sometimes occur and myositis is known to be one of the most frequent ones.[5]\n\n\nCytokine release syndrome (CRS) is a condition of immune system hyperactivation typically reported in leukemia patients after chimeric antigen receptor engineered T (CAR-T) cell therapy.678 Although uncommon, severe CRS can occur after the administration of ICIs.910111213 In this report, we describe a patient with fulminant CRS complicated by dermatomyositis after ICI combination therapy, who temporarily needed intubation and hemodialysis, but recovered after immunosuppressive therapy and plasma exchange followed by intravenous immunoglobulin (IVIg) therapy.\n\n2 Case report\nAn appropriate written informed consent for publication was obtained from the patient and his family.\n\n2.1 Patient background before admission\nA chest X-ray during a routine medical examination of a 70-year-old male on September 2018 revealed a large tumor in the right lung field. Truncal contrast-enhanced computed tomography (CT) for further evaluation showed multiple tumors in mediastinal lymph nodes, lung, left kidney, para-aortic lymph nodes, and vertebral bodies, as well as in the right thoracic wall, which had been identified in the chest X-ray (Fig. 1A (A1, A2)). The left renal biopsy confirmed the diagnosis of renal cell carcinoma with multiple metastases. It was evaluated as clinical stage 4, T4N1M1 in accordance with TNM classification of Malignant Tumor 8th edition (Union for International Cancer Control, Geneva, Switzerland) and pathological grade 4.[14] As a surgical operation was not applicable, a combination of the ICIs, nivolumab and ipilimumab, was chosen as the initial treatment (Fig. 2).[3] On the following day after the administration of the both drugs, erythema appeared on his dorsal hands and gradually spread to all extremities and body trunk on a daily basis. As the application of steroid ointment was not effective, 30 mg oral prednisolone was administered three weeks after the appearance of erythema. On the same day, nivolumab and ipilimumab were administered for the second time, because erythema was considered to be the only side effect of the first administration. Two days after the second administration, the patient began to have difficulty in elevating his upper limbs and standing up from a squatting position. Although erythema started to improve and oral prednisolone was reduced to 20 mg, he was referred to our Neurology Department by the urologist due to developing muscle weakness 1 week after the second administration. On physical examination, the patient did not have respiratory distress and was alert. He had Gottron sign, shawl sign, and mild erythema on the back, abdomen, and face. Neurological examination revealed proximal limb muscle and truncal weakness without easy fatigability. He had no gait disturbance but had difficulty in sitting up from the supine position. Cranial nerve abnormalities including impairment of ocular movement, ptosis, dysarthria, or dysphasia were not observed. All other neurological findings were normal. The blood test revealed marked elevation of creatinine kinase (CK, 17,386 U/L) (Table 1) and positive for anti-Mi-2 (>150; normal range, 0–52) and anti-transcriptional intermediary factor 1-γ (anti-TIF1-γ) antibodies (50; normal range, 0–31). The patient had a lower titer of anti-Mi-2 antibody (124) and was negative for anti-TIF1-γ antibody before the administration of the ICIs. Anti-aminoacyl tRNA synthetase antibodies and an acetylcholine receptor antibody were negative. Electromyography showed active myopathic changes in the left biceps, right deltoid, and left paraspinal muscles. Low-frequency repetitive stimulation demonstrated no decrement in the left ulnar, facial, and accessory nerves. Magnetic resonance imaging of the left proximal upper limb showed edema and inflammation (Fig. 1B). Therefore, the patient was diagnosed with dermatomyositis, which most likely was an ir-AE (Grade 3, according to the Common Terminology Criteria for Adverse Events [version 5.0])[15] induced by the two ICIs, and admitted to our Neurology Department.\n\nFigure 1 (A) Truncal contrast-enhanced computed tomography at the diagnosis of multiple tumors. (A1) Tumors of mediastinal lymph nodes and the right thoracic wall. (A2) Tumors of the left kidney and para-aortic lymph nodes. (B) Short-tau inversion recovery MRI showing broad hyperintensity in left upper limb muscles. (B1) Coronal section. (B2) Axial section.\n\nFigure 2 Clinical course after the administration of two immune checkpoint inhibitors (ICIs), nivolumab and ipilimumab. Rash, progressive muscle weakness, and high creatinine kinase level led us to the diagnosis of dermatomyositis induced by ICIs. Steroid therapy failed to prevent acute deterioration of symptoms such as high fever, mild drop in blood pressure, respiratory failure, mildly impaired consciousness, renal failure, and coagulation abnormality. Considerably elevated levels of C reactive protein, creatinine kinase, D-dimer, and ferritin were detected as shown in the graph in the middle. Antibiotic treatment was used until the confirmation that blood cultures were negative. All simultaneous acute symptoms likely represented cytokine release syndrome induced by ICIs. Although temporary intubation and hemodialysis were needed, administration of mycophenolate mofetil together with steroid and plasma exchange followed by intravenous immunoglobulin improved the above symptoms and abnormalities of laboratory parameters. Intractable oral enanthema and diarrhea followed the acute deterioration. Muscle weakness did not improve. CFPM = cefepime, CHDF = continuous hemodiafiltration, CK = creatinine kinase, CRP = C reactive protein, HD = hemodialysis, IVIg = intravenous immunoglobulin, MEPM = meropenem, MMF = mycophenolate mofetil, mPSL = methylprednisolone, PE = plasma exchange, PSL = prednisolone, VCM = vancomycin.\n\nTable 1 Laboratory parameters on days 1, 6, 16, and around day 30.\n\n2.2 Clinical course after admission\nAs his muscle weakness was progressing even after oral administration of prednisolone at 20 to 30 mg, he was treated with intravenous pulse therapy of 500 mg methylprednisolone for 3 days from the admission day (day 1), followed by 30 mg oral prednisolone (Fig. 2). Both ICIs were discontinued. The reduction in CK level was limited to mild, and muscle weakness remained at the same level. In the evening of day 5, the patient had an acute episode of high fever (39°C) and started shivering. Systolic blood pressure dropped to 100 mmHg from 150 mmHg. As the blood test revealed elevated white blood cell count (27,800/μL) and C reactive protein level (CRP, 8.89 mg/dL), sepsis was suspected, and intravenous administration of cefepime was initiated. Next morning (day 6), the patient had pale extremities, respiratory failure, anuria due to acute renal failure, and mildly impaired consciousness, in addition to high fever. The laboratory tests showed considerable elevation of CRP, CK, D-dimer, and ferritin levels, which indicated disseminated intravascular coagulation and cytokine storm (Table 1). Arterial blood showed lactic acidosis (lactate level, 6.2 mmol/L) and hypoxemia (PaO2, 57.4 mmHg). The patient's symptoms were getting worse hourly, and he was moved to the intensive care unit (ICU). His cardiac function was normal and the chest X-ray showed no abnormalities except for the known tumor in the right lung field. He was intubated due to acute respiratory failure and continuous hemodiafiltration (CHDF) was initiated for acute renal failure (Fig. 2). Catecholamine was not needed to keep the blood pressure. All acute events that occurred simultaneously on day 5 were considered to indicate CRS (Grade 4, according to the Common Terminology Criteria for Adverse Events [version 5.0])[15] induced by ICIs, which would be steroid-resistant, rather than sepsis. Therefore, from the ICU admission day immunosuppressive therapy was strengthened with 2000 mg of mycophenolate mofetil (MMF), which is recommended in various steroid refractory ir-AEs, together with second methylprednisolone pulse therapy.[16] In addition, plasma exchange was performed in order to remove abnormal cytokines and replace coagulation factors with fresh frozen plasma. IVIg therapy followed 6 times of plasma exchange. Blood cultures collected before the administration of antibiotics were predictably negative and sepsis was ruled out at this point. The immunosuppressive therapy and plasma exchange were effective. The patient was extubated 3 days after the intubation. CHDF was switched to intermittent hemodialysis, and he got off hemodialysis on day 29 and was discharged from the ICU. Laboratory parameters including CRP, CK, D-dimer, and ferritin levels improved gradually, and the levels of most cytokines decreased (Table 1). Thrombocytopenia gradually developed and platelet count reached the minimum of 19,000/μL on day 16. Bone marrow biopsy revealed mild hemophagocytosis, but megakaryocyte count was normal. Thrombocytopenia slowly improved, possibly as a result of immunotherapy. Anemia gradually progressed and did not improve conceivably due to renal dysfunction. Additional problems that occurred a few days after the acute deterioration were intractable oral enanthema and diarrhea without abdominal pain. Tests for serum β-D glucan, cytomegalovirus antigenemia, and Clostridium difficile toxin in the ICU were negative. The biopsy of oral mucosa and tongue ruled out pemphigus vulgaris and pemphigoid, suggesting mucosal damage by the ICIs. Oral enanthema improved around day 60. Colonoscopy revealed mildly white colon mucosa, and colon biopsy showed mild lymphocytic inflammation with edema, which was compatible with colitis induced by ICIs.1718 As it was difficult to continue enteral nutrition because of diarrhea, a central venous port was implanted for intravenous hyperalimentation. It was, of course, difficult to administer nivolumab and ipilimumab again due to the fulminant ir-AEs. Multiple tumors slightly enlarged within one month before the administration of the two ICIs, but remained almost the same size for two months after the admission, likely due to the positive effect of the ICIs. The muscle weakness did not improve possibly due to the complication of critical illness. The patient changed hospital for recuperation on day 93.\n\n3 Discussion\nWe present a case of fulminant CRS induced by ICI combination therapy. Dermatomyositis preceded the CRS and was steroid-resistant. Plasma exchange and immunosuppressive therapy with steroid and MMF gradually improved clinical symptoms and laboratory parameters.\n\nVarious ir-AEs including neuromuscular disorders have been reported so far in conjunction with ICI use.219 Myositis induced by ICIs (irMyositis) is one of the most common neuromuscular adverse events. Most cases of irMyositis can be successfully treated with steroid therapy[19] and IVIg or plasma exchange can be additional options.[16] In the present case, however, the effect of steroid was limited and fulminant CRS followed irMyositis. Additional plasma exchange and IVIg did not improve muscle weakness. As the rate of fetal myositis is higher in ICI combination therapy than in monotherapy,[20] the effect of steroid was limited in the present case possibly because of the combination therapy.\n\nDiarrhea due to colitis was another ir-AE which occurred in this case. Frequency of diarrhea and colitis are higher in ICI combination therapy than in monotherapy.[21] Gastrointestinal adverse events can occur any time during treatment with ICIs. The management of diarrhea and colitis is not standardized, but in severe cases, ICIs should be permanently discontinued and immunosuppressive therapy with steroid or infliximab is recommended.[21] In the present case, diarrhea did not improve by immunosuppressive therapy including steroid, MMF, and IVIg, inevitably resulting in the implantation of a central venous port. Infectious etiology was ruled out by colonoscopy and examinations for serum β-D glucan, cytomegalovirus antigenemia, and Clostridium difficile toxin.\n\nCRS is known to commonly occur after CAR-T cell therapy.[8] The symptoms can vary from mild to severe and include high fever, hypotension, respiratory failure, renal failure, hepatic damage, disseminated intravascular coagulation, and encephalopathy. As the most common initial symptom is high fever, it is often difficult to distinguish CRS from sepsis. Another differential diagnosis is tumor lysis syndrome, which can be diagnosed by laboratory findings. In the present case, several severe symptoms like those mentioned above occurred simultaneously, and blood cultures were negative. These findings strongly supported the diagnosis of CRS.\n\nTo the best of our knowledge, there have been only 4 reported cases of CRS after the administration of ICIs (Table 2)10111213. There likely were unreported or missed cases, which might have been misdiagnosed as sepsis. High fever was the first symptoms in all 4 cases, and CRS occurred between the first and fourth administration of ICIs, which was similar timing of the occurrence of other ir-AEs.[2] In the present case, high fever preceded all symptoms about 2 weeks after the second administration of ICIs. The symptoms of the present case were relatively severe compared to other four cases, and the complication of myositis prior to CRS was unique in the present case. Four reported cases had no other immunological disorders before CRS. Severe CRS following irMyositis in the present case might be because of the combination therapy of ICIs, whereas nivolumab monotherapy was used in the other four cases. Treatment of CRS is not established, but tocilizumab, an anti-interleukin 6 receptor antibody, and steroid are currently recommended for CRS after CAR-T cell therapy.[8] In addition, one case report suggested the effectiveness of plasma exchange.[22] As for CRS induced by ICIs, three of four reported cases underwent treatments: high-dose steroid and tocilizumab[11], oral prednisolone[12], and steroid pulse therapy, MMF, and thrombomodulin[13], which improved each clinical symptom at least partially. As preceding dermatomyositis was resistant to steroid therapy in the present case, immunosuppressive therapy was reinforced by MMF in addition to the second steroid pulse therapy, and plasma exchange was performed for the elimination of abnormal coagulation factors, which gradually improved our patient's symptoms.\n\nTable 2 Comparison between four reported cases of CRS after the administration of ICIs and the present case.\n\nThe risk factors for CRS after the administration of ICIs are unknown and even those for other relatively common ir-AEs post ICI treatment have not yet been elucidated.[2] It is considered that high disease burden (the percentage of blast cells in bone marrow) in leukemia is one of the most important risk factors for CRS after CAR-T cell therapy.[8] According to this point of view, large size of the tumor that included both primary and metastatic lesions might have contributed to the fulminant CRS in our case.\n\nICI combination therapy is associated with severe ir-AEs and multiorgan involvement more frequently than monotherapy.2023 As mentioned above, risk of fatal myositis and higher grade diarrhea is higher in combination therapy. Notably, fatal ir-AEs tend to occur early after ICI treatment and earlier in combination therapy. (Median time from therapy initiation to symptom onset: 14.5 days in combination therapy and 40 days in monotherapy)[20] In the present case, dermatomyositis (Grade 3) and CRS (Grade 4) occurred 23 days and 35 days after the first administration of ICIs, which were compatible timing with the previous reports.\n\nIn conclusion, dermatomyositis and fulminant CRS occurred after the combination therapy with ICIs. As the initial symptoms of CRS resemble sepsis, it is important to consider CRS as a differential diagnosis and to initiate immunosuppressive therapy early when needed. Due to a possible risk of severe CRS, more careful observation of symptoms may be necessary especially in the early phase if ICI combination therapy is performed for the patients with large tumors. In steroid-resistant cases, early introduction of additional immunosuppressive therapy and plasma exchange can be effective.\n\nAuthor contributions\n\nWriting – original draft: Junichiro Ohira.\n\n\nWriting – review & editing: Michi Kawamoto, Yoshio Sugino, Nobuo Kohara.\n\nAbbreviations: γ-GTP = γ-glutamyltransferase, ALP = alkaline phosphatase, ALT = alanine transaminase, APTT = activated partial thromboplastin time, ASPS = alveolar soft part sarcoma, AST = aspartate aminotransferase, BUN = blood urea nitrogen, CAR-T = chimeric antigen receptor engineered T, CFPM = cefepime, CHDF = continuous hemodiafiltration, CK = creatinine kinase, CRP = C reactive protein, CRS = cytokine release syndrome, CT = computed tomography, CTLA-4 = cytotoxic T-lymphocyte associated protein 4, HD = hemodialysis, HL = hodgkin lymphoma, HLH = hemophagocytic lymphohistocytosis, ICIs = immune checkpoint inhibitors, IL = interleukin, INF-γ = interferon-γ, ir-AEs = immune-related adverse events, IVIg = intravenous immunoglobulin, LDH = lactate dehydrogenase, MEPM = meropenem, MMF = mycophenolate mofetil, mPSL = methylprednisolone, MSAs = myositis specific autoantibodies, PD-1 = programmed cell death protein 1, PE = plasma exchange, PF = purpura fulminans, PSL = prednisolone, PT-INR = prothrombin time-international normalized ratio, sIL-2R = soluble interleukin-2 receptor, STNFR = soluble tumor necrosis factor receptor, TIF1-γ = transcriptional intermediary factor 1-γ, TM = thrombomodulin, TNF-α = tumor necrosis factor-α, TTP = thrombotic thrombocytopenic purpura, VCM = vancomycin.\n\nHow to cite this article: Ohira J, Kawamoto M, Sugino Y, Kohara N. A case report of fulminant cytokine release syndrome complicated by dermatomyositis after the combination therapy with immune checkpoint inhibitors. Medicine. 2020;99:15(e19741).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] \nPardoll DM \nThe blockade of immune checkpoints in cancer immunotherapy\n. Nat Rev Cancer \n2012 ;12 :252 –64\n.22437870 \n[2] \nPostow MA Sidlow R Hellmann MD \nImmune-related adverse events associated with immune checkpoint blockade\n. N Engl J Med \n2018 ;378 :158 –68\n.29320654 \n[3] \nPowles T Albiges L Staehler M \nUpdated European Association of Urology guidelines recommendations for the treatment of first-line metastatic clear cell renal cancer\n. Eur Urol \n2017 ;73 :311 –5\n.29223605 \n[4] \nLarkin J Chiarion-Sileni V Gonzalez R \nCombined nivolumab and ipilimumab or monotherapy in untreated melanoma\n. N Engl J Med \n2015 ;373 :23 –34\n.26027431 \n[5] \nMoreira A Loquai C Pföhler C \nMyositis and neuromuscular side-effects induced by immune checkpoint inhibitors\n. Eur J Cancer \n2019 ;106 :12 –23\n.30453170 \n[6] \nLee DW Gardner R Porter DL \nCurrent concepts in the diagnosis and management of cytokine release syndrome\n. Blood \n2014 ;124 :188 –95\n.24876563 \n[7] \nGrupp SA Kalos M Barrett D \nChimeric antigen receptor-modified T cells for acute lymphoid leukemia\n. N Engl J Med \n2013 ;368 :1509 –18\n.23527958 \n[8] \nShimabukuro-Vornhagen A Gödel P Subklewe M \nCytokine release syndrome\n. J Immunother Cancer \n2018 ;6 :56 .29907163 \n[9] \nKähler KC Hassel JC Heinzerling L \nManagement of side effects of immune checkpoint blockade by anti-CTLA-4 and anti-PD-1 antibodies in metastatic melanoma\n. J Dtsch Dermatol Ges \n2016 ;14 :662 –81\n.\n[10] \nZhao L Yang Y Li W \nNivolumab-induced cytokine-release syndrome in relapsed/refractory Hodgkin's lymphoma: a case report and literature review\n. Immunotherapy \n2018 ;10 :913 –7\n.30149764 \n[11] \nRotz SJ Leino D Szabo S \nSevere cytokine release syndrome in a patient receiving PD-1-directed therapy\n. Pediatr Blood Cancer \n2017 ;64 :e26642 .\n[12] \nOda H Ishihara M Miyahara Y \nFirst case of cytokine release syndrome after nivolumab for gastric cancer\n. Case Rep Oncol \n2019 ;12 :147 –56\n.31043953 \n[13] \nHonjo O Kubo T Sugaya F \nSevere cytokine release syndrome resulting in purpura fulminans despite successful response to nivolumab therapy in a patient with pleomorphic carcinoma of the lung: a case report\n. J Immunother Cancer \n2019 ;7 :97 .30944043 \n[14] \nMoch H \nThe WHO/ISUP grading system for renal carcinoma\n. Pathologe \n2016 ;37 :355 –60\n.27271258 \n[15] \nNational Cancer Institute: the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 .\n[16] \nBrahmer JR Lacchetti C Schneider BJ \nManagement of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline\n. J Clin Oncol \n2018 ;36 :1714 –68\n.29442540 \n[17] \nMichot JM Bigenwald C Champiat S \nImmune-related adverse events with immune checkpoint blockade: a comprehensive review\n. Eur J Cancer \n2016 ;54 :139 –48\n.26765102 \n[18] \nBeck KE Blansfield JA Tran KQ \nEnterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4\n. J Clin Oncol \n2006 ;24 :2283 –9\n.16710025 \n[19] \nFellner A Makranz C Lotem M \nNeurologic complications of immune checkpoint inhibitors\n. J Neurooncol \n2018 ;137 :601 –9\n.29332184 \n[20] \nWang DY Salem J-E Cohen JV \nFatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis\n. JAMA Oncol \n2018 ;4 :1721 –8\n.30242316 \n[21] \nTandon P Bourassa-Blanchette S Bishay K \nThe risk of diarrhea and colitis in patients with advanced melanoma undergoing immune checkpoint inhibitor therapy: a systematic review and meta-analysis\n. J Immunother \n2018 ;41 :101 –8\n.29401166 \n[22] \nXiao X He X Li Q \nPlasma exchange can be an alternative therapeutic modality for severe cytokine release syndrome after chimeric antigen receptor-T cell infusion: a case report\n. Clin Cancer Res \n2019 ;25 :29 –34\n.30322878 \n[23] \nZhou S Khanal S Zhang H \nRisk of immune-related adverse events associated with ipilimumab-plus-nivolumab and nivolumab therapy in cancer patients\n. Ther Clin Risk Manag \n2019 ;15 :211 –21\n.30774357\n\n",
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"abstract": "BACKGROUND\nThe outcome of childhood acute lymphoblastic leukemia has improved because of intensive chemotherapy and supportive care. The frequency of adverse events has also increased, but the data related to acute central nervous system complications during acute lymphoblastic leukemia treatment are sparse. The purpose of this study is to evaluate these complications and to determine their long term outcome.\n\n\nMETHODS\nWe retrospectively analyzed the hospital reports of 323 children with de novo acute lymphoblastic leukemia from a 13-year period for acute neurological complications. The central nervous system complications of leukemic involvement, peripheral neuropathy, and post-treatment late-onset encephalopathy, and neurocognitive defects were excluded.\n\n\nRESULTS\nTwenty-three of 323 children (7.1%) suffered from central nervous system complications during acute lymphoblastic leukemia treatment. The majority of these complications (n = 13/23; 56.5%) developed during the induction period. The complications included posterior reversible encephalopathy (n = 6), fungal abscess (n = 5), cerebrovascular lesions (n = 5), syndrome of inappropriate secretion of antidiuretic hormone (n = 4), and methotrexate encephalopathy (n = 3). Three of these 23 children (13%) died of central nervous system complications, one from an intracranial fungal abscess and the others from intracranial thrombosis. Seven of the survivors (n = 7/20; 35%) became epileptic and three of them had also developed mental and motor retardation.\n\n\nCONCLUSIONS\nAcute central neurological complications are varied and require an urgent approach for proper diagnosis and treatment. Collaboration among the hematologist, radiologist, neurologist, microbiologist, and neurosurgeon is essential to prevent fatal outcome and serious morbidity.",
"affiliations": "Department of Pediatric Hematology, Uludag University Medical Faculty, Bursa, Turkey. Electronic address: baytanbirol@yahoo.com.;Department of Pediatric Hematology, Uludag University Medical Faculty, Bursa, Turkey.;Department of Pediatric Hematology, Uludag University Medical Faculty, Bursa, Turkey.;Department of Pediatric Hematology, Uludag University Medical Faculty, Bursa, Turkey.;Department of Pediatric Neurology, Uludag University Medical Faculty, Bursa, Turkey.",
"authors": "Baytan|Birol|B|;Evim|Melike Sezgin|MS|;Güler|Salih|S|;Güneş|Adalet Meral|AM|;Okan|Mehmet|M|",
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"keywords": "ALL-BFM protocols; abscess; acute central nervous system complications; acute lymphoblastic leukemia; cerebrovascular complications; children",
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"mesh_terms": "D001386:Azides; D001921:Brain; D002493:Central Nervous System Diseases; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D015282:Octreotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012189:Retrospective Studies",
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{
"abstract": "To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC). The primary objective was attainment of a complete remission (CR). A Simon two-stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S-MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%-35%), 28% in the FLAM arm (10/36, 90% CI, 16%-43%), and 16% in the S-MEC arm (3/19, 90% CI, 4%-36%). There were nine treatment-related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients.",
"affiliations": "Departments of Hematology, Mayo Clinic, Rochester, Minnesota.;Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts.;Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.;Hematology/Medical Oncology, Johns Hopkins University, Baltimore, Maryland.;Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.;Departments of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Departments of Oncology Research, Mayo Clinic, Rochester, Minnesota.;Seidman Cancer Center, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio.;Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.;Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.;Hematology/Medical Oncology, Johns Hopkins University, Baltimore, Maryland.;Hematology/Oncology, Mayo Clinic, Jacksonville, Florida.;Hematology/Medical Oncology, Northwestern University School of Medicine, Chicago, Illinois.;Hematology/Oncology, Oncology Hematology Care, Inc, Jewish Hospital, Cincinnati, Ohio.;Medicine and Pathology, Penn State Hershey Cancer Institute, Hershey, Pennsylvania.;Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.;Hematology/Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Litzow|Mark R|MR|0000-0002-9816-6302;Wang|Xin V|XV|;Carroll|Martin P|MP|;Karp|Judith E|JE|;Ketterling|Rhett P|RP|;Zhang|Yanming|Y|;Kaufmann|Scott H|SH|;Lazarus|Hillard M|HM|;Luger|Selina M|SM|;Paietta|Elisabeth M|EM|;Pratz|Keith W|KW|0000-0002-1284-8266;Tun|Han Win|HW|;Altman|Jessica K|JK|;Broun|Edward R|ER|;Rybka|Witold B|WB|;Rowe|Jacob M|JM|;Tallman|Martin S|MS|",
"chemical_list": "D005419:Flavonoids; D010880:Piperidines; D003561:Cytarabine; C077990:alvocidib; D005047:Etoposide; D019772:Topotecan; D016190:Carboplatin; D008942:Mitoxantrone; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.25333",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "94(1)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D003561:Cytarabine; D018572:Disease-Free Survival; D005047:Etoposide; D005260:Female; D005419:Flavonoids; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases; D006402:Hematologic Diseases; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone; D010880:Piperidines; D012008:Recurrence; D012074:Remission Induction; D016879:Salvage Therapy; D020123:Sirolimus; D019772:Topotecan; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "111-117",
"pmc": null,
"pmid": "30370956",
"pubdate": "2019-01",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "21239698;12702569;29724899;2702835;29196412;21728742;16166443;22733022;22227525;19843663;17671131;25318680;9269999;25914884;11597333;8250970;8674031;11431468;12538483;24841975;16322302;16150937;26022709;28588020;17003373;19804455",
"title": "A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease.",
"title_normalized": "a randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease"
} | [
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"medicinalproduct": "CYTARABINE."
}
],
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"reaction": [
{
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},
{
"reactionmeddrapt": "Infection",
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}
],
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},
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"literaturereference": "LITZOW, M.. A RANDOMIZED TRIAL OF THREE NOVEL REGIMENS FOR RECURRENT ACUTE MYELOID LEUKEMIA DEMONSTRATES THE CONTINUING CHALLENGE OF TREATING THIS DIFFICULT DISEASE. AMERICAN JOURNAL OF HEMATOLOGY. 2019?94(1):111-117",
"literaturereference_normalized": "a randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20191128",
"receivedate": "20181203",
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},
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},
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},
{
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{
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],
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}
],
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},
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"receiptdate": "20191127",
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}
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"reaction": [
{
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}
],
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},
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"literaturereference": "LITZOW, M.. A RANDOMIZED TRIAL OF THREE NOVEL REGIMENS FOR RECURRENT ACUTE MYELOID LEUKEMIA DEMONSTRATES THE CONTINUING CHALLENGE OF TREATING THIS DIFFICULT DISEASE. AMERICAN JOURNAL OF HEMATOLOGY. 2019?94(1):111-117",
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"qualification": "1",
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},
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"receiptdate": "20191127",
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},
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},
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}
] |
{
"abstract": "The use of imiquimod 5% cream, a topical immunomodulator for the treatment of lentigo maligna (LM) was first described in 2000. Subsequent studies have indicated that imiquimod might be an effective nonsurgical treatment in patients who refuse to have, or are ineligible for surgery because of comorbidities, tumor size, or risk of cosmetic disfigurement. Herein, we outline our experience with treating LM on the nose in an 88-year-old skin cancer patient with significant comorbidities. Given our patient's strong preference against surgical intervention, he was treated with topical imiquimod cream applied once daily for a total of 12 weeks. A two-week treatment holiday was required for severe nausea and vomiting, treated effectively with ondansetron wafers. There were no clinical or dermoscopic signs of LM recurrence 12 months posttreatment. Topical imiquimod is an effective alternative to excision in nonsurgical candidates.",
"affiliations": "Veracity Clinical Research, Brisbane, Queensland. yolanka_lobo@yahoo.com.",
"authors": "Lobo|Yolanka|Y|;Templeman|Rupert|R|",
"chemical_list": "D000970:Antineoplastic Agents; D000077271:Imiquimod",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "26(7)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000287:Administration, Topical; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000072700:Conservative Treatment; D004334:Drug Administration Schedule; D006801:Humans; D018327:Hutchinson's Melanotic Freckle; D000077271:Imiquimod; D008297:Male; D009325:Nausea; D012878:Skin Neoplasms; D014839:Vomiting",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32898412",
"pubdate": "2020-07-15",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Conservative treatment of lentigo maligna with topical imiquimod 5% cream: a case report.",
"title_normalized": "conservative treatment of lentigo maligna with topical imiquimod 5 cream a case report"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-274538",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
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},
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"drugauthorizationnumb": "078602",
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"drugdosagetext": "UNK",
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"medicinalproduct": "ONDANSETRON"
},
{
"actiondrug": "1",
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"activesubstancename": "IMIQUIMOD"
},
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"drugdosagetext": "1 DOSAGE FORM, DAILY (12 WEEKS)",
"drugenddate": null,
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"drugindication": "LENTIGO MALIGNA",
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"drugstructuredosagenumb": "1",
"drugstructuredosageunit": "032",
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"medicinalproduct": "IMIQUIMOD."
}
],
"patientagegroup": null,
"patientonsetage": "88",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Inflammation",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LOBO Y, TEMPLEMAN R. CONSERVATIVE TREATMENT OF LENTIGO MALIGNA WITH TOPICAL IMIQUIMOD 5% CREAM: A CASE REPORT. DERMATOL ONLINE J. 2020?26(7):18:1?3",
"literaturereference_normalized": "conservative treatment of lentigo maligna with topical imiquimod 5 cream a case report",
"qualification": "1",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20210108",
"receivedate": "20210108",
"receiver": {
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},
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"safetyreportversion": 1,
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210419"
}
] |
{
"abstract": "Tobramycin for inhalation is a mainstay of therapy for cystic fibrosis. Routine monitoring of serum concentrations is not performed for patients receiving tobramycin by this route. This is a case of an adolescent with cystic fibrosis, renal failure and a serum concentration of 13.4 mg/dL who was diagnosed with profound sensorineural hearing loss after 3 weeks of inhaled tobramycin therapy.",
"affiliations": "Department of Pharmacy, Integris Baptist Medical Center, Oklahoma City, OK, USA. Leslie.Patatanian@integris-health.com",
"authors": "Patatanian|Leslie|L|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014031:Tobramycin",
"country": "United States",
"delete": false,
"doi": "10.1097/01.inf.0000202126.44544.41",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "25(3)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000280:Administration, Inhalation; D000293:Adolescent; D000900:Anti-Bacterial Agents; D003550:Cystic Fibrosis; D006319:Hearing Loss, Sensorineural; D006801:Humans; D008297:Male; D051437:Renal Insufficiency; D014031:Tobramycin",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "276-8",
"pmc": null,
"pmid": "16511399",
"pubdate": "2006-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Inhaled tobramycin-associated hearing loss in an adolescent with renal failure.",
"title_normalized": "inhaled tobramycin associated hearing loss in an adolescent with renal failure"
} | [
{
"companynumb": "PHEH2004US14110",
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{
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"activesubstancename": "TOBRAMYCIN"
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"reactionmeddrapt": "Ataxia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Deafness",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Ototoxicity",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Disability",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 1999"
}
},
"primarysource": {
"literaturereference": "PATATANIAN L. INHALED TOBRAMYCIN-ASSOCIATED HEARING LOSS IN AN ADOLESCENT WITH RENAL FAILURE. THE PEDIATRIC INFECTIOUS DISEASE JOURNAL. 2006;25:276-278",
"literaturereference_normalized": "inhaled tobramycin associated hearing loss in an adolescent with renal failure",
"qualification": "3",
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},
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"transmissiondate": "20150529"
}
] |
{
"abstract": "OBJECTIVE\nTo demonstrate the efficacy and safety of adding fixed-dose combination calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam to oral apremilast in treating moderate plaque psoriasis.\n\n\nMETHODS\nA 16-week, investigator-blinded study in patients with moderate psoriasis (Physician’s Global Assessment [PGA] score of 3). Patients were randomized 1:1 to Cal/BD foam plus apremilast or vehicle foam plus apremilast for 4 weeks, followed by 8 weeks of apremilast monotherapy, and then 4 weeks of combination therapy as in the original randomization schedule. Efficacy assessments – Psoriasis Area and Severity Index (PASI), PGA, body surface area (BSA), visual analog scale (VAS) for pruritus, and quality of life (QoL) – and safety were evaluated at weeks 1, 2, 3, 4, 12, and 16.\n\n\nRESULTS\n28 subjects were enrolled (mean age, 64 years; 67.9% males). Cal/BD foam plus apremilast group achieved statistically significantly greater improvement than vehicle foam plus apremilast in PASI75 (50% vs 7%; P=.003), PGA score of “clear” or “almost clear” (43% vs 7%; P=.001), and VAS score (2 vs 5; P=.0079) at week 4. BSA and QoL improvements were also observed. Most efficacy assessments worsened after withdrawing Cal/BD foam for 8 weeks but recovered after reinitiating Cal/BD foam from week 12 to week 16. Cal/BD foam plus apremilast appeared to be safe and well tolerated.\n\n\nCONCLUSIONS\nIn the treatment of moderate plaque psoriasis, Cal/BD foam plus apremilast provided more benefits than with apremilast alone. These improvements appeared to be lost when Cal/BD foam was withdrawn but recovered when Cal/BD foam was reinitiated. J Drugs Dermatol. 2020;19(9):874-880. doi:10.36849/JDD.2020.5020.",
"affiliations": null,
"authors": "Kircik|Leon H|LH|;Schlesinger|Todd E|TE|;Tanghetti|Emil|E|",
"chemical_list": "D000336:Aerosols; D003879:Dermatologic Agents; D004338:Drug Combinations; C055085:calcipotriene; D013792:Thalidomide; C011175:betamethasone-17,21-dipropionate; D001623:Betamethasone; D002117:Calcitriol; C505730:apremilast",
"country": "United States",
"delete": false,
"doi": "10.36849/JDD.2020.10.36849/JDD.2020.5020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "19(9)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000279:Administration, Cutaneous; D000284:Administration, Oral; D000328:Adult; D000336:Aerosols; D000368:Aged; D000369:Aged, 80 and over; D001623:Betamethasone; D002117:Calcitriol; D003879:Dermatologic Agents; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011537:Pruritus; D011565:Psoriasis; D011788:Quality of Life; D012720:Severity of Illness Index; D013792:Thalidomide; D016896:Treatment Outcome; D064232:Visual Analog Scale",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "874-880",
"pmc": null,
"pmid": "33026749",
"pubdate": "2020-09-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Efficacy and Safety of Calcipotriene 0.005%/Betamethasone Dipropionate 0.064% Foam With Apremilast for Moderate Plaque Psoriasis.",
"title_normalized": "efficacy and safety of calcipotriene 0 005 betamethasone dipropionate 0 064 foam with apremilast for moderate plaque psoriasis"
} | [
{
"companynumb": "US-AMGEN-USASP2020169210",
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"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BETAMETHASONE DIPROPIONATE"
},
"drugadditional": null,
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"drugcharacterization": "2",
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"drugdosagetext": "UNK (0.064%)",
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"drugindication": "PSORIASIS",
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"medicinalproduct": "BETAMETHASONE DIPROPIONATE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIPOTRIENE"
},
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"drugcharacterization": "2",
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"drugdosageform": null,
"drugdosagetext": "UNK (0.005 PERCENT)",
"drugenddate": null,
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"drugindication": "PSORIASIS",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CALCIPOTRIENE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APREMILAST"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "761028",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLET",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PSORIASIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "APREMILAST"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Abdominal pain",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Adverse event",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Psoriasis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TANGHETTI, E. EFFICACY AND SAFETY OF CALCIPOTRIENE 0.005% BETAMETHASONE DIPROPIONATE 0.064% FOAM WITH APREMILAST FOR MODERATE PLAQUE PSORIASIS.. JOURNAL OF DRUGS IN DERMATOLOGY:JDD. 2020?19(9):874-880",
"literaturereference_normalized": "efficacy and safety of calcipotriene 0 005 betamethasone dipropionate 0 064 foam with apremilast for moderate plaque psoriasis",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20201222",
"receivedate": "20201021",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18407986,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210114"
}
] |
{
"abstract": "BACKGROUND\nCalcium channel blockers (CCBs) are widely used drugs that have a narrow therapeutic index. Even minor overdoses must be treated in-hospital due to the risk of severe hypotension and bradycardia. We aimed to describe trends in CCB use and overdoses in Denmark.\n\n\nMETHODS\nData on enquiries concerning CCBs reported to the Danish Poisons Information Center (DPIC) from January 2009 to January 2015 was coupled with data on hospitalization and mortality obtained from Danish National Registers. We obtained data on the general use of CCBs in Denmark and retrieved medical charts on fatal cases.\n\n\nRESULTS\nFrom a total of 126,987 enquiries to the DPIC in 2009-2014 we identified 339 CCB unique exposures (3‰ of all). Children < 5 years accounted for 20% all exposures and these were classified as 'intake during playing' (61%) and 'medication errors' (39%). Among adults 'suicidal poisonings' (58%), and 'medication errors' (34%) were most frequent. A majority (81%) of exposures led to hospital admission. Seven patients (2%) died from the CCB exposure and all were adults with 'suicidal poisoning'. Amlodipine accounted for 95% of all CCB prescriptions, was involved in 71% of enquiries and in 29% of fatalities. Verapamil accounted for 3% of prescriptions, was involved in 13% of enquiries and 57% of fatalities.\n\n\nCONCLUSIONS\nFour fifths of enquiries to the DPIC result in hospitalization and one fifth concern small children. Mortality were infrequent and occurred only in adults with suicidal exposures and with and an overrepresentation of verapamil exposures.",
"affiliations": "Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400, Copenhagen, Denmark. mikkel.bring.christensen@regionh.dk.;Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400, Copenhagen, Denmark.;Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400, Copenhagen, Denmark.;Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400, Copenhagen, Denmark.;Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400, Copenhagen, Denmark.;Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400, Copenhagen, Denmark.;Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400, Copenhagen, Denmark.;Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400, Copenhagen, Denmark.",
"authors": "Christensen|Mikkel B|MB|0000-0002-8774-1797;Petersen|Kasper M|KM|;Bøgevig|Søren|S|;Al-Gibouri|Salam|S|;Jimenez-Solem|Espen|E|;Dalhoff|Kim P|KP|;Petersen|Tonny S|TS|;Andersen|Jon T|JT|",
"chemical_list": "D002121:Calcium Channel Blockers; D017311:Amlodipine",
"country": "England",
"delete": false,
"doi": "10.1186/s40360-018-0271-9",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 27110.1186/s40360-018-0271-9Research ArticleOutcomes following calcium channel blocker exposures reported to a poison information center http://orcid.org/0000-0002-8774-1797Christensen Mikkel B. mikkel.bring.christensen@regionh.dk 12Petersen Kasper M. kasper.meidahl.petersen.03@regionh.dk 1Bøgevig Søren soeren.boegevig.03@regionh.dk 1Al-Gibouri Salam salaam0007@gmail.com 1Jimenez-Solem Espen Espen.Jimenez-Solem@regionh.dk 12Dalhoff Kim P. Kim.Peder.Dalhoff@regionh.dk 12Petersen Tonny S. Tonny.Studsgaard.Petersen@regionh.dk 12Andersen Jon T. jon.thor.traerup.andersen@regionh.dk 121 0000 0000 9350 8874grid.411702.1Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400 Copenhagen, Denmark 2 0000 0001 0674 042Xgrid.5254.6Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 27 11 2018 27 11 2018 2018 19 7814 9 2018 13 11 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\nCalcium channel blockers (CCBs) are widely used drugs that have a narrow therapeutic index. Even minor overdoses must be treated in-hospital due to the risk of severe hypotension and bradycardia. We aimed to describe trends in CCB use and overdoses in Denmark.\n\nMethods\nData on enquiries concerning CCBs reported to the Danish Poisons Information Center (DPIC) from January 2009 to January 2015 was coupled with data on hospitalization and mortality obtained from Danish National Registers. We obtained data on the general use of CCBs in Denmark and retrieved medical charts on fatal cases.\n\nResults\nFrom a total of 126,987 enquiries to the DPIC in 2009–2014 we identified 339 CCB unique exposures (3‰ of all). Children < 5 years accounted for 20% all exposures and these were classified as ‘intake during playing’ (61%) and ‘medication errors’ (39%). Among adults ‘suicidal poisonings’ (58%), and ‘medication errors’ (34%) were most frequent. A majority (81%) of exposures led to hospital admission. Seven patients (2%) died from the CCB exposure and all were adults with ‘suicidal poisoning’. Amlodipine accounted for 95% of all CCB prescriptions, was involved in 71% of enquiries and in 29% of fatalities. Verapamil accounted for 3% of prescriptions, was involved in 13% of enquiries and 57% of fatalities.\n\nConclusion\nFour fifths of enquiries to the DPIC result in hospitalization and one fifth concern small children. Mortality were infrequent and occurred only in adults with suicidal exposures and with and an overrepresentation of verapamil exposures.\n\nKeywords\nOverdosePoisoningCalcium channel blockersCalcium antagonistVerapamilAmlodipinFelodipinIsradipinLacidipinLercanidipinNifedipinNimodipinNitrendipinDiltiazemissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nCalcium channel blockers (CCBs) are widely used drugs indicated for the treatment of cardiovascular disease and migraine. CCBs have a narrow therapeutic index, and consequently even minor overdoses have to be treated in-hospital due to the risk of severe hypotension and bradycardia [1, 2]. All of the CCBs block L-type voltage gated calcium channels, but individual agents differ in chemical structure and tissue selectivity [3]. At therapeutic doses CCBs belonging to the dihydropyridine class (e.g. amlodipine and felodipine) are primarily affecting calcium channels in the smooth muscle in peripheral vessels, whereas non-dihydropyridine agents (verapamil and diltiazem) are also affecting calcium channels in the heart [2, 3]. Tissue selectively has been reported to be attenuated with increasing doses, but nonetheless, non-dihydropyridine overdoses often leads to various degrees of conduction block and are therefore considered most dangerous [1, 2]. Metabolic and central nervous system (CNS) disturbances are also seen after CCB overdoses, but the cause of death after CCB toxicity is usually presumed to be circulatory collapse [1–4]. Thus, advising about and caring for patients, who have ingested CCBs deliberately or unintentionally is a challenging health care task; and there is limited information on the pharmacoepidemiology and outcomes of overdoses with CCBs. The objectives of this study are to describe trends in the general use of CCBs and to describe causes and consequences of CCB poisonings based on data from the Danish Poisons Information Center (DPIC), Danish national registers and medical charts.\n\nMethods\nData\nIn this retrospective study we identified all patients poisoned with CCBs from the DPIC-database from January 1st, 2009 to December 31st 2014. The DPIC is a telephone-based, 24-h service providing information on a national level to guide the public and health care professionals on all aspects related to acute poisonings including the management of the poisoned patient. All telephone enquiries to the DPIC are registered in a database with information on the suspected poisoning. The following are recorded: patient data including the unique personal identification number, a description of the poisoning (poison, amount in DDD, mode of exposure, etc.), clinical status of the patient, and the cause of poisoning. The cause of poisoning was divided into ‘suicidal intake’ or ‘accidental intake’, ‘abuse’ or ‘other’. Accidental intake includes ‘intake during playing’ and ‘medication errors’ e.g. incorrect dosage or drug, accident, or confusion of pills.\n\nIn the DPIC-database we identified all inquiries concerning CCBs by searching for synonyms of CCBs combined with all generic and brand names of CCBs marketed in Denmark during the study period. Only records with a complete personal identification number and a registration of a possible CCB overdose or poisoning were included in the study. The DPIC records of CCB exposures were then linked with hospital records from the Danish National Hospital Register [5] and information on death was retrieved from the Danish Register of Causes of Death [6]. All records were linked using the unique Danish personal identification number [7], which all persons living in Denmark get at birth or following immigration to Denmark.\n\nThe National Hospital Registry contains information on all hospitalizations and outpatient visits in Denmark, including 99% of all discharge records, length of hospital stay and discharge diagnoses (International Classification of Diseases 10th Edition (ICD-10) Danish revision) [5]. The Danish Register of Causes of Death holds information on all deaths in Denmark including place, time, and cause of death classified using ICD-10 Danish revision codes [6].\n\nSales numbers for CCBs expressed in Defined Daily Doses (DDDs) in the primary and secondary sectors in Denmark were extracted as additional information from the online database MEDSTAT [8].\n\nDetailed medical charts for the fatal cases (identified through national registers) were retrieved from the hospital departments, where these patients were admitted.\n\nStatistics\nAll analyses and data management were performed using SAS statistical software version 9.4 (SAS Institute Inc., Cary, NC, USA). Frequency distributions comparisons were analysed with Fisher’s exact test. For all analyses, a two-sided value of p < 0.05 was considered statistically significant, and all odds ratios are presented with 95% confidence intervals. Graphical presentation was prepared using Graphpad Prism version 7.02 (La Jolla, CA, USA).\n\nResults\nFrom a total of 126,987 enquiries to the DPIC in 2009–2014 we identified 339 records (3‰ of all) concerning patients with a CCB exposure, where outcome data was available through the national registries (Fig. 1).Fig. 1 Flow Chart for patient inclusion\n\n\n\nDescription of population\nAge and gender distribution\nThe age distribution among patients with a CCB exposure was bimodal with a peak in the preschool children and in adults aged 40–80 years (Fig. 2).Fig. 2 Age distribution among CCB exposures registered by the Danish Poison Information Center from 2009 to 2014\n\n\n\nChildren (i.e. boys and girls < 16 years) accounted for 24% of all CCB enquires (N = 78), and the youngest age group 0–5 years accounted for 20% all exposures (N = 69). There were slightly more boys (56%) among exposed children, whereas females were the majority in individuals above 16 years of age (61%) (p < 0.01).\n\nReason for exposure\nSuicidal exposures accounted for 46% of all enquiries. However, the reason for exposure differed across age groups. Only 6% (N = 5) of the children’s cases were caused by suicidal exposures, all concerning girls aged 13–15 years. The major reason for exposure (85%) in children were ‘medication errors’ (40%) or ‘intake during playing’ (54%). In the youngest age (i.e. < 5 years) group reasons for exposure were ‘intake during playing’ (61%) and ‘medication errors’ (39%). The age group 16–65 years had a high proportion (71%) of suicidal exposures compared to the age group above 65 years (35%) (p < 0.0001). The accidental exposures in the above 65 years age-group were most often (55%) ‘medication errors’.\n\nCCBs involved in poisonings and their sales in Denmark\nSingle drug exposures constituted 35% of all cases, but 65% of exposures in children. The majority (78%) of accidental exposures concerned intake of only one CCB, whereas the majority (84%) of suicidal exposures the CCBs were taken with other substances (i.e. mixed exposures). Among all enquiries (i.e. both suicidal and accidental) concerning CCBs, amlodipine was the most common and was involved in 72% (N = 249) of the cases, whereas verapamil was involved in 13% (N = 45), felodipine in 5% (N = 16), and diltiazem in 5% (N = 16).\n\nFrom 2009 to 2015, the sale of dihydropyridine CCBs increased, whereas sales of verapamil and diltiazem slightly decreased (Fig. 3a). The population-corrected frequency of enquiries concerning CCBs were 61 enquiries per million citizens (Fig. 3, Table 1 in appendix), with an increasing trend in enquiries over the study period (Fig. 3b).Fig. 3 a Sales in WHO defined daily doses (DDD) of calcium Channel Blockers in Denmark and b) CCB exposures registered by the Danish Poison Information Center from 2009 to 2014\n\n\n\nOutcome of exposure\nHospital admission\nA majority (81%) of cases were admitted to a hospital. Children were admitted in 88% of exposures, and adults were admitted in 78% of exposures. In adults with clear anamnestic information on exposure dose the length of in-hospital stay increased with higher DDD-intake/exposure of both dihydropyridine and non-dihydropyridine CCBs (Fig. 4). In children, the anamnestic information on dosage was too uncertain (e.g. worst-case scenarios) for the purpose of relating DDDs to length of hospital stay. In children the length of in-hospital stay had a median value of 1 day (range 0–4 days): Dihydropyridines accounted for 25 exposures in children that subdivided into: 4 exposures leading to: 0 days in-hospital stay; 17 exposures: 1 day; 3 exposures: 2 days; 1 exposure: 4 days. Verapamil intake by children accounted for six exposures: 2 exposures led to 1 day in-hospital stay and 4 exposures led to 3 days in-hospital stay.Fig. 4 Association of dose of CCB exposure (expressed in DDD) with duration of in-hospital stay in adults for a) the dihydropyridines (mostly amlodipine) or b) non-dihydropyridines (verapamil)\n\n\n\nMortality following CCB exposure\nSeven patients (2%) died within 30 days after CCB exposure, but one of the patients did not die from CCB poisoning (Table 2 in Appendix presents details from these lethal cases). Mortality occurred only in adults with suicidal exposures, and the lethal cases were all mixed exposures. The CCB’s involved were verapamil (N = 4), amlodipine (N = 2) or felodipine (N = 1). Of the four adults who died after verapamil exposure, information on intake was available for two, who ingested 25 and 100 DDDs, respectively. There were no deaths among 120 enquiries concerning an isolated intake of dihydropyridine CCB (both adults and children) – even after a severe overdose (e.g. in 6 patients with exposures exceeding 100 DDDs).\n\nDiscussion\nWe report that despite enquiries to the DPIC concerning CCBs being relatively infrequent, four-fifth of exposures resulted in hospitalization and 2% led to death. In that context, we find it reassuring that mortality only occurred in adults with suicidal intent. One fourth of exposures concerned children, and there were no deaths or prolonged in-hospital stays in pre-school children.\n\nOur data may therefore be used to question the relatively cautious guidelines for out-of-hospital management of CCB overdoses recommending that intake of amlodipine and felodipine doses of 0.3 mg/kg and 10 mg (2 DDDs) in children and adults, respectively, should be referred to the emergency department [1]. Our data is quite accurate on length of hospital stay and there were only very few in-hospital stays > 1 day in children after accidental dihydropyridine or verapamil overdoses. A similar finding was also reported by others, where intake of a relatively large amount of CCBs did not give rise to major symptoms in children under the age of 6 years [9, 10]. However, our data material is not precise enough on symptomatology or large enough to contradict reports of significant hypotension or severe toxicity even after minor accidental exposures ( [1, 11].\n\nThe finding of no fatalities in adults following accidental exposures (i.e. not counting suicidal or abuse exposures), are in line with other reports. Generally deaths have only rarely been reported following unintentional intake of CCBs and often other important complicating factors may have played important roles for the fatal course e.g. serious co-exposures such as other cardioactive drugs, co-morbidity such as heart failure, or very low age [1, 12]. It is noteworthy that there were no deaths in adults following isolated intake of dihydropyridines, which are by far the most widely used CCBs, even after intake of up to 200 DDDs. In contrast, verapamil was involved in four out of seven deaths despite only being involved in 13% of enquiries and in 3–5% of the total CCB sale in Denmark. Thus, our results seem to corroborate the larger risk attributed to verapamil also reported by others [1, 4, 13]. Our thorough review of the fatal cases underlines the differences between verapamil and dihydropyridines in toxicity: All verapamil overdoses presented with severe cardiotoxicity and conduction abnormalities (i.e. 3rd degree atrioventricular- and/or left bundle branch blocks, pulseless electric activity) that deteriorated after arrival and led to death within 3 days (Table 2 in Appendix). Of the two fatal dihydropyridine cases (one amlodipine and one felodipine), the felodipine exposure did not present with or develop in-hospital severe cardiac disturbances but died after 8 days of hypoxic-ischemic brain damage (developed before arrival to the hospital and likely related to co-ingestion of codeine and quinine). The fatal amlodipine exposure died of severe cardiotoxicity but had also co-ingested metoprolol and enalapril – whereof both, but in particular metoprolol is known to exert synergistic cardiodepressive effects with CCBs.\n\nA particular problem evident from the fatal cases presented in Table 2 in Appendix is the apparent lack of alignment with current treatment recommendations [14], which in all cases was advocated by the DPIC. Particular, therapies such as high-dose insulin (used in two of six cases), high-dose glucagon (used in three of six cases), and high-dose intravenous lipid emulsion (used in one of six cases), seem underused. Findings of lack of adherence to guidelines and poison center advice have also been reported by others [15, 16].\n\nCollectively, our findings correlate reasonably with other publications describing CCB exposures [1, 9, 17–20]. However, there are some discrepancies worth noticing. Our rate of hospital admission (81%) appears high compared to previous reports of approximately 50–73% hospital admissions following CCB exposures [1, 17] and may reflect the severity of exposures reported to the DPIC, where approximately half of the exposures were suicidal. Olson et al. [1] described death to occur only after verapamil, nifedipine, and diltiazem and Deters et al. [18] described death to occur most frequently after diltiazem exposures. In our material, nifedipine and diltiazem was only involved in few exposures and not involved in fatal cases. This difference likely reflects the relatively infrequent use of nifedipine and diltiazem in Denmark, where sales are decreasing for older dihydropyridines (e.g. nifedipine) and non-dihydropyridines (verapamil and diltiazem).\n\nStrengths and limitations\nThis study covers nationwide follow-up data in our study population due to the completeness of the Danish National Health Registers. Thus, we have reliable outcome data on all patients studied. Nevertheless, the major limitations of this study relate to the completeness of data: We identified exposures through the enquiries to the DPIC, and therefore these cases may not be representative all the CCB exposures in Denmark; some exposures may be handled at home or be hospitalized or die without contact to the DPIC. Furthermore, as discussed previously we have limited data on clinical symptoms and our data reflects the clinical scenario in acute poisonings, thus anamnestic information concerning exposures, i.e. dose and potential co-ingestants are somewhat uncertain – and in this retrospective study no formal validation (i.e. measurement of plasma concentration etc.) of offending drugs could be performed.\n\nConclusion\nFrom 2009 to 2014, the sale of dihydropyridine CCBs increased in Denmark, whereas sales of verapamil and diltiazem slightly decreased. In the same period, enquiries to the DPIC concerning CCBs were rare (3‰ of all enquiries), but often serious and with 80% resulting in hospitalization. One fourth of exposures concerned children and most of these were monoexposures. There were no deaths among 120 enquiries concerning an isolated intake of dihydropyridine CCB (both adults and children) – even after a severe overdose (e.g. in 6 patients with exposures exceeding 100 DDDs). Amlodipine accounted for 95% of all CCB prescriptions, was involved in 71% of enquiries and in 29% of fatalities. Verapamil accounted for 3% of prescriptions, was involved in 13% of enquiries and 57% of fatalities. Mortality occurred in 2% (N = 7) and only in adults with suicidal exposures.\n\nAppendix\n\nTable 1 Citizens, CCB-related enquiries, and CCB sales and in Denmark 2009–2014\n\nYear\t2009\t2010\t2011\t2012\t2013\t2014\t\nDanish population in persons\t5,532,531\t5,557,709\t5,579,204\t5,599,665\t5,623,501\t5,655,750\t\nCCB related enquiries\t40\t52\t57\t44\t61\t89\t\nTotal CCB sale in DDD\t148,626\t159,483\t168,374\t174,585\t179,149\t182,916\t\nDihydropyridines sale in DDD (% of total CCB sale)\t137,779 (93)\t149,428 (94)\t159,057 (94)\t165,904 (95)\t171,181 (96)\t175,518 (96)\t\nAmlodipine sale in DDD (% of total CCB sale)\t110,792 (75)\t122,425 (77)\t131,922 (78)\t138,074 (79)\t142,678 (80)\t146,330 (80)\t\nVerapamil sale in DDD (% of total CCB sale)\t7314 (4.9)\t6940 (4.4)\t6543 (3.9)\t6201 (3.6)\t5872 (3.3)\t5566 (3.0)\t\nDiltiazem sale in DDD (% of total CCB sale)\t3409 (2.3)\t3079 (1.9)\t2764 (1.6)\t2480 (1.4)\t2096 (1.2)\t1832 (1.0)\t\n\n\n\n\nTable 2 Fatal cases\n\nGender and age\tComorbidity\tAnamnestic drug exposure (doses noted if known)\tInterval to presentation and death post intake\tClinical presentation at hospital\n\nTime from intake to admission if known) and symptoms (GCS, temperature, hemodynamic, renal, other\n\tParaclinical parameters\nArterial blood gas (pH, base excess, lactate) blood samples (e.g. glucose, calcium,) and ECGs\tTreatment\nGastrointestinal decontamination (e.g. gastric emptying, activated charcoal).\nInotropes, vasopressors and vasoactive therapy (e.g. isoprenaline, norepinephrine).\nOther interventions (e.g. dialysis, calcium, glucagon)\t\nFemale, 82 y\tMorbus Meniere.\nCardiovascular disease.\nSeveral previous suicidal attempts.\tVerapamil 24,000 mg (as extended release tablets 240 mg)\nEscitalopram 280 mg\t3 days\t12 h after intake:\nSomnolent.\nBP 80/35 mmHg, HR 35 increasing to 50.\nAnuria.\nMuscle twitches and cramps in the extremities.\tABG: pH 7.33, BE −10.8, lactate 1,6–3,2 mmol/l.\nP-glucose 9.1 mmol/l,\nP-calcium (ion)1.17 mmol/l\nIncreasing creatinine\nECG: Initially AV nodal rhythm, atrial fibrillation with LBBB\tGastric aspiration (without lavage) without any tablets retrieved. Activated charcoal - single dose.\nAtropine, Isoprenaline, norepinephrine (up to 0.56 μg/kg/minute), epinephrine (up to 0.4 μg/kg/minute).\nLevosimendan.\nOther: Plasmapheresis and CRRT, temporary pacemaker (bradycardia), non-invasive ventilation due to carbon dioxide retention\t\nMale, 49 y\tAnxiety Periodic Depression, Epilepsy.\tVerapamil (as extended release tablets 240 mg)\nQuetiapine\nCodeine\nAcetaminophen\nTramadol Topiramate\t2 h\tWithin 12 h after intake:\nGCS 3. Temperature 32,5 °C. Seizure in ambulance,\nBP low, cold and pale.\nLow urine production.\tABG: pH 6.88, lactate 11.3 mmol/L.\nECG: ST-depression V2-V6 turning into first bradycardia, then PEA and finally cardiac arrest.\tGastric aspiration (without lavage) with small amounts of tablets retrieved. Activated charcoal - single dose.\nEndotracheal intubation\nAtropine, epinephrine, norepinephrine, phenylephrine,\nOther: Sodium bicarbonate, calcium, dobutamine, naloxone\nAfter PEA: Glucagon, amiodarone, infusion with insulin-glucose (high dose).\t\nFemale 76 y\tObesity.\nCOPD.\nArterial hypertension.\nAnxiety disorder, Several previous suicidal attempts.\tVerapamil\nAcetaminophen ozaxepam\t12 h\tTime unknown. Admission status:\nGCS 9. Temperature 32,7 °C.\nBP 80/50 mmHg, HR 40 initially increases to 65.\nAKI.\nMyoglobin 1167 μg/L.\tABG: pH 7.2, BE 3, lactate 2.4 mmol/L\nP-glucose 16,1 mmol/L\nECG: Bradycardia, 3rd degree AV-block, asystole turning into cardiac arrest.\t(GID not performed)\nAtropine, isoprenaline, norepinephrine (up to 0.7 μg/kilo/minute), epinephrine (0.4 μg/kilo/minute).\nOther: Flumazenil, N-acetylcysteine, calcium, dopamine, sodium bicarbonate, naloxone.\t\nFemale 63 y\tUnknown.\tAmlodipine 425 mg,\nMetoprolol 4250 mg Enalapril\t2 days\t6 h after intake:\nComatose.\nMAP 50, HR 44 (SR), cold.\nAnuria.\tABG: pH 7.1, BE-19.8, lactate 17 mmol/L.\nECG: Atrioventricular Junctional Rhythm (25–40 bpm)\tGastric aspiration (without lavage) with unknown result. Activated charcoal - single dose.\nEndotracheal intubation, controlled ventilation with high oxygen demand.\nAtropine, norepinephrine, epinephrine, isoprenaline. Levosimendan, Other: temporary pacemaker, calcium infusion, glucagon, intravenous lipid emulsion.\nDialysis.\t\nFemale, 61 y\tCOPD.\nDepression.\nMultiple previous suicide attempts.\tVerapamil 6000 mg\nRamipril 150 mg Ibuprofen 20 g\nZolpidem 200 mg\t2\tTime unknown. Admission status:\nUnconscious. Reacts to pain. Mumbles. Temperature 34,2 °C.\nBP 60/ 35, HR 36, cold, pale and sweaty.\nAnuria.\tABG: pH 7.26, BE − 6,8, lactate 11.1 mmol/L\nECG: Wide QRS-complexes.\tActivated charcoal - single dose.\nEndotracheal intubation.\nAtropine isoprenaline, noradrenaline, adrenaline, dopamine, ephedrine.\nOther: temporary pacemaker, calcium, glucagon,\nCalcium (bolus and infusion), glucagon, insulin, flumazenil.\nDialysis.\nAfter temperature increases to 39 °C: Tazobactam/piperacillin, ciprofloxacin, metronidazole.\t\nMale, 83 y\tParanoid psychosis\nCerebral infarction\nDementia\nArterial hypertension.\nAortic valve insufficiency.\tFelodipine\n(as 5 mg tablets)\nAcetaminophen 10 g\nBaclofen\nQuinine 4 g, Acetylsalicylic acid (as 75 mg tablets)\t8 days\tTime unknown. Admission status:\nSomnolence.\nBP 111/45, HR 77\nUrine production.\tABG: pH 7.24, BE 8\nP-creatinine: 207 mmol/L\nP-calcium (ion): 0,96\nECG: 1st degree AV block,\nRight bundle branch block (pre-existing) (\t(GID nor performed).\nadrenalin, noradrenalin\nEndotracheal intubation.\nOther: calcium, sodium bicarbonate, N-acetylcysteine.\nFurosemide, labetalol.\nSymptomatic treatment (morphine, diazepam)\t\nMale, 30 y\tDepression Hypertension\tAmlodipine (as 10 mg tablets)\nAcetylsalicylic acid\n(as 75 mg tablets)\nRamipril\t12 h\tTime unknown. Admission status:\nAwake and fully aware of the situation. Nausea and sweaty – otherwise as usual.\tP-salicylate 0.4 mmol/L\nECG: Normal\nNo further test - patient leaves the hospital.\tActivated charcoal - single dose.\n\nPatient leaves the hospital before any other treatment is started. The patient dies 12 h later of carbon monoxide poisoning.\n\t\nAbbreviations: ABG Arterial Blood Gas, COPD Chronic Obstructive Pulmonary Disease, CRRT Continous Renal Replacement Therapy, ECG ElectroCardioGram, GCS Glasgow Coma Score, BE Base Excess, LBBB Left Bundle Branch Blockade, GID Gastrointestinal Decontamination\n\n\n\n\nAbbreviations\n(CCB)Calcium channel blocker\n\n(DDDs)Defined Daily Doses\n\n(DPIC)Danish Poisons Information Center\n\n(ICD-10)International Classification of Diseases 10th Edition\n\nAcknowledgements\nNone.\n\nFunding\nThe authors received no funding in relation to data analysis or manuscript preparation.\n\nAvailability of data and materials\nThe dataset supporting the conclusions of this article are included within the article and its additional files.\n\nAuthors’ contributions\nMC and JTA designed the study. MC, SG and JTA performed the data analyses. JTA, SG and MC drafted the manuscript. All authors (MC, KMP, SB, SA-G, EJS, KD, TSP, JTA) contributed to editing of and approved the final manuscript.\n\nEthics approval and consent to participate\nThe study was approved by the Danish Data Protection Agency (2012-58-0004). In Denmark, the Act on Processing of Personal Data does not require obtained consent or ethical approval for anonymized retrospective registry studies. The Danish Patient Safety Authority approved (journal number 3–3013-1382/1) the retrieval of data from the DPIC database and from the local clinical departments, who forwarded then forwarded the clinical data from medical charts on non-anonymous poisoned patients.\n\nConsent for publication\nNot applicable. In Denmark, the Act on Processing of Personal Data does not require obtained consent or ethical approval for anonymized retrospective registry studies.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Olson Kent R. Erdman Andrew R. Woolf Alan D. Scharman Elizabeth J. Christianson Gwenn Caravati E. Martin Wax Paul M. Booze Lisa L. Manoguerra Anthony S. Keyes Daniel C. Chyka Peter A. Troutman William G. Calcium Channel Blocker Ingestion: An Evidence-Based Consensus Guideline for Out-of-Hospital Management Clinical Toxicology 2005 43 7 797 822 10.1080/15563650500357404 16440509 \n2. Hoffman RS, Howland MA, Lewin NA, Nelson L, Goldfrank LR, Flomenbaum N, redaktører. Goldfrank’s toxicologic emergencies. Tenth edition. New York: McGraw-hill Education; 2015. 1882 s.\n3. Abernethy DR Schwartz JB Calcium-antagonist drugs N Engl J Med 1999 341 19 1447 1457 10.1056/NEJM199911043411907 10547409 \n4. Levine Michael Boyer Edward W. Pozner Charles N. Geib Ann-Jeannette Thomsen Todd Mick Nathan Thomas Stephen H. Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil* Critical Care Medicine 2007 35 9 2071 2075 10.1097/01.CCM.0000278916.04569.23 17855820 \n5. Lynge E Sandegaard JL Rebolj M The Danish National Patient Register Scand J Public Health 2011 39 7 Suppl 30 33 10.1177/1403494811401482 21775347 \n6. Helweg-Larsen K The Danish register of causes of death Scand J Public Health 2011 39 7 Suppl 26 29 10.1177/1403494811399958 \n7. Pedersen CB The Danish civil registration system Scand J Public Health 2011 39 7 Suppl 22 25 10.1177/1403494810387965 21775345 \n8. Schmidt M Hallas J Laursen M Friis S Data resource profile: Danish online drug use statistics (MEDSTAT) Int J Epidemiol 2016 45 5 1401 1402g 10.1093/ije/dyw116 27892409 \n9. Hetterich N Lauterbach E Stürer A Weilemann LS Lauterbach M Toxicity of Antihypertensives in unintentional poisoning of young children J Emerg Med 2014 47 2 155 162 10.1016/j.jemermed.2014.02.006 24746907 \n10. Benson BE Spyker DA Troutman WG Watson WA Bakhireva LN Amlodipine toxicity in children less than 6 years of age: a dose-response analysis using national poison data system data J Emerg Med 2010 39 2 186 193 10.1016/j.jemermed.2009.02.016 19535212 \n11. Ranniger C Roche C Are one or two dangerous? Calcium Channel Blocker Exposure in Toddlers J Emerg Med 2007 33 2 145 154 10.1016/j.jemermed.2007.02.010 17692766 \n12. Truitt CA Brooks DE Dommer P LoVecchio F Outcomes of unintentional beta-blocker or Calcium Channel blocker overdoses: a retrospective review of poison center data J Med Toxicol 2012 8 2 135 139 10.1007/s13181-011-0209-8 22311669 \n13. Marraffa JM Cohen V Howland MA Antidotes for toxicological emergencies: a practical review Am J Health Syst Pharm 2012 69 3 199 212 10.2146/ajhp110014 22261941 \n14. St-Onge M Anseeuw K Cantrell FL Gilchrist IC Hantson P Bailey B M.fl. Experts consensus recommendations for the Management of Calcium Channel Blocker Poisoning in adults Crit Care Med marts 2017 45 3 e306 e315 10.1097/CCM.0000000000002087 \n15. St-Onge M Archambault P Lesage N Guimont C Poitras J Blais R Adherence to calcium channel blocker poisoning treatment recommendations in two Canadian cities Clin Toxicol Phila Pa 2012 50 5 424 430 10.3109/15563650.2012.687741 \n16. Darracq MA Thornton SL Do HM Bok D Clark RF Cantrell FL Utilization of hyperinsulinemia euglycemia and intravenous fat emulsion following poison center recommendations J Med Toxicol Off J Am Coll Med Toxicol 2013 9 3 226 230 10.1007/s13181-013-0290-2 \n17. Belson MG Gorman SE Sullivan K Geller RJ Calcium channel blocker ingestions in children Am J Emerg Med 2000 18 5 581 586 10.1053/ajem.2000.9264 10999574 \n18. Deters M. Bergmann I. Enden G. Kutz S. Liebetrau G. Plenert B. Prasa D. Hentschel H. Calcium channel antagonist exposures reported to the Poisons Information Center Erfurt European Journal of Internal Medicine 2011 22 6 616 620 10.1016/j.ejim.2011.05.002 22075291 \n19. Mowry JB Spyker DA Cantilena LR McMillan N Ford M 2013 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st annual report Clin Toxicol 2014 52 10 1032 1283 10.3109/15563650.2014.987397 \n20. Zyoud SH Al-Jabi SW Sweileh WM Waring WS Scientific research related to calcium channel blockers poisoning: bibliometric analysis in Scopus, 1968-2012 Hum Exp Toxicol 2015 34 11 1162 1170 10.1177/0960327115571768 25673180\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-6511",
"issue": "19(1)",
"journal": "BMC pharmacology & toxicology",
"keywords": "Amlodipin; Calcium antagonist; Calcium channel blockers; Diltiazem; Felodipin; Isradipin; Lacidipin; Lercanidipin; Nifedipin; Nimodipin; Nitrendipin; Overdose; Poisoning; Verapamil",
"medline_ta": "BMC Pharmacol Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017311:Amlodipine; D002121:Calcium Channel Blockers; D002648:Child; D002675:Child, Preschool; D003718:Denmark; D062787:Drug Overdose; D005260:Female; D006760:Hospitalization; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008508:Medication Errors; D008875:Middle Aged; D011039:Poison Control Centers; D013406:Suicide, Attempted; D055815:Young Adult",
"nlm_unique_id": "101590449",
"other_id": null,
"pages": "78",
"pmc": null,
"pmid": "30482251",
"pubdate": "2018-11-27",
"publication_types": "D016428:Journal Article",
"references": "19535212;23412936;10547409;21775345;17692766;25673180;25559822;22578114;27892409;22075291;27749343;24746907;21775346;17855820;22311669;16440509;10999574;21775347;22261941",
"title": "Outcomes following calcium channel blocker exposures reported to a poison information center.",
"title_normalized": "outcomes following calcium channel blocker exposures reported to a poison information center"
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{
"abstract": "Some malignant tumors in childhood require high-dose chemotherapy with stem cell support to achieve a cure. In patients heavily pretreated with myelosuppressive chemotherapy or irradiation, granulocyte colony-stimulating factor (G-CSF) may fail to mobilize stem cells from the bone marrow. Based on the experience with lymphoma and myeloma patients in whom peripheral blood-derived stem cell (PBSC) collection following mobilization with G-CSF failed, we successfully employed plerixafor in a 14-year-old female diagnosed with Ewing's sarcoma in early relapse treated with three lines of chemotherapy in whom PBSC could not be mobilized using either G-CSF alone or G-CSF following chemotherapy. No side effects were observed. Plerixafor may be an effective and safe agent for stem cell collection in pediatric patients with solid tumors, although new studies addressed to evaluate its effectiveness and safety are needed.",
"affiliations": "Clinical Hematology Department, ICO-Hospital Germans Trias i Pujol Badalona, Jose Carreras Leukemia Research Institute, Universitat Autonòma of Barcelona, Badalona, Spain. svives@iconcologia.net",
"authors": "Vives|Susana|S|;Sancho|Juan-Manuel|JM|;Almazán|Francisco|F|;Juncà|Jordi|J|;Grifols|Joan-Ramon|JR|;Ribera|Josep-Maria|JM|",
"chemical_list": "D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21234",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "27(5)",
"journal": "Journal of clinical apheresis",
"keywords": null,
"medline_ta": "J Clin Apher",
"mesh_terms": "D000293:Adolescent; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001596:Benzylamines; D000080027:Cyclams; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006571:Heterocyclic Compounds; D006801:Humans; D036102:Peripheral Blood Stem Cell Transplantation; D012512:Sarcoma, Ewing; D016896:Treatment Outcome",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "260-2",
"pmc": null,
"pmid": "22566276",
"pubdate": "2012-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Plerixafor plus G-CSF in combination with chemotherapy for stem cell mobilization in a pediatric patient with Ewing's sarcoma.",
"title_normalized": "plerixafor plus g csf in combination with chemotherapy for stem cell mobilization in a pediatric patient with ewing s sarcoma"
} | [
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{
"abstract": "The incidence of tricuspid valve endocarditis secondary to cardiac device-related infective endocarditis is rising, probably due to an increasing number of implantations. We describe a novel therapy approach using standard cardiology diagnostic catheter guided by periinterventional transesophageal echocardiographic imaging for aspiration-based endocarditis debridement of the tricuspid valve in a high-risk-patient.\n\n\n\nA 65-year-old patient presented with right-heart endocarditis associated with cardiac device-related infective endocarditis. He had a history of ischemic cardiomyopathy, 3-vessel coronary artery disease and was successfully resuscitated one year ago with subsequent implantation of an implantable cardioverter-defibrillator (ICD).\n\n\n\nEchocardiography revealed typical endocarditis vegetations on the defibrillator lead and the tricuspid valve. Moreover peripheral septic embolism was suspected.\n\n\n\nThe cardioverter-defibrillator was explanted and extensive antiinfective therapy was established as the patient was in a state of persistent bacteremia and prolonged septic shock. Open heart surgery was dismissed due the patient´s increased risk of mortality. After interdisciplinary consensus an aspiration-based endocarditis debridement of the tricuspid valve with maintained valve-functionality using a standard cardiology was carried out.\n\n\n\nAspiration-based endocarditis debridement in right-heart endocarditis in high-risk patients using a standard cardiology diagnostic catheter can be an alternative to open heart surgery. However, larger clinical studies are needed to define the safety and prognostic benefit of an interventional catheter approach in infective endocarditis.",
"affiliations": "Klinik für Innere Medizin III, Medizinische Interdisziplinäre Intensivstation, Universität Freiburg.;Klinik für Innere Medizin III, Medizinische Interdisziplinäre Intensivstation, Universität Freiburg.;Klinik für Innere Medizin III, Medizinische Interdisziplinäre Intensivstation, Universität Freiburg.",
"authors": "Heger|Lukas Andreas|LA|0000-0002-9419-5675;Sekandarzad|Asieb|A|;Wengenmayer|Tobias|T|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1537-8557",
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"issn_linking": "0012-0472",
"issue": "146(16)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
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"medline_ta": "Dtsch Med Wochenschr",
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"nlm_unique_id": "0006723",
"other_id": null,
"pages": "1060-1063",
"pmc": null,
"pmid": "34416773",
"pubdate": "2021-08",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Aspiration-based endocarditis debridement of a competent tricuspid valve in a high-risk case of tricuspid valve endocarditis secondary to cardiac device-related infective endocarditis.",
"title_normalized": "aspiration based endocarditis debridement of a competent tricuspid valve in a high risk case of tricuspid valve endocarditis secondary to cardiac device related infective endocarditis"
} | [
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"drugindication": "Endocarditis",
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},
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"drugindication": "Endocarditis",
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},
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"drugdosagetext": "900 MILLIGRAM DAILY;",
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"drugindication": "Staphylococcal bacteraemia",
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"medicinalproduct": "RIFAMPIN"
}
],
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"reaction": [
{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Coagulopathy",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
}
],
"summary": null
},
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"literaturereference": "Heger LA, Sekandarzad A, Wengenmayer T. [Aspiration-based endocarditis debridement of a competent tricuspid valve in a high-risk case of tricuspid valve endocarditis secondary to cardiac device-related infective endocarditis]. [German]. Dtsch-Med-Wochenschr 2021;146(16):1060-1063.",
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"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20220413",
"receivedate": "20220324",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20633208,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20220721"
},
{
"companynumb": "DE-drreddys-LIT/GER/22/0147656",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugindication": "Atrial fibrillation",
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},
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},
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"drugindication": "Staphylococcal bacteraemia",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "DAPTOMYCIN"
},
{
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"drugindication": "Staphylococcal infection",
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"medicinalproduct": "Flucloxazillin"
},
{
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"activesubstancename": "RIFAMPIN"
},
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"drugindication": "Staphylococcal infection",
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"medicinalproduct": "RIFAMPIN"
}
],
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"reactionmeddrapt": "Coagulopathy",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Heger L, Sekandarzad A, Wengenmayer T. Aspiration-based endocarditis debridement of a competent tricuspid valve in a high-risk case of tricuspid valve endocarditis secondary to cardiac device-related infective endocarditis. Dtsch Med Wochenschr. 2021;146(16):1060-3. doi:10.1055/a-1537-8557",
"literaturereference_normalized": "aspiration based endocarditis debridement of a competent tricuspid valve in a high risk case of tricuspid valve endocarditis secondary to cardiac device related infective endocarditis",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20220315",
"receivedate": "20220315",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20596503,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20220424"
}
] |
{
"abstract": "OBJECTIVE\nCurrent management of submacular hemorrhage (SMH) favors vitrectomy and gas with subretinal administration of recombinant tissue plasminogen activator (rtPA) over mere intravitreal rtPA injections and gas. In this study, we aimed to compare the effectiveness of both treatment modalities to displace submacular blood.\n\n\nMETHODS\nTwenty-four patients with SMH secondary to age-related macular degeneration were included. The SMH had to exist ≤14 days at time of surgery and SMH thickness had to be between 250 μm and 1,250 μm. Patients were randomized to either intravitreal injections of rtPA, perfluoropropane (C3F8) gas, and bevacizumab (n = 12) or vitrectomy with subretinal rtPA administration, intravitreal C3F8 gas, and bevacizumab (n = 12). The SMH volume change was measured on spectral domain optical coherence tomography postoperatively within a 2.5-mm cylinder centered at the fovea.\n\n\nRESULTS\nMedian relative volume reduction of subretinal blood at 6 weeks postoperatively was 97% (95% confidence interval: 91-99%) in the intravitreal rtPA group and 100% (95-100%) in the subretinal rtPA group and did not differ significantly between groups (P = 0.56).\n\n\nCONCLUSIONS\nBoth treatment modalities effectively displaced SMH in this exploratory clinical trial. To more definitely study the noninferiority of intravitreal rtPA with gas to subretinal rtPA, vitrectomy with gas, a larger clinical trial would be necessary.",
"affiliations": "*The Rotterdam Eye Hospital, Rotterdam, the Netherlands; †Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands; ‡Eye Clinic, Department of Clinical and Biomedical Science \"Luigi Sacco,\" Sacco Hospital, University of Milan, Milan, Italy; and §Department of Ophthalmology, Erasmus University Rotterdam, Rotterdam, the Netherlands.",
"authors": "de Jong|Jan H|JH|;van Zeeburg|Elsbeth J T|EJ|;Cereda|Matteo G|MG|;van Velthoven|Mirjam E J|ME|;Faridpooya|Koorosh|K|;Vermeer|Koenraad A|KA|;van Meurs|Jan C|JC|",
"chemical_list": "D005343:Fibrinolytic Agents; D005466:Fluorocarbons; D011994:Recombinant Proteins; C042852:perflutren; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1097/IAE.0000000000000954",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0275-004X",
"issue": "36(5)",
"journal": "Retina (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Retina",
"mesh_terms": "D000208:Acute Disease; D003131:Combined Modality Therapy; D058450:Endotamponade; D005343:Fibrinolytic Agents; D005466:Fluorocarbons; D006801:Humans; D056965:Injections, Intraocular; D058449:Intravitreal Injections; D011446:Prospective Studies; D011994:Recombinant Proteins; D012166:Retinal Hemorrhage; D010959:Tissue Plasminogen Activator; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D014821:Vitrectomy; D057135:Wet Macular Degeneration",
"nlm_unique_id": "8309919",
"other_id": null,
"pages": "914-25",
"pmc": null,
"pmid": "26807631",
"pubdate": "2016-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "INTRAVITREAL VERSUS SUBRETINAL ADMINISTRATION OF RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR COMBINED WITH GAS FOR ACUTE SUBMACULAR HEMORRHAGES DUE TO AGE-RELATED MACULAR DEGENERATION: An Exploratory Prospective Study.",
"title_normalized": "intravitreal versus subretinal administration of recombinant tissue plasminogen activator combined with gas for acute submacular hemorrhages due to age related macular degeneration an exploratory prospective study"
} | [
{
"companynumb": "NL-ROCHE-1941293",
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"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
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"drugdosageform": "SOLUTION FOR INFUSION",
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"drugindication": "RETINAL HAEMORRHAGE",
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"medicinalproduct": "BEVACIZUMAB"
},
{
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"activesubstancename": "ALTEPLASE"
},
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"drugindication": "RETINAL HAEMORRHAGE",
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"medicinalproduct": "ALTEPLASE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PERFLUTREN"
},
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"drugindication": "RETINAL HAEMORRHAGE",
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"medicinalproduct": "PERFLUOROPROPANE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Retinal detachment",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": ", VAN ZEEBURG E, CEREDA M, VAN VELTHOVEN M, FARIDPOOYA K, VERMEER K AND VAN MEURS J. INTRAVITREAL VERSUS SUBRETINAL ADMINISTRATION OF RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR COMBINED WITH GAS FOR ACUTE SUBMACULAR HEMORRHAGES DUE TO AGE-RELATED MACULAR DEGENERATION: AN EXPLORATORY PROSPECTIVE STUDY. RETINA 2016 MAY 01;36 (5):914-925.",
"literaturereference_normalized": "intravitreal versus subretinal administration of recombinant tissue plasminogen activator combined with gas for acute submacular hemorrhages due to age related macular degeneration an exploratory prospective study",
"qualification": "1",
"reportercountry": "NL"
},
"primarysourcecountry": "NL",
"receiptdate": "20170630",
"receivedate": "20170530",
"receiver": {
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},
"reporttype": "2",
"safetyreportid": 13593369,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170830"
}
] |
{
"abstract": "We report an original case of reversible antiphospholipid syndrome (APS) due to minocycline in a young male patient who experienced recurrent strokes while taking minocycline. He started minocycline therapy (50 mg twice daily) at 15 years old for acne. After three years of treatment, the patient experienced a lateral medullary syndrome. He was treated with aspirin while minocycline was continued. Eighteen months later, the patient complained about horizontal binocular diplopia. MRI revealed an infarct of the oculomotor nerve nucleus. Laboratory investigations revealed high titers of anti-beta 2 glycoprotein 1 (antiβ2GP1) antibodies of 470 U/ml (normal range <15 U/ml) and antiphosphatidylethanolamine antibodies of 137.4 U/ml (normal range <18 U/ml). Other laboratory tests were normal. Six weeks after discontinuation of minocycline, anti-β2GP1 antibodies decreased to 335 U/ml and to 36 U/ml at six months and then remained negative for six years. Many drugs have been considered as possibly causing APS but only in a limited number of patients. To our knowledge this is the first case of drug-induced APS with complete disappearance of high titers of anti-β2GP1 antibodies after minocycline withdrawal. This case also illustrates the need to monitor the levels of antiphospholipid antibodies, even though initial values are high and confirmed after 12 weeks.",
"affiliations": "1 CHRU de Nancy, Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy, France.;3 Hospital Universitario Clementino Fraga Filho, Department of Internal Medicine, Rio de Janeiro, Brazil.;4 CHRU de Nancy, Department of Diagnostic and Therapeutic Neuroradiology, Nancy, France.;5 CHRU de Nancy, Regional Center of Pharmacovigilance, Department of Clinical Pharmacology and Toxicology, Nancy, France.;1 CHRU de Nancy, Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy, France.;1 CHRU de Nancy, Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy, France.",
"authors": "Risse|J|J|;Vieira|M|M|;Beuret|F|F|;Petitpain|N|N|;Zuily|S|S|;Wahl|D|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017152:Antibodies, Antiphospholipid; D053482:beta 2-Glycoprotein I; D008911:Minocycline",
"country": "England",
"delete": false,
"doi": "10.1177/0961203317712463",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "27(2)",
"journal": "Lupus",
"keywords": "Antiphospholipid syndrome; antiphospholipid antibodies; drug-induced; minocycline; reversible; stroke; vasculitis",
"medline_ta": "Lupus",
"mesh_terms": "D000900:Anti-Bacterial Agents; D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome; D006801:Humans; D014854:Lateral Medullary Syndrome; D008279:Magnetic Resonance Imaging; D008297:Male; D008911:Minocycline; D020521:Stroke; D016896:Treatment Outcome; D014657:Vasculitis; D055815:Young Adult; D053482:beta 2-Glycoprotein I",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "333-335",
"pmc": null,
"pmid": "28592198",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible drug-induced antiphospholipid syndrome.",
"title_normalized": "reversible drug induced antiphospholipid syndrome"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00680",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "204454",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosagetext": "UNK",
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"drugindication": "ACNE",
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"drugrecurreadministration": "3",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MINOCYCLINE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DROSPIRENONE\\ETHINYL ESTRADIOL"
},
"drugadditional": null,
"drugadministrationroute": "048",
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"drugcharacterization": "2",
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"drugdosageform": null,
"drugdosagetext": "UNK",
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"drugenddateformat": null,
"drugindication": "ORAL CONTRACEPTION",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "DROSPIRENONE/ETHINYL ESTRADIOL"
}
],
"patientagegroup": null,
"patientonsetage": "26",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Vasculitis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Ischaemic stroke",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Polyarteritis nodosa",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
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"abstract": "BACKGROUND\nOvarian cancer is one of the most lethal cancers and women with type 2 diabetes (T2D) have even poorer survival from it. We assessed the prognosis of ovarian cancer in women with type 2 diabetes treated with metformin, other forms of antidiabetic medication, or statins.\n\n\nMETHODS\nStudy cohort consisted of women with T2D diagnosed with ovarian cancer in Finland 1998-2011. They were identified from a nationwide diabetes database (FinDM), being linked to several national registers. Patients were grouped according to their medication in the three years preceding ovarian cancer diagnosis. The Aalen-Johansen estimator was used to describe cumulative mortality from ovarian cancer and from other causes in different medication groups. Mortality rates were analysed by Cox models, and adjusted hazard ratios (HR) with 95% confidence intervals (95% CIs) were estimated in relation to the use of different forms of medication. Main outcome measures were death from ovarian cancer and death from other causes.\n\n\nRESULTS\nDuring the accrual period 421 newly diagnosed ovarian cancers were identified in the FinDM database. No evidence was found for any differences in mortality from ovarian cancer or other causes between different antidiabetic medication groups. Pre-diagnostic use of statins was observed to be associated with decreased mortality from ovarian cancer compared with no such use (HR 0.72, 95% CI 0.56-0.93).\n\n\nCONCLUSIONS\nOur findings are inconclusive as regards the association between metformin and ovarian cancer survival. However, some evidence was found for improved prognosis of ovarian cancer with pre-diagnostic statin use, requiring cautious interpretation, though.",
"affiliations": "Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, P.O. Box 23, FIN-90029, Oulu, Finland. elina.urpilainen@gmail.com.;Children, Adolescents and Families Unit, Department of Welfare, National Institute for Health and Welfare, P.O. Box 310, FIN-90101, Oulu, Finland.;Research Unit of Mathematical Sciences, University of Oulu, P.O. Box 8000, FIN-90014, Oulu, Finland.;Service System Research Unit, National Institute for Health and Welfare, P.O. Box 30, FIN-00271, Helsinki, Finland.;Centre for Research Methods, Department of Social Research, University of Helsinki, Helsinki, Finland.;The Diabetes Center, Finnish Diabetes Association, FIN-33680, Tampere, Finland.;Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, P.O. Box 23, FIN-90029, Oulu, Finland.;Medical Research Center Oulu, University of Oulu, P.O. Box 8000, FIN-90014, Oulu, Finland.;Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, P.O. Box 23, FIN-90029, Oulu, Finland.;Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, P.O. Box 23, FIN-90029, Oulu, Finland.;Research Unit of Mathematical Sciences, University of Oulu, P.O. Box 8000, FIN-90014, Oulu, Finland.",
"authors": "Urpilainen|Elina|E|;Marttila|Mikko|M|;Hautakoski|Ari|A|;Arffman|Martti|M|;Sund|Reijo|R|;Ilanne-Parikka|Pirjo|P|;Arima|Reetta|R|;Kangaskokko|Jenni|J|;Puistola|Ulla|U|;Hinkula|Marianne|M|;Läärä|Esa|E|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-018-4676-z",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 467610.1186/s12885-018-4676-zResearch ArticlePrognosis of ovarian cancer in women with type 2 diabetes using metformin and other forms of antidiabetic medication or statins: a retrospective cohort study Urpilainen Elina elina.urpilainen@gmail.com 1Marttila Mikko mikko@mikkomarttila.com 2Hautakoski Ari ari.hautakoski@gmail.com 3Arffman Martti martti.arffman@thl.fi 4Sund Reijo reijo.sund@helsinki.fi 56Ilanne-Parikka Pirjo pirjo.ilanne-parikka@diabetes.fi 7Arima Reetta reetta.arima@gmail.com 1Kangaskokko Jenni jenni.kangaskokko@coronaria.fi 89Puistola Ulla ulla.puistola@oulu.fi 1Hinkula Marianne Marianne.hinkula@oulu.fi 1Läärä Esa esa.laara@oulu.fi 31 0000 0004 4685 4917grid.412326.0Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, P.O. Box 23, FIN-90029 Oulu, Finland 2 0000 0001 1013 0499grid.14758.3fChildren, Adolescents and Families Unit, Department of Welfare, National Institute for Health and Welfare, P.O. Box 310, FIN-90101 Oulu, Finland 3 0000 0001 0941 4873grid.10858.34Research Unit of Mathematical Sciences, University of Oulu, P.O. Box 8000, FIN-90014 Oulu, Finland 4 0000 0001 1013 0499grid.14758.3fService System Research Unit, National Institute for Health and Welfare, P.O. Box 30, FIN-00271 Helsinki, Finland 5 0000 0004 0410 2071grid.7737.4Centre for Research Methods, Department of Social Research, University of Helsinki, Helsinki, Finland 6 0000 0001 0726 2490grid.9668.1Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland 7 0000 0004 0632 2975grid.478734.bThe Diabetes Center, Finnish Diabetes Association, FIN-33680 Tampere, Finland 8 0000 0001 0941 4873grid.10858.34Medical Research Center Oulu, University of Oulu, P.O. Box 8000, FIN-90014 Oulu, Finland 9 Coronaria Diagnostics Oy, Oulu laboratory, FIN-90100 Oulu, Finland 28 7 2018 28 7 2018 2018 18 7678 3 2018 18 7 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\nOvarian cancer is one of the most lethal cancers and women with type 2 diabetes (T2D) have even poorer survival from it. We assessed the prognosis of ovarian cancer in women with type 2 diabetes treated with metformin, other forms of antidiabetic medication, or statins.\n\nMethods\nStudy cohort consisted of women with T2D diagnosed with ovarian cancer in Finland 1998–2011. They were identified from a nationwide diabetes database (FinDM), being linked to several national registers. Patients were grouped according to their medication in the three years preceding ovarian cancer diagnosis. The Aalen–Johansen estimator was used to describe cumulative mortality from ovarian cancer and from other causes in different medication groups. Mortality rates were analysed by Cox models, and adjusted hazard ratios (HR) with 95% confidence intervals (95% CIs) were estimated in relation to the use of different forms of medication. Main outcome measures were death from ovarian cancer and death from other causes.\n\nResults\nDuring the accrual period 421 newly diagnosed ovarian cancers were identified in the FinDM database. No evidence was found for any differences in mortality from ovarian cancer or other causes between different antidiabetic medication groups. Pre-diagnostic use of statins was observed to be associated with decreased mortality from ovarian cancer compared with no such use (HR 0.72, 95% CI 0.56–0.93).\n\nConclusions\nOur findings are inconclusive as regards the association between metformin and ovarian cancer survival. However, some evidence was found for improved prognosis of ovarian cancer with pre-diagnostic statin use, requiring cautious interpretation, though.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12885-018-4676-z) contains supplementary material, which is available to authorized users.\n\nKeywords\nOvarian cancerCancer survivalCancer prognosisType 2 diabetesMetforminStatinsAntidiabetic medicationhttp://dx.doi.org/10.13039/501100004012Jane ja Aatos Erkon SäätiöT59127Arima Reetta The Cancer Foundation of FinlandT59129Arima Reetta Finnish Government Research Funds K77729Urpilainen Elina issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nOvarian cancer (OC) is one of the most lethal cancers, causing 140,000 deaths annually worldwide [1]. The high mortality rate is attributed to the fact that women present with the disease at a late stage, as the symptoms are unspecific and do not emerge until the cancer is advanced [2]. Standard treatment includes cytoreductive surgery and adjuvant chemotherapy with platinum and taxane-based cytostatics. In early disease, treatment with chemotherapy can be curative but in advanced ovarian cancer, most patients will have a recurrent disease within 18 months [3].\n\nWomen with type 2 diabetes (T2D) are reported to have poorer survival from OC compared with those without T2D [4]. Metformin is a type of oral antidiabetic medication recommended as first-line treatment in T2D [5]. In some previous studies its use has been linked to favourable survival in cases of OC [6–8]. Other studies have not been able to find an association between metformin use and better prognosis of OC in women with T2D [4]. The main problem in previous studies is the small number of patients.\n\nMetformin has anti-mitotic, anti-angiogenic and anti-inflammatory properties [9]. It inhibits growth of OC cells in a time- and dose-dependent way, and inhibition is also seen in platinum-resistant cell lines [10]. Preclinical in vivo studies have suggested that metformin-treated mice develop smaller ovarian tumours and fewer metastatic nodules than controls [11]. It has also been shown that metformin decreases proliferation of OC cells, decreases angiogenesis and potentiates the cytotoxic effect of cisplatin [12].\n\nPatients with T2D have an elevated risk of cardiovascular diseases and hypercholesterolaemia, and are widely treated with statins. In Finland, 40% of patients diagnosed with T2D have been found to use lipid-lowering medication without diagnosis of coincident coronary heart disease, and the percentage of medication users increases to 73% in patients with T2D having coronary heart disease [13]. Statins (HMG-CoA [3-hydroxy-3-methylglutaryl-CoA] reductase inhibitors) block formation of cholesterol by inhibiting HMG-COA conversion to mevalonate [14]. Both in vitro and in vivo studies indicate that statins have antiproliferative, proapoptotic, anti-invasive and radio-sensitizing effects [15].\n\nIn most previous reports, OC patients who used statins showed better overall survival [16–18]. However, in a large population-based study by Nielsen et al., statin use predicted reduced cancer-specific mortality among all cancer patients. No sufficient evidence for improved prognosis was found when investigating OC patients alone [19]. Also, Habis et al. found no difference between statin users and non-users as regards OC survival [20].\n\nIn the present nationwide register-based cohort study the associations between use of metformin, other types of antidiabetic medication and statins, and the prognosis of OC in patients with T2D was evaluated.\n\nMethods\nStudy population and design\nSTROBE guidelines for observational studies were followed in writing this report [21]. The data on people with diabetes were collected from a Finnish diabetes database (FinDM), which combines information from several nationwide registers including the Care Register for Health Care and the Finnish Hospital Discharge Register of the National Institute for Health and Welfare, the Causes of Death Statistics of Statistics Finland and the Register on Medical Special Reimbursements and the Register on Reimbursed Drug purchases of the Social Insurance Institution [22].\n\nThe FinDM database includes about 244,000 women with prevalent (at the beginning of 1996, n = 172,000) or incident (from 1 January 1996 to 31 December 2011, n = 72,000) T2D. Persons with diabetes were entered in the FinDM database if they met at least one of these criteria: diagnosis of diabetes in some of the used registers (Finnish Health Care Register, the Hospital Benchmarking database, the Medical Birth Register, the Diabetes in Finland study or the Register of Causes of Death) or reimbursement for antidiabetic medication (ADM) in the register on Reimbursed Drug purchases of the Social Insurance Institution [22]. The diagnosis of type 2 diabetes is based on World Health Organization (WHO) criteria in Finland [23]. Data on diagnoses in hospital records have been available since 1969 for inpatients and since 1998 for outpatients [22]. Classification to type 1 (primarily insulin-dependent) and type 2 diabetes is based on the ADM which was used as the first-line treatment [22]. Good coverage of persons with diabetes was shown in FinDM when compared with a local diabetes register covering the Helsinki region [24]. The FinDM database holds information about the quantity and the date of purchase of all medication prescribed by doctors and reimbursed by the Social Insurance Institution, including antidiabetic and statin medication, starting from 1994 [22].\n\nFrom the FinDM database we identified 757 women who were diagnosed with epithelial ovarian cancer between 1 January 1998 and 31 December 2011 (Fig. 1). We excluded those women with a prior cancer diagnosis (other than non-melanoma skin cancer). We included women in whom the estimated duration of T2D was at least 180 days before OC diagnosis. We further excluded those women whose ovarian cancer were diagnosed at autopsy. Data on the cancer cases, their histology and stage were obtained from the Finnish Cancer Registry (ICD-O-3 [International Classification of Diseases for Oncology, Third Edition] codes are shown in Additional file 1) [25]. Stage was categorized as local, advanced (including growth to adjacent tissues, metastasis in regional lymph nodes and distant metastasis) or unknown. The final study cohort contained 421 women with T2D, who were diagnosed with epithelial ovarian cancer at least 180 days after the diagnosis of T2D in 1998–2011 (Fig. 1).Fig. 1 Flowchart\n\n\n\nExposure and covariates assessment\nPatients were classified into mutually exclusive groups according to ADM purchased during the three years before OC diagnosis: metformin only, other oral ADM only, metformin and other oral ADM, insulin at any time and no history of ADM. Regardless of patients ADM use, they were also classified as statin users and non-users. The Anatomical Therapeutic Chemical (ATC) Classification System was used to define used medication. ATC codes for different types of oral ADM and statins are shown in Additional file 2. For all types of medication, exposure was considered to begin 180 days after the date of purchase. A patient was classified as a user of ADM when she had purchased metformin or other oral ADM for 180 days or longer in the three years preceding OC diagnosis, with no history of insulin purchases. If a patient had purchased oral ADM for less than 180 days, she was classified in the group “no history of antidiabetic medication”. One purchase of insulin was enough to place the patients in the “insulin ever” group. Respectively, a patient was classified as a statin user if she had purchased statin for 180 days or longer in the three years preceding OC diagnosis. The cumulative use of metformin and statins, respectively, was estimated by way of defined daily doses (DDDs) purchased within three years before diagnosis of ovarian cancer.\n\nOutcome ascertainment\nFollow-up of the study cohort began at the date of diagnosis of ovarian cancer and ended at the time of death, emigration or closure of the follow-up on 31 December 2011, whichever happened first. Follow-up information was collected from the Finnish Cancer Registry. By using personal identity codes, the records of the Finnish Cancer Registry are annually matched with those in the Cause of Death Statistics database, which is maintained by Statistics Finland. This way, dates and causes of death (using ICD-10 [International Statistical Classification of Diseases and Related Health Problems, 10th Revision] codes) are attached to the records in the Registry. Personnel at the Finnish Cancer Registry compare the official causes of death of each patient with diagnosed cancer with all available data for that cancer, and make a judgement as to whether the patient died of that cancer or of something else. The classification of deaths into the two categories in this study, i.e. deaths from OC and deaths resulting from other causes, was based on that judgement. Data in the Finnish Cancer Registry is also linked regularly to the Central Population Register of Finland to check the correctness of personal identity codes, complete name, vital status, possible date of death or emigration and the official place of residence before the date of diagnosis [26].\n\nStatistical analysis\nMortality from OC and from other causes, respectively, was assessed in different medication groups by using the Aalen–Johansen estimator of the cumulative incidence function for competing risks [27, 28]. Cox proportional hazards models were fitted for the two causes of death separately to adjust for the effects of calendar year, age, duration of T2D, and stage at diagnosis of OC. Hazard ratios (HRs), with accompanying 95% confidence intervals (CIs) of related to the two causes of death between medication groups were estimated from the adjusted Cox models. In supplementary analysis, the medication group membership indicators in the Cox models were replaced with cubic spline terms for the total amount of DDDs of each type of medication purchased [29]. This allowed estimation of a potentially nonlinear dose-dependent effect of the medications on the mortality from OC. Plots of scaled Schoenfeld residuals were visually inspected [30], but no evidence for a violation of the proportional hazards assumption could be observed which would have any impact on inference. R environment version 3.3.2 was used throughout for data preparation and statistical analysis; the Cox models were fitted and assumptions checked with functions provided in the “survival” package [31, 32].\n\nResults\nThe age range in the final study cohort (n = 421) was 42 to 92 years at the time of OC diagnosis (Table 1). The greatest percentage (38%) of ovarian cancers were diagnosed at the ages of 70 to 79 years. The majority (78%) of OC cases were at an advanced stage at the time of diagnosis. The median duration of follow-up for a patient was 2.2 years, with a total of 1378 person-years observed in the study.Table 1 Distribution of prognostic factors in different medication groupsa\n\n\tAntidiabetic medication\tUse of statins\t\nMetforminb\tOther oral ADMb\tMetformin and other oral ADMb\tInsulin\tNo use of ADM\tYesb\tNo\tTotal\t\nNumber of patients\t77\t58\t100\t82\t104\t186\t235\t421\t\nAge at diagnosis, years\t\n Median\t69\t75\t70\t71\t72\t71\t71\t71\t\n IQRc\t63─77\t66─80\t61─77\t65─78\t64─79\t65─77\t62─78\t64─78\t\nAge categories, years (%)\t\n 42─59\t8 (10)\t6 (10)\t19 (19)\t9 (11)\t17 (16)\t18 (10)\t41 (17)\t59 (14)\t\n 60─69\t33 (43)\t13 (22)\t31 (31)\t28 (34)\t27 (26)\t66 (35)\t66 (28)\t132 (31)\t\n 70─79\t30 (39)\t24 (41)\t42 (42)\t29 (35)\t35 (34)\t74 (40)\t86 (37)\t160 (38)\t\n 80─92\t6 (8)\t15 (26)\t8 (8)\t16 (20)\t25 (24)\t28 (15)\t42 (18)\t70 (17)\t\nDuration of T2D, years (%)\t\n Median\t3.1\t5.0\t6.2\t10.8\t7.0\t6.3\t5.7\t6.2\t\n IQRc\t2.0─5.5\t3.1─8.3\t4.1─8.9\t6.8─15.0\t2.0─10.1\t3.1─10.0\t3.1─10.0\t3.1─10.1\t\n 0.5 ─ < 3\t37 (48)\t15 (26)\t13 (13)\t4 (5)\t34 (33)\t45 (24)\t58 (25)\t103 (24)\t\n 3 ─ < 6\t24 (31)\t20 (34)\t30 (30)\t13 (16)\t13 (12)\t40 (22)\t60 (26)\t100 (24)\t\n 6 ─ < 12\t14 (18)\t19 (33)\t44 (44)\t30 (37)\t41 (39)\t71 (38)\t77 (33)\t148 (35)\t\n 12 ─ < 34\t2 (3)\t4 (7)\t13 (13)\t35 (43)\t16 (15)\t30 (16)\t40 (17)\t70 (17)\t\nStage (%)\t\n Local\t14 (18)\t6 (10)\t11 (11)\t11 (13)\t10 (10)\t24 (13)\t28 (12)\t52 (12)\t\n Advanced\t58 (75)\t45 (78)\t77 (77)\t64 (78)\t86 (83)\t142 (76)\t188 (80)\t330 (78)\t\n Unknown\t5 (6)\t7 (12)\t12 (12)\t7 (9)\t8 (8)\t20 (11)\t19 (8)\t39 (9)\t\naThe entries are number and percentages (in parenthesis) if not otherwise stated\n\nbDuration of medication ≥180 days\n\ncInterquartile range\n\n\n\nEighteen per cent of the OC patients used metformin as the only antidiabetic drug, 14% used other types of oral ADM, 24% used metformin combined with other types of ADM and 19% used insulin (Table 1). A quarter of the OC patients did not have a history of ADM use. On average, metformin-only users were younger (median 69 years old) and patients who used other types of oral ADM only were older (median 75 years old) when compared with patients in other ADM groups (Table 1). The duration of diabetes was shorter in the metformin-only group (median 3.1 years) and longer in the insulin group (median 10.8 years) (Table 1). The stage distribution of ovarian cancer was similar across the ADM groups (Table 1).\n\nOne hundred and eighty-six (44%) of the OC patients were statin users. Statin users and non-users were similar as regards age distribution, duration of diabetes and OC stage (Table 1). The most commonly used statins were lipophilic statins, i.e. simvastatin (56.5% of statin users) and atorvastatin (26.9%).\n\nThree hundred and ten patients (74%) died during the follow-up period, most of them (276 patients, 89%) from ovarian cancer. Unadjusted cumulative mortality from OC by 10 years after diagnosis varied from 61 to 80% across the ADM groups and from 69 to 73% between the groups defined by statin use, whereas the mortality from other causes by 10 years was on average around 10% with less variability across various ADM and statin groups (Fig. 2). When adjusted for age, calendar year and duration of diabetes at diagnosis of OC and for stage and use of statins, the mortality from OC and from other causes were not found to differ by ADM (Table 2). Pre-diagnostic use of metformin as the only treatment for T2D had an adjusted HR of 1.15 (95% CI 0.74–1.79) for ovarian cancer death and an adjusted HR of 1.85 (95% CI 0.44–7.73) for death from other causes (Table 2), compared with use of other forms of oral ADM. Duration of diabetes was not found to be associated with mortality from ovarian cancer, nor from other causes (Table 2). Pre-diagnostic use of statin was observed to predict decreased mortality from ovarian cancer compared with no use of statin (adjusted HR 0.72, 95% CI 0.56–0.93) (Table 2). No sufficient evidence was found for cumulative use of metformin or statins (DDDs) to be associated with mortality from OC (Additional file 3). The results of Cox modelling for the association of all-cause mortality with ADM and with statins were essentially the same as those for deaths from OC (data not shown).Fig. 2 Cumulative incidence function curves of death from OC and from other causes in different groups\n\nTable 2 Estimation results from Cox proportional hazard models of mortality from OC and from other causes\n\nVariable\tMortality from OC\tMortality from other causes\t\nGroup size\tDeaths\tHR\t(95% CI)\tDeaths\tHR\t(95% CI)\t\nYear of diagnosis\t\n 1998─2002\t115\t84\t1.00\tRef.\t13\t1.00\tRef.\t\n 2003─2007\t149\t106\t1.17\t(0.86–1.59)\t12\t1.16\t(0.45–2.99)\t\n 2008─2011\t157\t86\t0.97\t(0.69–1.37)\t9\t1.13\t(0.39–3.27)\t\nAge at diagnosis (years)\t\n 42─59\t59\t30\t0.67\t(0.44–1.04)\t1\t0.18\t(0.02–1.53)\t\n 60─69\t132\t76\t1.00\tRef.\t9\t1.00\tRef.\t\n 70─79\t160\t120\t1.53\t(1.14–2.05)\t14\t2.49\t(1.03–6.05)\t\n 80─92\t70\t50\t2.88\t(1.98–4.20)\t10\t5.40\t(1.99–14.65)\t\nDuration of diabetes (years)\t\n 0.5─ < 3\t103\t61\t1.00\tRef.\t11\t1.00\tRef.\t\n 3─ < 6\t100\t70\t1.31\t(0.91–1.90)\t3\t0.35\t(0.09–1.36)\t\n 6─ < 12\t148\t101\t1.15\t(0.81–1.63)\t11\t0.88\t(0.34–2.27)\t\n 12─ < 34\t70\t44\t0.98\t(0.61–1.57)\t9\t1.20\t(0.42–3.44)\t\nStage\t\n Local\t52\t9\t1.00\tRef.\t9\t1.00\tRef.\t\n Advanced\t330\t256\t9.05\t(4.60–17.82)\t19\t0.80\t(0.32–2.01)\t\n Unknown\t39\t11\t1.60\t(0.66–3.89)\t6\t1.01\t(0.32–3.23)\t\nPre-diagnostic statin use\t\n No\t235\t162\t1.00\tRef.\t20\t1.00\tRef.\t\n Yes\t186\t114\t0.72\t(0.56–0.93)\t14\t0.66\t(0.30–1.43)\t\nPre-diagnostic ADM group\t\n Metformin\t77\t46\t1.15\t(0.74–1.79)\t5\t1.85\t(0.44–7.73)\t\n Othera\t58\t44\t1.00\tRef.\t4\t1.00\tRef.\t\n Metformin and othera\t100\t67\t1.21\t(0.82–1.80)\t6\t1.19\t(0.32–4.38)\t\n Insulin\t82\t59\t1.49\t(0.96–2.30)\t7\t1.61\t(0.42–6.18)\t\n None\t104\t60\t0.69\t(0.46–1.03)\t12\t1.48\t(0.46–4.78)\t\nAll HRs were adjusted for the other factors in this table\n\naother oral antidiabetic medication\n\nOC Ovarian cancer, HR Hazard ratio, 95% CI 95% confidence interval\n\n\n\nDiscussion\nWe found no statistically discernible differences in mortality from ovarian cancer or from other causes between the groups of ovarian cancer patients with T2D on different types of ADM in the three years before cancer diagnosis. However, pre-diagnostic use of statin was observed to be associated with an improved prognosis of OC, but this result must be interpreted with due caution. To our knowledge, this study is the first one to explore the association between statin use and ovarian cancer survival in women with T2D. Our study also has one of the largest study populations in addressing the relationship between ADM and ovarian cancer survival.\n\nIn studies carried out in vitro, statins have shown a favourable effect on cancer prognosis when combined with chemotherapy. In human ovarian cancer-cell lines, synergistic cytotoxicity is seen when combining fluvastatin and cisplatin. This has been suggested to be brought about by dysregulation of Ras-pathway proteins [33]. Simvastatin is especially cytotoxic when combined with carboplatin or paclitaxel at higher than physiologically used concentrations [34].\n\nThere are some previous cohort studies on statins and OC survival. Only two of them did not report a difference between statin users and non-users [20, 35]. In studies by Lavie et al. [16], Elmore et al. [17] and Vogel et al. [18], those ovarian cancer patients who used statins were observed to have better overall survival similarly to our study. In one of these studies, the suggested favourable effect on OC survival was seen only with lipophilic statins [18].\n\nIn a large population-based Danish study, post-diagnostic statin use was not found to be related to decreased all-cause or cancer-specific mortality among ovarian cancer patients unlike in our study [36]. However, a reduction in mortality from endometrioid and clear-cell ovarian cancer subtypes was observed in that study, although the limited numbers of these rare histological types of OC decreased the reliability of the results [36]. Mortality was also lower among those statin users who did not use low-dose aspirin or had started statin use after OC diagnosis [36]. In our study registered information on aspirin use was not available, as in Finland, aspirin is an over-the-counter drug.\n\nThe results of some previous studies have suggested that metformin use is associated with better survival in cases of ovarian cancer [6–8, 37] unlike in our study, whereas similarly to our findings, in one study such an association was not found [38]. The most recent study on metformin and OC survival also suggested that continuous use of metformin in women with T2D decreases the occurrence of relapses of ovarian cancer and ovarian cancer-related deaths [37]. In line with our findings, Garcia et al. found no association between metformin use and better overall survival [38]. However, the study populations in these two investigations were not limited to women with type 2 diabetes [37, 38].\n\nSelection of the reference medication affects interpretation of the results. In our study, the reference group for metformin users was the group of users of other forms of oral ADM, which is relevant when addressing the possible influence of metformin on cancer survival in T2D patients. Using “no antidiabetic medication” as the reference group could lead to bias, as persons with T2D without any proper medication would represent a selective group with prognostic differences. In some previous studies the reference groups for metformin users have been non-users of metformin [8, 37, 38]. In a study carried out by Kumar et al. [6], the reference group comprised non-diabetic non-metformin users and women with diabetes who used insulin or other types of ADM.\n\nA major strength of our study is the availability of reliable and comprehensive Finnish national registers. A unique personal identification code (PIC) is used in all registers involved. FinDM database covers whole Finland and therefore it is an exceptional resource. Data quality is usually considered to be high in Finnish registers, such as, for example, the Finnish Hospital Discharge Register [39]. The duration of diabetes is considered to be relatively accurately recorded in the FinDM database, even though there can be some minor errors connected to diet-controlled diabetes. In Finland, all forms of ADM and statins are prescribed by doctors and reimbursed by the Social Insurance Institution, and therefore data on the duration of use of medication is accurate. Also, the Finnish Cancer Registry is recognized to have high quality with regard to completeness and accuracy, 93% of cancer cases being microscopically verified [25].\n\nIn addition to the above, the size of our study cohort is greater than in previous studies addressing the roles of metformin and statins in connection with OC survival. In particular, the number of metformin users among OC patients was relatively large in our study compared with those in prior studies [6–8]. However, our study population is limited to women with T2D, and therefore the results can strictly be generalized only to women with T2D.\n\nObesity has been associated with poorer ovarian cancer prognosis [40], and, therefore, may be an important confounder in our study. However, our study lacked data on BMI. Also, the FinDM database does not contain information on aspects of life style, such as smoking, alcohol consumption, exercise or diet, which can also have an influence on ovarian cancer survival. Neither does FinDM database include measures regarding the severity of T2D, including data on HbA1c but duration of T2D and history of insulin use can be observed as surrogate indicators of the severity of T2D. In addition, we do not have data on cholesterol levels of the patients, and therefore we cannot be sure whether the observed association of mortality from OC with the use of statins is partly or wholly attributable to cholesterol levels, insofar as the latter were an independent prognostic marker of OC.\n\nComorbidities are not recorded in adequate completeness and detail in FinDM, and therefore not included in our study. It is known that statin use is linked to heart diseases [13] and is thus related to mortality from causes other than cancer. Despite our relatively large cohort, the number of deaths from causes other than cancer was small with the consequence that our estimation results on this component of mortality are highly unreliable with a wide margin of error.\n\nThe Finnish Cancer Registry also contains some information about the treatment of cancer, but the data are not comprehensive or complete enough and thus were not included in our study. However, the national ovarian cancer treatment schedule has guidelines concerning surgery and first-line chemotherapy, and these guidelines did not change during the study period [41].\n\nIn pharmacoepidemiological studies exposure assessment can never be completely free from misclassification. Therefore, some information bias as to the use of drugs under study is to be expected. However, the concordance between self-reported medication use and information contained in the prescription register has been shown to be good [42]. The reimbursement connected with the costs of ADM and statins also strengthens the reliability of our data. However, drugs dispensed in hospitals and outpatient clinics are not covered by the Register on Reimbursed Drug purchases and therefore we lack data on medication used by the small proportion of patients who were treated in healthcare facilities.\n\nSocioeconomic differences might be associated with statin use. It has been found that in patients with lower income, the use of statins is 10% lower compared with the overall level [13]. In our study, data on socioeconomic status was not available and therefore not adjusted for in our results, and this could lead to a healthy-user bias in statin users.\n\nConclusion\nOur findings are inconclusive as regards an association between metformin and OC survival. However, there is some evidence of improved prognosis of ovarian cancer with pre-diagnostic statin use. Ovarian cancer is a rare disease associated with high mortality, and more research is needed to find new forms of medication to improve its prognosis.\n\nAdditional files\n\nAdditional file 1: ICD-10 and ICD-O-3 codes for epithelial ovarian cancer and different histological types. (XLSX 10 kb)\n\n \nAdditional file 2: ATC codes for different types of oral ADM and statins. (XLSX 10 kb)\n\n \nAdditional file 3: Label: Estimated HRs (with 95% CIs) of OC death in relation to cumulative use of medications. Fitted curves are cubic splines, with inner knots at 1.5 and 3 years, estimated from a mutually adjusted Cox regression model. OC ovarian cancer, HR hazard ratio, 95% CI 95% confidence interval, DDD defined daily dose. (PDF 251 kb)\n\n \n\n\nAbbreviations\nADMAntidiabetic medication\n\nATCAnatomical therapeutic chemical\n\nBMIBody mass index\n\nCIConfidence interval\n\nDDDDefined daily doses\n\nFinDMNationwide diabetes database\n\nHMG-CoA3-hydroxy-3-methylglutaryl-CoA\n\nHRHazard ratio\n\nICD-10International statistical classification of diseases and related health problems, 10th revision\n\nICD-O-3International classification of diseases for oncology, third edition\n\nOCOvarian cancer\n\nPICPersonal identification code\n\nT2DType 2 diabetes\n\nWHOWorld Health Organization\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s12885-018-4676-z) contains supplementary material, which is available to authorized users.\n\nFunding\nThis work was supported by Finnish Government Research Funds allocated to the University Hospital of Oulu and by grants from the Jane and Aatos Erkko Foundation and the Cancer Foundation of Finland. The organisations concerned had no role in study design, collection, analysis or interpretation of the data, in the writing of the report or in the decision to submit the article for publication.\n\nAvailability of data and materials\nThe data that support the findings of this study are available from the National Institute for Health and Welfare but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the National Institute for Health and Welfare.\n\nAuthors’ contributions\nEU drafted the article. MM, AH, MA and RS had access to the databases, MM undertook and EL supervised the analyses. EU, UP, MH, MM, AH, EL, MA, RS, PI-P, RA and JK reviewed the drafts. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nAccording to Finnish legislation, no separate ethical approval or informed consent is needed for studies that utilise only administrative registers. However, ethical approval was obtained for the FinDM study from the research ethics committee of National Institute of Health and Welfare (30.1.2014, meeting 1/2014, §609). Permissions to use data were obtained from the maintainers of original registers (National Institute for Health and Welfare, Social Insurance Institution, Statistics Finland).\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nMM started working in Orion Corporation after this study was designed and the results were analysed. Orion Corporation had no role in study design, the collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the article for publication. EU, AH, MA, RS, PI-P, RA, JK, UP, MH and EL declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Ferlay J Shin HR Bray F Forman D Mathers C Parkin DM Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 Int J Cancer 2010 127 12 2893 2291 10.1002/ijc.25516 21351269 \n2. Hunn J Rodriguez GC Ovarian cancer: etiology, risk factors, and epidemiology Clin Obstet Gynecol 2012 55 1 3 23 10.1097/GRF.0b013e31824b4611 22343225 \n3. Jayson GC Kohn EC Kitchener HC Ledermann JA Ovarian cancer Lancet 2014 384 9951 1376 1388 10.1016/S0140-6736(13)62146-7 24767708 \n4. Shah MM Erickson BK Matin T McGwin G Jr Martin JY Daily LB Pasko D Haygood CW Fauci JM Leath CA 3rd Diabetes mellitus and ovarian cancer: more complex than just increasing risk Gynecol Oncol 2014 135 2 273 277 10.1016/j.ygyno.2014.09.004 25220626 \n5. Inzucchi SE Majumdar SK Current therapies for the medical Management of Diabetes Obstet Gynecol 2016 127 4 780 794 10.1097/AOG.0000000000001332 26959197 \n6. Kumar S Meuter A Thapa P Langstraat C Giri S Chien J Rattan R Cliby W Shridhar V Metformin intake is associated with better survival in ovarian cancer: a case-control study Cancer 2013 119 3 555 562 10.1002/cncr.27706 23208739 \n7. Bar D Lavie O Stein N Feferkorn I Shai A The effect of metabolic comorbidities and commonly used drugs on the prognosis of patients with ovarian cancer Eur J Obstet Gynecol Reprod Biol 2016 207 227 231 10.1016/j.ejogrb.2016.09.005 27890326 \n8. Romero IL McCormick A McEwen KA Park S Karrison T Yamada SD Pannain S Lengyel E Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity Obstet Gynecol 2012 119 1 61 67 10.1097/AOG.0b013e3182393ab3 22183212 \n9. Gadducci A Biglia N Tana R Cosio S Gallo M Metformin use and gynecological cancers: a novel treatment option emerging from drug repositioning Crit Rev Oncol Hematol 2016 105 73 83 10.1016/j.critrevonc.2016.06.006 27378194 \n10. Rattan R Giri S Hartmann LC Shridhar V Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner J Cell Mol Med 2011 15 1 166 178 10.1111/j.1582-4934.2009.00954.x 19874425 \n11. Rattan R Graham RP Maguire JL Giri S Shridhar V Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo Neoplasia 2011 13 5 483 491 10.1593/neo.11148 21532889 \n12. Shank JJ Yang K Ghannam J Cabrera L Johnston CJ Reynolds RK Buckanovich RJ Metformin targets ovarian cancer stem cells in vitro and in vivo Gynecol Oncol 2012 127 2 390 397 10.1016/j.ygyno.2012.07.115 22864111 \n13. Vehko T Sund R Arffman M Manderbacka K Ilanne-Parikka P Keskimäki I Monitoring the use of lipid-lowering medication among persons with newly diagnosed diabetes: a nationwide register-based study BMJ Open 2013 3 11 e003414 10.1136/bmjopen-2013-003414 24189078 \n14. Solomon KR Freeman MR Do the cholesterol-lowering properties of statins affect cancer risk? Trends Endocrinol Metab 2008 19 4 113 121 10.1016/j.tem.2007.12.004 18356074 \n15. Chan KK Oza AM Siu LL The statins as anticancer agents Clin Cancer Res 2003 9 1 10 19 12538446 \n16. Lavie O Pinchev M Rennert HS Segev Y Rennert G The effect of statins on risk and survival of gynecological malignancies Gynecol Oncol 2013 130 3 615 619 10.1016/j.ygyno.2013.05.025 23718932 \n17. Elmore RG Ioffe Y Scoles DR Karlan BY Li AJ Impact of statin therapy on survival in epithelial ovarian cancer Gynecol Oncol 2008 111 1 102 105 10.1016/j.ygyno.2008.06.007 20698078 \n18. Vogel TJ Goodman MT Jeon CY Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer Gynecol Oncol 2017 146 2 340 345 10.1016/j.ygyno.2017.05.009 28596017 \n19. Nielsen SF Nordestgaard BG Bojesen SE Statin use and reduced cancer-related mortality N Engl J Med 2012 367 19 1792 1802 10.1056/NEJMoa1201735 23134381 \n20. Habis M Wroblewski K Bradaric M Ismail N Yamada SD Litchfield L Lengyel E Romero IL Statin therapy is associated with improved survival in patients with non-serous-papillary epithelial ovarian cancer: a retrospective cohort analysis PLoS One 2014 9 8 e104521 10.1371/journal.pone.0104521 25118694 \n21. von Elm E Altman DG Egger M Pocock SJ Gøtzsche PC Vandenbroucke JP The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies J Clin Epidemiol 2008 61 4 344 349 10.1016/j.jclinepi.2007.11.008 18313558 \n22. 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Pukkala E Söderman B Okeanov A Finland – cancer registration. Cancer Atlas of Northern Europe 2001 Helsinki Cancer Society of Finland Publication \n27. Putter H Fiocco M Geskus RB Tutorial in biostatistics: competing risks and multi-state models Stat Med 2007 26 11 2389 2430 10.1002/sim.2712 17031868 \n28. de Glas NA Kiderlen M Vandenbroucke JP de Craen AJ Portielje JE van de Velde CJH Liefers G Bastiaannet E Le Cessie S Performing survival analyses in the presence of competing risks: a clinical example in older breast cancer patients J Natl Cancer Inst 2016 108 5 1 10.1093/jnci/djv366 \n29. Heinzl H Kaider A Gaining more flexibility in cox proportional hazards regression models with cubic spline functions Comput Methods Prog Biomed 1997 54 3 201 208 10.1016/S0169-2607(97)00043-6 \n30. Grambsch PM Therneau TM Proportional hazards tests and diagnostics based on weighted residuals Biometrika 1994 81 3 515 526 10.1093/biomet/81.3.515 \n31. Therneau T. A Package for Survival Analysis in S_version 2.38. https://CRAN.Rproject.org/package=survival. Accessed 23 Apr 2017.\n32. R Core Team R: A language and environment for statistical computing 2017 Vienna R Foundation for Statistical Computing \n33. Taylor-Harding B Orsulic S Karlan BY Li AJ Fluvastatin and cisplatin demonstrate synergistic cytotoxicity in epithelial ovarian cancer cells Gynecol Oncol 2010 119 3 549 556 10.1016/j.ygyno.2010.08.017 20837358 \n34. Robinson E Nandi M Wilkinson LL Arrowsmith DM Curtis AD Richardson A Preclinical evaluation of statins as a treatment for ovarian cancer Gynecol Oncol 2013 129 2 417 424 10.1016/j.ygyno.2013.02.003 23402903 \n35. Chen HY Wang Q Xu QH Yan L Gao XF Lu YH Wang L Statin as a combined therapy for advanced-stage ovarian Cancer: a propensity score matched analysis Biomed Res Int 2016 2016 9125238 27975064 \n36. Verdoodt F Kjaer Hansen M Kjaer SK Pottegard A Friis S Dehlendorff C Statin use and mortality among ovarian cancer patients: a population-based cohort study Int J Cancer 2017 14 2 279 286 10.1002/ijc.30738 \n37. Wang SB Lei KJ Liu JP Jia YM Continuous use of metformin can improve survival in type 2 diabetic patients with ovarian cancer: a retrospective study Medicine (Baltimore) 2017 96 29 e7605 10.1097/MD.0000000000007605 28723808 \n38. Garcia C Yao A Camacho F Balkrishnan R Cantrell LA A SEER-Medicare analysis of the impact of metformin on overall survival in ovarian cancer Gynecol Oncol 2017 146 2 346 350 10.1016/j.ygyno.2017.05.006 28499649 \n39. Sund R Quality of the Finnish hospital discharge register: a systematic review Scand J Public Health 2012 40 6 505 515 10.1177/1403494812456637 22899561 \n40. Nagle CM Dixon SC Jensen A Kjaer SK Modugno F de Fazio A Ovarian cancer association consortium: obesity and survival among women with ovarian cancer: results from the ovarian Cancer association consortium Br J Cancer 2015 113 5 817 826 10.1038/bjc.2015.245 26151456 \n41. Leminen A Bützow R Grénman S Kuoppala T Mervaala E Mäenpää J Munasarjasyöpä Duodecim; lääketieteellinen aikakauskirja 2007 123 19 2339 18020151 \n42. Haukka J Suvisaari J Tuulio-Henriksson A Lonnqvist J High concordance between self-reported medication and official prescription database information Eur J Clin Pharmacol 2007 63 11 1069 1074 10.1007/s00228-007-0349-6 17712552\n\n",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D008687:Metformin; D008875:Middle Aged; D010051:Ovarian Neoplasms; D011379:Prognosis; D012189:Retrospective Studies",
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{
"abstract": "Adenosine is frequently used during coronary angiography to induce hyperaemia and allow operators to perform quantitative measurements of lesion severity. Acute bronchospasm is a recognised side effect relating to the activation of 'off target' A2B receptors. The true incidence of severe bronchospasm relating to adenosine administration is not known.\n\n\n\nUsing an electronic patient database, we analysed 100,253 consecutive coronary angiograms over almost 19 years. Fractional flow reserve (FFR) was measured under systemic adenosine in 9,440 cases.\n\n\n\nAdenosine-related bronchospasm was reported in only five cases (0.05%). One case resulted in a life-threatening respiratory arrest.\n\n\n\nThis study reveals the incidence of acute bronchospasm during FFR testing to be extremely low. Although rare, these reactions can be severe and are not simply limited to patients with brittle airways disease. Physicians should be aware of the utility of bolus intravenous aminophylline providing targeted therapy to reverse and treat adenosine-related bronchospasm.",
"affiliations": "Golden Jubilee National Hospital, Glasgow, UK.;British Heart Foundation Glasgow Cardiovascular Research Centre (University of Glasgow), Glasgow, UK.;West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Agamemnon Street, Clydebank G81 4DY, UK, richard.brogan@nhs.net.",
"authors": "Morrow|Andrew|A|;Ford|Thomas J|TJ|;Brogan|Richard|R|",
"chemical_list": "D014665:Vasodilator Agents; D000241:Adenosine",
"country": "Scotland",
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"doi": "10.4997/JRCPE.2019.307",
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"issue": "49(3)",
"journal": "The journal of the Royal College of Physicians of Edinburgh",
"keywords": "FFR; adenosine; bronchospasm; coronary artery disease; hyperaemia",
"medline_ta": "J R Coll Physicians Edinb",
"mesh_terms": "D000241:Adenosine; D000368:Aged; D001249:Asthma; D001986:Bronchial Spasm; D017023:Coronary Angiography; D006801:Humans; D015994:Incidence; D007262:Infusions, Intravenous; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive; D012189:Retrospective Studies; D014665:Vasodilator Agents",
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"pages": "204-206",
"pmc": null,
"pmid": "31497787",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence of acute bronchospasm during systemic adenosine administration for coronary angiography.",
"title_normalized": "incidence of acute bronchospasm during systemic adenosine administration for coronary angiography"
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{
"abstract": "OBJECTIVE\nTo evaluate the clinical course of idiopathic multifocal choroiditis (MFC) and punctate inner choroidopathy (PIC) and the efficacy and safety of treatment options during pregnancy.\n\n\nMETHODS\nPatients with MFC or PIC and a pregnancy in 2011-2019 from two academic centres were enrolled. For the most recent pregnancy, data on best-corrected visual acuity (BCVA) before and after pregnancy, relapse rate in pregnancy and postpartum period and obstetric, maternal and neonatal outcomes were collected. Treatment regimens consisted of a wait-and-see regime and an immunosuppressive treatment regime with systemic corticosteroids and/or azathioprine, both combined with intravitreal antivascular endothelial growth factor injections when indicated.\n\n\nRESULTS\nSixteen women (26 affected eyes) were included. Median Snellen BCVA was 20/19 before pregnancy and 20/18 after delivery. In seven pregnancies a wait-and-see regime and in nine pregnancies an immunosuppressive treatment regime was carried out. Fourteen intravitreal anti-VEGF injections were given in six pregnancies. The relapse rate during pregnancy was 44% and in the postpartum period 31%. Maternal/obstetrical and fetal complications occurred in 31% and 13% of the pregnancies, respectively. Fifteen healthy children were born and one pregnancy ended in a stillbirth in a patient with a complicated obstetrical history. One patient treated with azathioprine developed intrahepatic cholestasis of pregnancy (ICP).\n\n\nCONCLUSIONS\nAmong women with MFC and PIC BCVA remained stable during pregnancy despite a relapse rate of 44% in pregnancy. No major maternal, obstetric and fetal complications occurred in pregnant patients treated with systemic corticosteroids, azathioprine or intravitreal anti-VEGF injections, though one patient developed ICP while treated with azathioprine.",
"affiliations": "Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands.;Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.;Department of Obstetrics, Birth Center Wilhelmina's Children Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.;Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands.;Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands.",
"authors": "de Groot|Evianne L|EL|https://orcid.org/0000-0001-9452-6940;van Huet|Ramon A C|RAC|https://orcid.org/0000-0003-2786-3511;Bloemenkamp|Kitty W M|KWM|;de Boer|Joke H|JH|;Ossewaarde-van Norel|Jeannette|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/aos.14898",
"fulltext": "\n==== Front\nActa Ophthalmol\nActa Ophthalmol\n10.1111/(ISSN)1755-3768\nAOS\nActa Ophthalmologica\n1755-375X\n1755-3768\nJohn Wiley and Sons Inc. Hoboken\n\n34009733\n10.1111/aos.14898\nAOS14898\nOriginal Article\nOriginal Articles\nIdiopathic multifocal choroiditis and punctate inner choroidopathy: an evaluation in pregnancy\nacta ophthalmologica 2021\nde Groot Evianne L. https://orcid.org/0000-0001-9452-6940\n1 e.l.degroot-24@umcutrecht.nl\n\nvan Huet Ramon A.C. https://orcid.org/0000-0003-2786-3511\n2\nBloemenkamp Kitty W.M. 3\nde Boer Joke H. 1\nOssewaarde‐van Norel Jeannette 1\n1 Department of Ophthalmology University Medical Center Utrecht Utrecht the Netherlands\n2 Department of Ophthalmology Radboud University Medical Center Nijmegen the Netherlands\n3 Department of Obstetrics Birth Center Wilhelmina’s Children Hospital University Medical Center Utrecht Utrecht the Netherlands\n* Correspondence\nEvianne L. de Groot\nDepartment of Ophthalmology, University Medical Center Utrecht\nPO Box 85500, Room E 03.136, 3508 GA Utrecht\nthe Netherlands.\nTel: +31 885560980\nFax: +31 887555405\nEmail: e.l.degroot-24@umcutrecht.nl\n\n19 5 2021\n2 2022\n100 1 10.1111/aos.v100.1 8288\n02 10 2020\n18 4 2021\n© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nPurpose\n\nTo evaluate the clinical course of idiopathic multifocal choroiditis (MFC) and punctate inner choroidopathy (PIC) and the efficacy and safety of treatment options during pregnancy.\n\nMethods\n\nPatients with MFC or PIC and a pregnancy in 2011–2019 from two academic centres were enrolled. For the most recent pregnancy, data on best‐corrected visual acuity (BCVA) before and after pregnancy, relapse rate in pregnancy and postpartum period and obstetric, maternal and neonatal outcomes were collected. Treatment regimens consisted of a wait‐and‐see regime and an immunosuppressive treatment regime with systemic corticosteroids and/or azathioprine, both combined with intravitreal antivascular endothelial growth factor injections when indicated.\n\nResults\n\nSixteen women (26 affected eyes) were included. Median Snellen BCVA was 20/19 before pregnancy and 20/18 after delivery. In seven pregnancies a wait‐and‐see regime and in nine pregnancies an immunosuppressive treatment regime was carried out. Fourteen intravitreal anti‐VEGF injections were given in six pregnancies. The relapse rate during pregnancy was 44% and in the postpartum period 31%. Maternal/obstetrical and fetal complications occurred in 31% and 13% of the pregnancies, respectively. Fifteen healthy children were born and one pregnancy ended in a stillbirth in a patient with a complicated obstetrical history. One patient treated with azathioprine developed intrahepatic cholestasis of pregnancy (ICP).\n\nConclusions\n\nAmong women with MFC and PIC BCVA remained stable during pregnancy despite a relapse rate of 44% in pregnancy. No major maternal, obstetric and fetal complications occurred in pregnant patients treated with systemic corticosteroids, azathioprine or intravitreal anti‐VEGF injections, though one patient developed ICP while treated with azathioprine.\n\nanti‐VEGF\nimmunomodulatory therapy\nMFC\nmultifocal choroiditis\npregnancy\npunctate inner choroidopathy\nF.P.Fischer‐StichtingFoundation Beheer het SchildOogfonds 10.13039/501100010321 Louise Rottinghuis FoundationRotterdamse Stichting Blindenbelangen 10.13039/501100010372 Landelijke Stichting voor Blinden en Slechtzienden 10.13039/501100010318 source-schema-version-number2.0\ncover-dateFebruary 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:18.07.2022\nFunding/Support: F.P.Fischer‐Stichting; Achtersloot 212‐C, 3401 NZ IJsselstein, the Netherlands. Foundation Beheer het Schild; Wolfhezerweg 101, 6874 AD Wolfheze, the Netherlands. Landelijke Stichting voor Blinden en Slechtzienden (LSBS); Galvanistraat 1, 6716 AE Ede, the Netherlands. Rotterdamse Stichting Blindenbelangen (RBS); Schiekade 77, 3033 BE Rotterdam, the Netherlands. Stichting Louise Rottinghuis Fonds; Ringenum 6, 9934 PM Delfzijl, the Netherlands. Oogfonds; Churchilllaan 11, 3527 GV Utrecht, the Netherlands\n\nThe corresponding author is a member of the Dutch Ophthalmological Societies\n==== Body\npmcIntroduction\n\nIdiopathic multifocal choroiditis (MFC) and punctate inner choroidopathy (PIC) are rare types of noninfectious posterior uveitis within the spectrum of white dot syndromes. Both MFC and PIC are characterized by a relapsing inflammatory activity in the choroid in the posterior pole resulting in multiple chorioretinal scars within the temporal vascular arcades. The disease predominantly affects young women with myopia often in their reproductive years (Ahnood et al. 2017). Inflammation, even without symptoms, is thought to trigger the development and reactivation of choroidal neovascularization (CNV), which is considered the most frequent complication in MFC and PIC (Dhingra et al. 2010; Agarwal et al. 2018). CNV demands treatment with intravitreal antivascular endothelial growth factor (VEGF) injections to minimize irreversible retinal damage. There are two viewpoints on how the inflammatory component in MFC and PIC can best be treated. The first treatment strategy is based on the wait‐and‐see principle, where patients are only treated in case of active choroidal inflammation for a relatively short period with periocular, intraocular or systemic corticosteroids. The second treatment strategy is focused on a continuous suppression of the immune system with disease‐modifying antirheumatic drugs (DMARDs), if necessary in combination with systemic corticosteroids, sometimes biologicals are used. As a result, the number of relapses of inflammation and reactivation of CNV is proposed to decline (Turkcuoglu et al. 2011; Goldberg et al. 2014; de Groot et al. 2020).\n\nPregnancy is well known to be associated with numeral immunological and hormonal changes, favouring the maternal tolerance of the fetus (Chiam & Lim 2014; Grotting & Papaliodis 2017). Most studies regarding noninfectious uveitis demonstrate a decline of disease activity during the second and third trimester of pregnancy with an increase in the relapse rate within the first 6 months postpartum to the prepregnancy situation (Rabiah & Vitale 2003; Kump et al. 2006; Chiam et al. 2013; Verhagen et al. 2017). However, these studies did not specifically investigate patients with MFC and PIC, but noninfectious uveitis in general. Since anti‐VEGF is considered to be potentially teratogenic and embryo‐fetotoxic, treatment with intravitreal anti‐VEGF injections is advised to be avoided in pregnancy, especially in the first trimester (Polizzi & Mahajan 2015; Peracha & Rosenfeld 2016; Fossum et al. 2018). Therefore, it is of utmost importance to prohibit the development or reactivation of CNV during pregnancy in patients with MFC and PIC. Treatment with azathioprine (AZA), a steroid‐sparing immunomodulatory agent, is recognized to be safe in pregnancy though complications have been described (Skorpen et al. 2016). Therefore, whether or not a patient is treated with AZA during pregnancy, is a shared decision of the ophthalmologist, the obstetrician and the patient. Due to the rarity of the disease, and the fact that pregnant women are excluded from medication trials for several reasons (Illamola et al. 2018), literature is scarce regarding different treatment options for MFC and PIC during pregnancy. A few case series have been described for the different treatment options, varying from treatment with intravitreal anti‐VEGF injections, corticosteroid therapy and an observational approach (Sim et al. 2008; Rao et al., 2011; Fossum et al. 2018). This retrospective cohort study aims to contribute to the knowledge concerning the course of MFC and PIC during pregnancy and the postpartum period and to evaluate different treatment options for pregnant women.\n\nPatients and Methods\n\nFor this retrospective multicentre cohort study, patients treated in two tertiary academic centres (the University Medical Center Utrecht, Utrecht, the Netherlands, and the Radboud University Medical Center, Nijmegen, the Netherlands) were included. This study received institutional review board approval from both the University Medical Center Utrecht and the Radboud University Medical Center and was performed in accordance with the tenets of the Declaration of Helsinki regarding research involving human subjects. All participants provided written informed consent.\n\nStudy participants\n\nPatients with PIC were included as well as patients with MFC in case they presented with chorioretinal scars within the temporal vascular arcades without other signs of ocular inflammation, including no vasculitis, no papillitis and no cells in the anterior chamber or vitreous. The diagnosis of PIC was made in patients with chorioretinal scars situated exclusively within the temporal vascular arcades. In case patients had chorioretinal scars both within and outside the temporal vascular arcades, the diagnosis of MFC was made. Other frequent causes of posterior uveitis including tuberculosis and sarcoidosis were ruled out, as well as Birdshot chorioretinopathy. Patients with MFC and PIC, who were pregnant between 2011 and 2019, were included.\n\nData collection\n\nData were distracted from the medical records for the period between 12 months before pregnancy and 6 months after delivery. In case of multiple pregnancies, only the most recent pregnancy was included. Collected data consisted of maternal, fetal and neonatal variables, ophthalmic information before, during and after pregnancy (best‐corrected visual acuity (BCVA), number of relapses of disease activity), imaging results on the Heidelberg Spectralis® (Heidelberg engineering, Heidelberg, Germany) including spectral domain optical coherence tomography (SD‐OCT) and fluorescein and indocyanine angiography (FA‐ICGA) and information regarding treatment regimens. Treatment regimens were divided into a wait‐and‐see regime and an immunosuppressive treatment regime consisting of treatment with systemic corticosteroids and/or azathioprine. In both treatment regimens, patients with a relapse of disease activity during pregnancy were generally treated with intravitreal anti‐VEGF injections in case of secondary CNV, after careful consideration of the risks for the fetus versus the benefits for the patient, and/or periocular or intravitreal corticosteroid injections in case of active inflammation.\n\nOutcome measures\n\nTo evaluate disease activity during pregnancy, we analysed whether a relapse of disease activity occurred before pregnancy, during pregnancy or in the postpartum period. A relapse of disease activity was defined as either the development of new choroidal inflammatory lesions or new CNV, or the growth of pre‐existent choroidal scars due to choroidal inflammation or reactivation of CNV after previously inactive disease confirmed by imaging (SD‐OCT and if available FA‐ICGA). In case of a relapse of disease activity, the fetus’s gestational age in weeks and initiated treatment were points of interest.\n\nTo evaluate the efficacy and safety of different treatment regimens in pregnancy, the main outcome measures were the BCVA of the mother before and after pregnancy as well as maternal, fetal and obstetrical complications during the pregnancy and postpartum period. The characteristics and clinical outcomes examined for women with MFC and PIC were maternal age and obstetrical complications including gestational diabetes, gestational hypertension, intrahepatic cholestasis of pregnancy (ICP), delivery before 37 weeks (World Health Organization 2015) and mode of delivery, including caesarean section for ophthalmic indication. Evaluated maternal ocular complications included elevated intraocular pressure, cataract and subretinal bleeding of CNV induced by Valsalva manoeuvre during labour. Evaluated fetal complications were miscarriages, birth defects, still birth, birth weight <2500 g (World Health Organization 2011), early‐onset neonatal sepsis and neonatal hypoglycaemia.\n\nBest‐corrected visual acuity was recorded in Snellen values. Best‐corrected visual acuity was converted to LogMAR (logarithm of the minimum angle of resolution) values in order to perform the Wilcoxon signed‐rank test and patients were case‐wise excluded when data were missing. A p‐value <0.05 was considered significant.\n\nResults\n\nStudy participants\n\nSixteen women (26 affected eyes) with MFC (n = 9) and PIC (n = 7) with a pregnancy between 2011 and 2019 were identified. The median age at the start of the pregnancy was 35 years (range 24–41). Bilateral disease was present in 10/16 women (63%), and 11/16 women (69%) had developed the complication of CNV at any point before the start of pregnancy. In seven patients a wait‐and‐see regime was carried out, and nine patients received immunosuppressive treatment during pregnancy. Immunosuppressive treatment consisted of low‐to‐medium‐dose oral corticosteroids in three patients, azathioprine in one patient and a combination of low‐to‐medium‐dose corticosteroids and azathioprine in the remaining five patients. All patients treated with azathioprine received weight‐based doses varying between 100 and 200 mg/day (Table 1). In advance, an alternative DMARD such as mycophenolate mofetil or methotrexate was switched to azathioprine because of the wish to become pregnant in three patients (Table 2).\n\nTable 1 Maternal, obstetrical and fetal complications during pregnancy and postpartum period including initiated medical treatment in pregnancy.\n\nCase\tDiagnose\tMedical treatment in pregnancy in mg (GA in weeks)\tComplications during pregnancy and 6 months postpartum\t\nDMARD\tSystemic corticosteroids (prednisolone)*\tSubconjunctival (SC)/ intravitreal injection (IVI) TA\tAnti‐VEGF intravitreal injection\tMaternal and obstetrical complications\tFetal complications\t\n1\tMFC\tAZA 150\t7.5\t–\t–\tNone\tNone\t\n2\tPIC\tAZA 100\t7.5–12.5\t–\t–\tGestational hypertension and diabetes †\tNone\t\n3\tPIC\tAZA 100\t17.5–20\tTA SC (8) ‡\t–\tNone\tNone\t\n4\tMFC\tAZA 200\t20\t–\tRZB (5, 11, 20, 25, 30)\tPlacental abruption\tIntrauterine fetal death §\t\n5\tMFC\tAZA 125\t10\t–\t–\tIntrahepatic cholestasis\tLate preterm birth+LBW ¶\t\n6\tMFC\t–\t10\t–\t–\tNone\tNone\t\n7\tPIC\tAZA 100\t–\t–\t–\tNone\tNone\t\n8\tMFC\t–\t5–15\tTA IVI (20)\tRZB (30, 37)\tElevated IOP\tNone\t\n9\tMFC\t–\t7.5–12.5\tTA SC (6)\n\nTA IVI (9 + 13)\n\n\t–\tNone\tNone\t\n10\tMFC\t–\t–\tTA IVI (24)\t½ RZB** (32)\n\n1 RZB (36)\n\n\tNone\tNone\t\n11\tPIC\t–\t–\tTA IVI (33)\tRZB (33 + 37)\tNone\tNone\t\n12\tPIC\t–\t–\t–\tRZB (27)\tNone\tNone\t\n13\tPIC\t–\t–\t–\tBVZ (2)\n\nRZB (20)\n\n\tC–section ††\tNone\t\n14\tMFC\t–\t–\t–\t–\tNone ‡‡\tNone ‡‡\t\n15\tPIC\t–\t–\t–\t–\tNone\tNone\t\n16\tMFC\t–\t–\t–\t–\tNone ‡‡\tNone ‡‡\t\nAZA, azathioprine; BVZ, bevacizumab; C‐section, caesarean section; DMARD, disease‐modifying antirheumatic drug; GA, gestational age; IOP, intraocular pressure; LBW, low‐birth weight; MFC, idiopathic multifocal choroiditis; NA, not available; PIC, punctate inner choroidopathy; RZB, ranibizumab; TA, triamcinolone acetonide; VEGF, vascular endothelial growth factor.\n\n* The minimum and maximum dose of prednisolone during pregnancy.\n\n† Two months prior to the start of the pregnancy, the weight of the patient was 110kg (243 LBS).\n\n‡ Subjective relapse of disease activity. After subconjunctival TA complaints did not improve and a relapse of disease activity was never objectified.\n\n§ Intrauterine fetal death at a gestational age of 33 weeks due to a placental abruption. Obstetrical history of multiple miscarriages and 2 intrauterine fetal deaths, all prior to the diagnosis of MFC. Histopathology of the three placentas of the stillborn children demonstrated similar abnormalities with unknown origin.\n\n¶ Late preterm birth at GA 36 + 6 with a low‐birth weight of 2240 g.\n\n** In consultation with the patient and the partner of the patient, the shared decision was made to administer ½ a dose of ranibizumab at GA of 32 weeks.\n\n†† Ophthalmic indication for caesarean section due to active choroidal neovascularization with risk of bleeding.\n\n‡‡ No complete follow‐up of 6 months is available in the postpartum period (case 14 has 5,5 months of follow‐up and case 16 has 4 months of follow‐up).\n\nJohn Wiley & Sons, Ltd\n\nTable 2 Summary of the number of relapses of disease activity in the 12 months before pregnancy, during pregnancy and in the postpartum period.\n\nCase\t12 months before pregnancy\tDuring pregnancy\t6 months postpartum\t\nSystemic CS*\tDMARD\tRelapses\tSystemic CS*\tDMARD\tRelapses (GA)\tRelapses\t\n1\t+\tMMF → AZA\t0\t+\tAZA\t0\t1 (24)\t\n2\t+/−\t−\t1\t+\tAZA\t0\t0\t\n3\t+/−\tMMF → AZA\t2\t+\tAZA\t0\t0\t\n4\t+/−\tMMF → MTX → AZA\t1\t+\tAZA\t1 (5) †\t0\t\n5\t+\tAZA\t0\t+\tAZA\t0\t0\t\n6\t+/−\t−\t1\t+\t−\t0\t1 (26)\t\n7\t+/−\tAZA ‡\t1\t−\tAZA\t0\t0\t\n8\tNA §\tNA §\tNA §\t+\t−\t1 (20) †\t1 (11)\t\n9\t+/−\tMMF → AZA ¶\t1\t+\t−\t1 (6) †\t0\t\n10\t−\t−\t1\t−\t−\t2 (24 + 32)\t0\t\n11\tNA §\tNA §\tNA §\t−\t−\t1 (33)\t0\t\n12\t−\t−\t0\t−\t−\t1 (27)\t0\t\n13\tNA §\tNA §\tNA §\t−\t−\t2 (9 + 20)\t0\t\n14\t−\t−\t0\t−\t−\t0\t1 (6)**\t\n15\t−\t−\t0\t−\t−\t0\t2 (3 + 20)\t\n16\t−\t−\t1\t−\t−\t0\t0**\t\nAZA, azathioprine; CS, corticosteroids; DMARD, disease‐modifying antirheumatic drug; GA, gestational age; MMF, mycophenolate mofetil; MTX, methotrexate; NA, not available.\n\n* Treatment with systemic corticosteroids: maintenance dose of prednisolone (+), prednisolone in tapering schedule (+/−), no prednisolone (−).\n\n† A relapse of disease activity occurred while treated with prednisolone. At the time of a relapse of disease activity, the doses were 20 mg (case 4), 15 mg (case 8) and 7.5 mg (case 9).\n\n‡ Azathioprine was started 5 months prior to pregnancy.\n\n§ No information was present concerning the period before pregnancy. Case 8 was referred to the UMCU Utrecht at GA of 5 weeks, case 11 presented for the first time with symptoms during the third trimester of pregnancy and case 13 was referred to the Radboud UMC at GA of 9 weeks.\n\n¶ Azathioprine was discontinued prior to the start of the pregnancy due to intolerance (elevated liver enzymes).\n\n** No complete follow‐up of 6 months is available in the postpartum period (case 14 has 5.5 months of follow‐up and case 16 has 4 months of follow‐up).\n\nJohn Wiley & Sons, Ltd\n\nRelapse during pregnancy and postpartum period\n\nThe number of relapses in the 12 months prior to pregnancy, during pregnancy and postpartum period are demonstrated in Table 2. Figure 1 illustrates an example of a case with relapses of disease activity during pregnancy and in the postpartum period. The percentage of patients with relapse‐free survival over the time course of 40 weeks after conception is demonstrated in Fig. 2A. In 7/16 pregnancies (44%), a relapse of disease activity occurred, demanding for prompt treatment. When analysing the treatment regimens separately, in 3/9 (33%) pregnancies with patients receiving an immunosuppressive treatment regime and in 4/7 (57%) of the pregnancies with patients receiving a wait‐and‐see regime, a relapse of disease activity was observed (Table 2, Fig. 2B). In 5/16 (31%) pregnancies, a relapse of disease activity occurred in the postpartum period, though in two pregnancies no complete follow‐up of 6 months was available (Table 2).\n\nFigure 1 Disease activity in pregnancy and postpartum period in case 8. (A, B) Colour fundus pictures taken at gestational age (GA) of 5 weeks (A) and 11 weeks postpartum (B) showing growth of central choroidal lesions during pregnancy and the postpartum period. (C, D) Optical coherence tomography scans on the Heidelberg Spectralis® with eye‐tracker function. (C) No disease activity at GA 10 weeks. (D) A relapse of disease activity at GA of 20 weeks. (E, F) A relapse of disease activity at 11 weeks postpartum. Fluorescein (E) and indocyanine green (F) pictures at 20 min showing (E) leakage of active CNV and (F) dark choroidal lesions with blurred boundaries indicating inflammatory activity.\n\nFigure 2 Relapse‐free survival during pregnancy. (A) Demonstrates the relapse‐free survival during pregnancy of all treatment regimens. (B) Demonstrates the relapse‐free survival during pregnancy split out in treatment regimens. The continuing line represents the patients treated with a wait‐and‐see regime, the dashed line represents the patients treated with an immunosuppressive treatment regime with systemic corticosteroids and/or azathioprine.\n\nIntravitreal anti‐VEGF injections in pregnancy\n\nA total number of 14 intravitreal anti‐VEGF injections were given in six pregnancies. Thirteen intravitreal anti‐VEGF injections with ranibizumab and one intravitreal injection with bevacizumab were administered. In general, intravitreal anti‐VEGF injections were not given in the first trimester except for one patient. In this case, the shared decision was made to continue treatment with intravitreal anti‐VEGF injections in the first trimester to preserve vision despite the pregnancy (Table 1).\n\nVisual acuity\n\nBest‐corrected visual acuity prior to pregnancy and after delivery was available for 13 pregnancies (20 eyes). The median Snellen BCVA measured in the visit prior to the start of pregnancy was 20/19. This is not significantly different from the median Snellen BCVA of 20/18 measured in the first consult after delivery (Table 3). When evaluating both treatment regimens separately, no significant difference was observed (wait‐and‐see regime p = 0.78, immunosuppressive treatment p = 0.58).\n\nTable 3 Summary of visual functioning before pregnancy and after delivery of 20 eyes*.\n\n\tBefore pregnancy\n\nMedian (range)\n\n\tAfter delivery\n\nMedian (range)\n\n\tp‐value\t\nLogMAR BCVA\t−0.02\n\n(−0.15 to 1.30)\n\n\t−0.04\n\n(−0.18 to 1.78)\n\n\t0.86 †\t\nSnellen BCVA\t20/19\n\n(20/14–20/400)\n\n\t20/18\n\n(20/13–20/1200)\n\n\tNA\t\nTime to consult in weeks ‡\t4\n\n(0–25)\n\n\t8\n\n(2–15)\n\n\tNA\t\nBCVA, best‐corrected visual acuity; NA, not applicable.\n\n* Missing data prior to pregnancy for 6 eyes.\n\n† Wilcoxon signed‐rank test.\n\n‡ The time in weeks between the moment of evaluation of BCVA prior to the start of pregnancy and after delivery.\n\nJohn Wiley & Sons, Ltd\n\nMaternal, obstetric and fetal outcomes\n\nA total of 16 pregnancies resulted in the birth of 15 healthy children. Maternal/obstetrical complications occurred in 5/16 (31%) pregnancies. One patient developed an elevated intraocular pressure following an intravitreal corticosteroid injection. Nonocular complications included a placental abruption in one patient, gestational hypertension and diabetes in one patient and ICP in one patient. Moreover, in one patient an elective caesarean section was performed because of an active CNV with increased risk of subretinal bleeding during Valsalva manoeuvre (Table 1). Fetal complications occurred in 2/16 (13%) of the unborn children. One pregnancy resulted in a stillbirth at a gestational age of 33 weeks due to a placental abruption and one infant was born late preterm with a birth weight of 2240 g but was otherwise healthy. None of the infants had birth defects or suffered from complications in the neonatal period (Table 1).\n\nDiscussion\n\nIn this study, we report that in 44% of the pregnancies a relapse of disease activity occurred demanding for prompt treatment. Remarkable was the higher relapse rate in the women with a wait‐and‐see regime compared to the women with an immunosuppressive treatment regime, though due to the small number of patients no direct conclusions can be drawn from this observation. Despite these relapses of disease activity, the median BCVA remained stable throughout the pregnancy and no difference was observed between treatment regimens. Surprisingly, a considerable proportion of the relapses of disease activity occurred in the third trimester of pregnancy whereas most studies regarding uveitis in general, report a decline in uveitis activity in the second and third trimester (Rabiah & Vitale 2003; Kump et al. 2006; Chiam et al. 2013).\n\nWe report that none of the infants had birth defects and the majority of the children were healthy term infants. The reported rate of the different maternal, obstetrical and fetal complications does not seem notably higher than the overall complication rate in the general population. (Wilcox et al. 1988; Beck et al. 2010; Ammon Avalos, Galindo & Li 2012; Blencowe et al. 2012; Gillon et al. 2014; Williamson & Geenes 2014; Zhu & Zhang 2016; Eades, Cameron & Evans 2017; Shen et al. 2017; Magnus et al. 2019; Smith & Rood 2020). One pregnancy ended in a stillbirth due to a placental abruption. The obstetrical history of this patient before this pregnancy was complicated and stated four miscarriages and two stillborn children with unknown cause all prior to the diagnosis of MFC.\n\nLiterature on the use of intravitreal anti‐VEGF injections during pregnancy is scarce. The signal protein VEGF plays an important role in the embryo implantation and the development of the lungs, kidneys and central nervous system of the fetus (Peracha & Rosenfeld 2016). Keeping this in mind, it is reasonable that anti‐VEGF can potentially harm the fetus particularly during the development of the vital organs in the first trimester. One publication summarizes 20 cases of pregnant women who were treated with intravitreal anti‐VEGF injections (18 with bevacizumab and two with ranibizumab) during pregnancy. In three pregnancies a miscarriage was observed, all treated with bevacizumab within 5 weeks of gestational age (GA) (Polizzi & Mahajan 2015). To understand the difference between ranibizumab on the one hand, and aflibercept and bevacizumab on the other hand, one should take the pharmacological differences into account. Firstly, ranibizumab has the shortest half‐life and therefore is most rapidly cleared when entering the systemic circulation. Due to the short period of drug exposure in ranibizumab, it affects the plasma level of free VEGF molecules for the shortest time period (Avery et al. 2014; Peracha & Rosenfeld 2016). Secondly, aflibercept has the highest affinity with VEGF and therefore leads to the most dramatic suppression of free VEGF molecules in the plasma (Avery et al. 2014). Thirdly, ranibizumab does not have a Fc fragment and therefore is not expected to be able to bind to the neonatal Fc receptor. It is proposed that this receptor is important for transporting the antibodies (f.e. bevacizumab) over the placental barrier to the fetus (Krohne, Holz & Meyer 2016). Based on this theory, ranibizumab will not reach the fetal circulation, for it will not pass the placental barrier, in contrast to bevacizumab and aflibercept.\n\nTreatment with steroid‐sparing immunomodulatory therapy in pregnancy is contraindicated for some agents including mycophenolate mofetil and methotrexate. On the contrary, no increase in the rate of miscarriages and congenital malformations is observed in pregnant patients treated with azathioprine, cyclosporine, tacrolimus and anti‐tumour necrosis factor inhibitors and thus treatment with these agents is considered to be safe in pregnancy (Skorpen et al. 2016). Literature regarding the influence of azathioprine on the prevalence of low‐birth weight, preterm birth and small for gestational age is conflicting (Saavedra et al. 2015; Plauborg, Hansen & Garne 2016). In our study, one patient treated with azathioprine developed the complication of ICP and spontaneously delivered preterm an infant with a low‐birth weight. Two case reports documented a similar finding in patients treated with azathioprine for Vogt–Koyanagi–Harada disease and Crohn’s disease (Ingolotti et al. 2019; Lauterbach et al. 2020).\n\nThis retrospective study comes with several limitations. Firstly, the number of patients was small and more importantly, limited to patients treated in tertiary academic centres. As a result, it is possible that the real‐life relapse rate is lower than the reported relapse rate due to selection bias. Secondly, we report that the median BCVA remained stable throughout follow‐up despite multiple relapses. Though, for a more thorough evaluation of the visual function in these patients, central visual field tests should be performed and evaluated before and after pregnancy to monitor the number and size of the scotomas due to the chorioretinal scars. Thirdly, it is possible that minor relapses of disease activity are missed during pregnancy since fluorescein and indocyanine green angiography is preferably not performed during pregnancy, though can be performed in urgent cases. Both fluorescein and indocyanine green are classified as a category C drug by the Food and Drug Administration indicating that it is unknown to what extent it will harm the fetus. Though indocyanine green has proven to be harmless for nonophthalmic indications, many ophthalmologists remain reluctant to use it (Fineman 2001).\n\nDespite the limitations of this study, this is the first study of this extent to report on the course of disease and different treatment options in pregnancy specifically for patients with MFC and PIC. We expect that the current data are of great value for clinicians dealing with this blinding disease and could be helpful in the process of shared decision‐making.\n\nIn conclusion, we report that BCVA remained stable during pregnancy despite a considerable relapse rate of 44% in pregnancy. Overall, no major maternal, obstetrical and fetal complications were observed in patients treated with corticosteroids, azathioprine or intravitreal anti‐VEGF injections, though one patient developed ICP while treated with azathioprine. We emphasize no conclusions can be drawn based on these results, due to the small number of patients. The optimal medical treatment of MFC and PIC during pregnancy should be established by the ophthalmologist together with the obstetrician considering the health of the unborn child and the risk of loss of visual function in the mother. Moreover, at all times medical treatment should be established within the concept op shared decision‐making.\n==== Refs\nReferences\n\nAgarwal A , Invernizzi A , Singh RB et al. (2018): An update on inflammatory choroidal neovascularization: epidemiology, multimodal imaging, and management. J Ophthalmic Inflamm Infect 8 : 13.30209691\nAhnood D , Madhusudhan S , Tsaloumas MD , Waheed NK , Keane PA & Denniston AK (2017): Punctate inner choroidopathy: a review. Surv Ophthalmol 62 : 113–126.27751823\nAmmon Avalos L , Galindo C & Li DK (2012): A systematic review to calculate background miscarriage rates using life table analysis. Birth Defects Res Part A ‐ Clin Mol Teratol 94 : 417–423.\nAvery RL , Castellarin AA , Steinle NC et al. (2014): Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular amd. Br J Ophthalmol 98 : 1636–1641.25001321\nBeck S , Wojdyla D , Say L et al. 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"keywords": "MFC; anti-VEGF; immunomodulatory therapy; multifocal choroiditis; pregnancy; punctate inner choroidopathy",
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"title": "Idiopathic multifocal choroiditis and punctate inner choroidopathy: an evaluation in pregnancy.",
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"abstract": "Primary illness with cytomegalovirus leads to latent infection with possible reactivations especially in the immunocompromised patients. Toxic epidermal necrolysis is an immune mediated cytotoxic reaction.A fifty years old female diabetic hypertensive patient with end stage renal disease was admitted with fever of unknown origin, constitutional symptoms, vague upper gastrointestinal symptoms and skin rash. Upper gastrointestinal endoscopic biopsy confirmed her diagnosis with cytomegalovirus esophagitis and duodenitis. Cytomegalovirus immunoglobulin M and immunoglobulin G levels were negative but polymerase chain reaction showed fulminant viremia. Biopsy of the skin rash was consistent with toxic epidermal necrolysis. Despite treatment with Ganciclovir, intravenous immunoglobulins, and granulocyte colony stimulating factor the patient's condition rapidly deteriorated and she died due to multiorgan failure, disseminated intravascular coagulopathy and overwhelming sepsis.Probably there is a true association linking toxic epidermal necrolysis to fulminant reactivation of cytomegalovirus. The aim of this anecdote is reporting a newly recognized presentation of cytomegalovirus.",
"affiliations": "MSc in Internal Medicine, Cairo University, Egypt.",
"authors": "Khalaf|Dina|D|;Toema|Bassem|B|;Dabbour|Nidal|N|;Jehani|Fathi|F|",
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"fulltext": "\n==== Front\nMediterr J Hematol Infect DisMediterranean Journal of Hematology and Infectious DiseasesMediterranean Journal of Hematology and Infectious Diseases2035-3006Università Cattolica del Sacro Cuore 2162530810.4084/MJHID.2011.004mjhid-3-e2011004Case ReportToxic epidermal necrolysis associated with severe cytomegalovirus infection in a patient on regular hemodialysis Khalaf Dina 1Toema Bassem 12Dabbour Nidal 3Jehani Fathi 41 MSc in Internal Medicine, Cairo University, Egypt2 MSc in Experimental Therapeutics, University of Oxford, United Kingdom3 Clinical Fellow in Dermatopathology, The State University of New York, USA4 MBChB, DIM, MSc, MRCP(UK), FRCPath, Consultant HematologistCorrespondence to: Dina Khalaf, Hematology-Medical Oncology department, Saad Specialist Hospital, Prince Faisal Bin Fahed Street, P.O.Box 30353, AlKhobar, 31952, Saudi Arabia. Telephone number: +96638826666, Ext. 1533, Fax: +9668823334. E-mail address: dgkhalaf@gmail.com2011 14 1 2011 3 1 e201100417 11 2010 15 12 2010 2011This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Primary illness with cytomegalovirus leads to latent infection with possible reactivations especially in the immunocompromised patients. Toxic epidermal necrolysis is an immune mediated cytotoxic reaction.\n\nA fifty years old female diabetic hypertensive patient with end stage renal disease was admitted with fever of unknown origin, constitutional symptoms, vague upper gastrointestinal symptoms and skin rash. Upper gastrointestinal endoscopic biopsy confirmed her diagnosis with cytomegalovirus esophagitis and duodenitis. Cytomegalovirus immunoglobulin M and immunoglobulin G levels were negative but polymerase chain reaction showed fulminant viremia. Biopsy of the skin rash was consistent with toxic epidermal necrolysis. Despite treatment with Ganciclovir, intravenous immunoglobulins, and granulocyte colony stimulating factor the patient’s condition rapidly deteriorated and she died due to multiorgan failure, disseminated intravascular coagulopathy and overwhelming sepsis.\n\nProbably there is a true association linking toxic epidermal necrolysis to fulminant reactivation of cytomegalovirus. The aim of this anecdote is reporting a newly recognized presentation of cytomegalovirus.\n==== Body\nIntroduction\nPrimary illness with cytomegalovirus (CMV) leads to latent infection with possible reactivations especially in the immunocompromised patients. Both the primary illness and the reactivations are active CMV infections with viral replication.1\n\nToxic epidermal necrolysis (TEN) is an immune mediated cytotoxic destruction of keratinocytes that express foreign antigens. Most commonly it is drug induced but it may occur secondary to infections, malignancies, and vaccinations. It mimics type IV hypersensitivity reaction with characteristic delayed reaction to an initial exposure and an increasingly rapid reaction with repeated exposure.2 The estimated annual incidence of TEN is reported to be between 0.4 and 1.3 cases per million per year and may occur in all age groups. Reported mortality varies from 30 to 50% with the primary cause of death being infection and multiorgan failure.3\n\nThe incidence of TEN increased to a thousand fold in patients with Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome.4 This is due to an imbalance in the inherent activation and detoxification mechanisms as well as an altered innate immune response. Specific viral infections had been shown to increase CD95 (Fas) and/or Fas Ligand expression and increased sensitivity to Fas/Fas Ligand dependent apoptosis.5 Authors have hypothesized that reactivation of human herpesvirus type 6 may seriously interact with some of the enzymes that detoxify the drugs, such as cytochrome P450. The toxic and immunogenic metabolites of these drugs are deposited in the epidermis leading to a series of immune reactions causing TEN.6\n\nCase report\nA fifty years old caucasian female patient with positive family history for hypertension and negative family history for malignancy, having hypertension controlled by lisinopril, amlodipine and bisoprolol fumarate, Diabetes mellitus type II (DM II) controlled by short acting regular insulin, and end stage renal disease (ESRD) on regular hemodialysis. She was admitted to the intensive care unit (ICU) with fever of unknown origin (FUO) of fourteen days duration associated with agitation, irritability, tachycardia (120 beats/minute), generalized weakness, anorexia, nausea, vomiting, diarrhea, scratch marks and maculopapular rash (Figures 1 and 2). Sepsis workup was done followed by infusion of empirical intravenous broad spectrum antibiotics with the dose adjusted according to renal function and systemic steroids were started with methyl prednisolone 40 milligrams intravenous infusion once daily.\n\nOn Day two, the patient developed severe upper epigastric pain. Upper gastrointestinal endoscopic biopsy confirmed her diagnosis with severe CMV esophagitis and duodenitis. Treatment was started with intravenous Ganciclovir at a dose of 1.25 milligrams/kilogram administered three times/week following each hemodialysis session.\n\nOn day three the maculopapular rash progressed to erythroderma, followed by development of bullous lesions all over the body associated with skin peeling, bleeding, positive Nikolsky’s sign and mucous membrane involvement (Figures 3). Skin biopsy was done and the pathology showed extensive epidermal necrosis, focal subepidermal necrotic blisters and extensive vacuolar degeneration of dermoepidermal junction with separation of the epidermis from the dermis. The dermis showed melanin incontinence and moderate perivascular lymphocytic infiltrate in the absence of eosinophils, neutrophils and viral inclusions (Figure 4). TEN was confirmed. All the immunoflourescence markers that were done on the skin biopsy showed negative staining with nonspecific granular deposition in the necrotic epidermis. The immunoflourescence markers included Immunoglobulin G (IgG), Immunoglobulin A (IgA), Immunoglobulin M (IgM) and Complement factor 3. On day 15, she developed pneumonia which was complicated by respiratory failure. Intubation and mechanical ventilation were initiated.\n\nOn day 48 the patient, whose SCORTEN (severity-of-illness score) was five and expected mortality rate was 90%, passed away due to overwhelming sepsis, shock and multiorgan failure.\n\nDiscussion\nThe case presented showed suggestive evidence linking CMV to TEN. To associate CMV with TEN, we had to differentiate TEN from similar skin diseases, explore other possible causes of TEN and reactivation of CMV, assess the temporal relationship and biological plausibility, show recognized association with the herpes viruses group and identify CMV.\n\nDifferentiate TEN from similar skin diseases: Differential diagnosis included Staphylococcal Scalded Skin Syndrome (SSSS), Toxic Shock Syndrome, Pemphigus Vulgaris, Bullous Pemphegoid and Bullous Dermatosis of hemodialysis. Skin biopsy in SSSS and Toxic Shock Syndrome shows superficial intra epidermal bullous formation but in TEN there is pan-epidermal necrosis with subepidermal bullous formation. Treatment of SSSS and Toxic Shock Syndrome includes antibiotics, but in TEN the antibiotics may cause the disease.7 Pemphigus Vulgaris, Bullous Pemphegoid and Bullous Dermatosis of hemodialysis are usually self limited and occur on the photo-exposed parts but TEN is a rare, potentially life-threatening medical emergency characterized by wide-spread epidermal sloughing of skin accompanied by mucus membrane involvement.8\n\nExploring other possible causes of TEN and reactivation of CMV: Etiology of TEN includes drugs, malignancies and infections especially in immunocompromised patients with multiple comorbidities. Apart from her regular medications, there was no history of recent new drug or herbal ingestion. Her regular medications (lisinopril, amlodipine, bisoprolol fumarate and short acting regular insulin) are not reported to cause Stevens-Johnson syndrome or TEN. Furthermore, the patient had used her regular medications for many years without developing this severe skin disease. The patient had negative history of malignancy. Multiple chronic diseases and comorbidities as long standing DM II, hypertension, and ESRD, in addition to regular hemodialysis, systemic steroids, prolonged ICU stay and sepsis kept her in an immunocompromised state which increased the risk for reactivation of CMV, augmentation of the viral load and the virulence of CMV, and development of TEN.\n\nTemporal relationship and biological plausibility: In TEN the clinical features typically include a prodrome of 2 to 3 days characterized by fever, cough, sore throat, and general malaise before the cutaneous manifestations of TEN become apparent. Symptoms of CMV infection in immunocompromised patients cover a broad range, from direct manifestations of viral replication like fever, leucopenia, thrombocytopenia, hepatitis, enteritis, and pneumonia to indirect sequelae like an impaired cellular immune response. It is possible that the fourteen days FUO that the patient experienced before ICU admission represent reactivation of CMV with viral replication that predisposed to TEN when the patient was admitted to ICU and started receiving empirical intravenous antibiotics.9\n\nRecognized association with the herpes viruses group: Cytomegalovirus (human herpesvirus type 5) is a herpes viral genus of the herpesviruses group. High rate of skin reactions to ampicillin (80% to 100%) was noticed in patients with acute Epstein-Barr virus (human herpesvirus type 4). Reactivation of human herpesvirus type 6 has been reported in drug induced hypersensitivity syndrome.10\n\nIdentification of CMV: Despite negative CMV IgG level of 15 grams/liter (reference range: 7–16) and IgM level of 0.531 grams/liter (reference range: 0.4–2.3), yet CMV polymerase chain reaction (PCR) was conclusive of fulminant viremia at 680,876 copies/milliliter (Threshold: 350).\n\nConclusions\nPatients involved are only one (single case report). Cause implicated is CMV. Probably there is a true association linking CMV to TEN. Suggestive reasons are the temporal relationship and biological plausibility, recognition of the association with the herpes viruses group, identification of CMV and all other possible causes of TEN were ruled out.\n\nThe hypothesis generated is whether TEN is linked to fulminant CMV infection or not and does CMV trigger an interaction between cytotoxic T-lymphocytes, natural killer cells and keratinocytes or not. Further observational studies are warranted.\n\nImplications for clinical practice include:\n\nScreening for CMV with PCR as a causative agent for TEN even in the absence of a clear history of offending drug ingestion and even if CMV IgM and IgG levels are negative.\n\nSystemic steroids are absolutely contraindicated in the treatment of TEN in case the causative agent is fulminant viral infection.\n\nTreatment strategies for TEN associated with CMV include treatment of the cause with Ganciclovir, avoidance of possible offending drugs associated with TEN and avoidance of systemic steroids assuming that most likely the underlying mechanism is interaction of CMV with some of the enzymes that detoxify the offending drugs associated with TEN causing the deposition of the toxic and immunogenic metabolites of these drugs in the epidermis leading to a series of immune reactions that end in TEN.\n\nAcknowledgements\nNidal Almasri performed the histopathological examination of the skin biopsy.\n\nCompeting interests: The authors have declared that no competing interests exist.\n\nFigure 1 Illustration shows erythroderma and scaly skin of the upper extremity.\n\nFigure 2 Illustration shows erythroderma and scaly skin of the trunk.\n\nFigure 3 Illustration shows bullous lesions of the lower extremities associated with skin peeling, bleeding and positive Nikolsky’s sign.\n\nFigure 4 Histopathological examination of the skin biopsy. The black arrows illustrate the pan epidermal necrosis and the red arrows demonstrate the separation of the epidermis from the dermis\n==== Refs\nReferences\n1 Ljungman P Griffiths P Paya C Definitions of cytomegalovirus infection and disease in transplant recipients Clin Infect Dis 2002 34 1094 1097 10.1086/339329 11914998 \n2 Paul C Wolkenstein P Adle H Wechsler J Garchon HJ Revuz J Roujeau JC Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis Br J Dermatol 1996 134 710 714 10.1111/j.1365-2133.1996.tb06976.x 8733377 \n3 Fritsch PO Sidoroff A Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis Am J Clin Dermatol 2000 1 349 360 10.2165/00128071-200001060-00003 11702611 \n4 Rzany B Mockenhaupt M Stocker U Hamouda O Schöpf E Incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with the acquired immunodeficiency syndrome in Germany Arch Dermatol 1993 129 1059 10.1001/archderm.129.8.1059 8352614 \n5 Teraki Y Shiohara T Apoptosis and the skin Eur J Dermatol 1999 9 413 425 10417450 \n6 Suzuki Y Inagi R Aono T Yamanishi K Shiohara T Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome Arch Dermatol 1998 134 1108 1112 10.1001/archderm.134.9.1108 9762023 \n7 Amon RB Dimond RL Toxic epidermal necrolysis. Rapid differentiation between staphylococcal- and drug-induced disease Arch Dermatol 1975 111 1433 1437 10.1001/archderm.111.11.1433 1200650 \n8 Ruiz-Maldonado R Acute disseminated epidermal necrosis types 1, 2 and 3: a study of sixty cases J Am Acad Dermatol 1985 13 623 635 10.1016/S0190-9622(85)70207-1 4078051 \n9 Fishman JA Rubin RH Infection in organ-transplant recipients N Engl J Med 1998 338 1741 1751 10.1056/NEJM199806113382407 9624195 \n10 Pullen H Wright N Murdoch JMC Hypersensitivity reactions to antibacterial drugs in infectious mononucleosis Lancet 1967 290 1176 1178 10.1016/S0140-6736(67)91893-4 4168380\n\n",
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"medicinalproduct": "METHYLPREDNISOLONE SODIUM SUCCINATE."
}
],
"patientagegroup": null,
"patientonsetage": "50",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cytomegalovirus infection reactivation",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cytomegalovirus oesophagitis",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Toxic epidermal necrolysis",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cytomegalovirus duodenitis",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KHALAF, D.. TOXIC EPIDERMAL NECROLYSIS ASSOCIATED WITH SEVERE CYTOMEGALOVIRUS INFECTION IN A PATIENT ON REGULAR HEMODIALYSIS. MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES. 2011?3 (1):10.4084/MJHID.2011.004",
"literaturereference_normalized": "toxic epidermal necrolysis associated with severe cytomegalovirus infection in a patient on regular hemodialysis",
"qualification": "3",
"reportercountry": "EG"
},
"primarysourcecountry": "EG",
"receiptdate": "20200417",
"receivedate": "20200417",
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"receiverorganization": "FDA",
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},
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"safetyreportversion": 1,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
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}
] |
{
"abstract": "OBJECTIVE\nWe aim to report the major congenital malformation (MCM) rates for new and old anti-epileptic drugs (AED) exposures during the first trimester of pregnancy in women with epilepsy (WWE).\n\n\nMETHODS\nWe extracted relevant data on drug exposure and malformation rate from the records of a prospective observational registry (Kerala Registry of Epilepsy and Pregnancy) for all completed pregnancies between 1998 and 2019. A comprehensive and uniform criterion with detailed guideline was used for assessment of malformations. We employed generalised linear model to generate adjusted incidence rate ratios (aIRR) of MCM in AED exposed group as compared to AED unexposed group, after adjustment for age and educational status of mothers' and epilepsy classification.\n\n\nRESULTS\nThe unadjusted MCM rate was 6.2% for all the infants included in the study (148/2328); 4.7% for the unexposed group (16/340), and 6.6% for the exposed group (132/1988). The aIRR of MCM as compared to unexposed group was similar for all monotherapies; lamotrigine (0.50; 95% CI 0.07-3.68), levetiracetam (1.16; 0.43-3.11), oxcarbazepine (1.61; 0.62-4.21) valproate (1.71, 0.93-3.19), phenytoin (1.21, 0.51-2.90), carbamazepine (0.99, 0.54-1.82), and phenobarbitone (1.20, 0.52-2.74). However, the point estimates suggest least risk with lamotrigine and highest risk with valproate. Polytherapy with high-dose valproate carried significantly higher risk of MCM as compared to the unexposed group (aIRR=4.12; 2.18-7.79, p<0.001). The aIRR of GTCS during pregnancy was 1.63 (95% CI 1.12-2.37, p = 0.011) for monotherapy with new AEDs (lamotrigine, levetiracetam or oxcarbazepine) as compared to old AEDs (phenobarbitone, phenytoin, carbamazepine, or valproate).\n\n\nCONCLUSIONS\nThe MCM risk was significantly higher for polytherapy with high dose valproate. It did not differ substantially between different AED monotherapies although point estimate was lowest with lamotrigine. Pregnant women on new AEDs report higher likelihood of GTCS than women on old AEDs during pregnancy.",
"affiliations": "Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India; Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India. Electronic address: sanjeev.v.thomas@gmail.com.;Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India; AMCHSS, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India. Electronic address: jeemon@sctimst.ac.in.;Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India; Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India.;Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India; Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India.;Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India; Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India.;Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India; Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India.;Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India; Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India.;Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India; Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India.;Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India; Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India.",
"authors": "Thomas|Sanjeev V|SV|;Jeemon|Panniyammakal|P|;Pillai|Rajit|R|;Jose|Manna|M|;Lalithakumari|Arya M|AM|;Murali|Sruthy|S|;Sanalkumar|Arjun|A|;Salini|Reshma A|RA|;Pavithran|Veena|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.seizure.2021.10.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "93()",
"journal": "Seizure",
"keywords": "Antiseizure medicine; Birth defect; Epilepsy; Major congenital malformation; Teratogenicity",
"medline_ta": "Seizure",
"mesh_terms": null,
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "127-132",
"pmc": null,
"pmid": "34740142",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Malformation risk of new anti-epileptic drugs in women with epilepsy; observational data from the Kerala registry of epilepsy and pregnancy (KREP).",
"title_normalized": "malformation risk of new anti epileptic drugs in women with epilepsy observational data from the kerala registry of epilepsy and pregnancy krep"
} | [
{
"companynumb": "IN-UCBSA-2021054511",
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{
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"activesubstancename": "LEVETIRACETAM"
},
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"reaction": [
{
"reactionmeddrapt": "Congenital cardiovascular anomaly",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Urinary tract malformation",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Congenital musculoskeletal anomaly",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Maternal exposure during pregnancy",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Thomas SV, Jeemon P, Pillai R, Jose M, Lalithakumari AM, Murali S, et al. Malformation risk of new anti-epileptic drugs in women with epilepsy; observational data from the Kerala registry of epilepsy and pregnancy (KREP). Seizure: European Journal of Epilepsy. 2021;93:127?32",
"literaturereference_normalized": "malformation risk of new anti epileptic drugs in women with epilepsy observational data from the kerala registry of epilepsy and pregnancy krep",
"qualification": "1",
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},
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},
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},
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"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
},
{
"companynumb": "IN-GLAXOSMITHKLINE-IN2021GSK230927",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "4",
"drugadministrationroute": "064",
"drugauthorizationnumb": "020241",
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"drugcharacterization": "1",
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"drugdosagetext": "UNK",
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"drugindication": "Epilepsy",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "LAMOTRIGINE"
}
],
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"reaction": [
{
"reactionmeddrapt": "Heart disease congenital",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Urinary tract malformation",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Thomas SV, Jeemon P, Pillai R, Jose M, Lalithakumari AM, Murali S et al. Malformation risk of new anti-epileptic drugs in women with epilepsy; observational data from the Kerala registry of epilepsy and pregnancy (KREP). Seizure. 2021;93:127-132",
"literaturereference_normalized": "malformation risk of new anti epileptic drugs in women with epilepsy observational data from the kerala registry of epilepsy and pregnancy krep",
"qualification": "3",
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},
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"transmissiondate": "20220303"
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] |
{
"abstract": "Acute hippocampal injury represents a relatively rare cause of amnesia. Interestingly however, between 2012 and 2017, 18 patients were reported at hospitals in Massachusetts with sudden-onset amnesia in the setting of complete diffusion-weighted hyperintensity of both hippocampi on magnetic resonance imaging. Notably, 17 of the 18 patients tested positive for opioids or had a recorded history of opioid use. This observation suggests an association between opioids and acute hippocampal injury. With particular attention to the Massachusetts cluster and data on fentanyl and its congeners, the epidemiological and pathophysiological evidence that supports this hypothesis is presented, as are potential underlying mechanisms.",
"affiliations": "a Department of Medicine , Quigley Memorial Hospital, Soldiers' Home , Chelsea , MA , USA.;b Department of Anesthesiology and Critical Care , University of Pennsylvania School of Medicine , Philadelphia , PA , USA.",
"authors": "Barash|Jed A|JA|;Kofke|W Andrew|WA|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "England",
"delete": false,
"doi": "10.1080/13554794.2018.1475572",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-4794",
"issue": "24(2)",
"journal": "Neurocase",
"keywords": "Hippocampus; amnesia; fentanyl; memory; opioids",
"medline_ta": "Neurocase",
"mesh_terms": "D000328:Adult; D000647:Amnesia; D000701:Analgesics, Opioid; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D006624:Hippocampus; D006801:Humans; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "9511374",
"other_id": null,
"pages": "124-131",
"pmc": null,
"pmid": "29774783",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Connecting the dots: an association between opioids and acute hippocampal injury.",
"title_normalized": "connecting the dots an association between opioids and acute hippocampal injury"
} | [
{
"companynumb": "US-PFIZER INC-2018491314",
"fulfillexpeditecriteria": "1",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": "3",
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"medicinalproduct": "GABAPENTIN."
}
],
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"patientonsetage": "51",
"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Amnestic disorder",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2014"
}
},
"primarysource": {
"literaturereference": "BARASH, J.. CONNECTING THE DOTS: AN ASSOCIATION BETWEEN OPIOIDS AND ACUTE HIPPOCAMPAL INJURY.. NEUROCASE. 2018?24(2):124-131",
"literaturereference_normalized": "connecting the dots an association between opioids and acute hippocampal injury",
"qualification": "3",
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},
"primarysourcecountry": "US",
"receiptdate": "20191015",
"receivedate": "20181207",
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"receivertype": "6"
},
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"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnessother": 1,
"transmissiondate": "20200122"
}
] |
{
"abstract": "OBJECTIVE\nThe objective of this sub-analysis of the BeCet study (NCT01136005) was to examine health-related quality of life (HRQoL) of patients experiencing dermatological adverse events (AEs) during the first 6 weeks of epidermal growth factor receptor inhibitor (EGFRI) treatment.\n\n\nMETHODS\nPatients (n = 85) treated with EGFRI completed five questionnaires during the first 6 weeks of treatment. 77 patients provided enough data for the sub-analysis. Experienced AEs were reported in the Dermatological Reactions Targeted Therapy-Patients (DERETT-P), a symptom experience diary for patients treated with targeted therapy. The impact of EGFRI-associated dermatological adverse events on HRQoL was examined using four HRQoL questionnaires; the Functional Assessment of Cancer Therapy-EGFRI (FACT-EGFRI-18), the Functional Assessment of Cancer Therapy-General (FACT-G), the 36-Item Short Form Health Survey (SF-36), and the Skindex-16.\n\n\nRESULTS\nDuring the first 6 weeks of EGFRI treatment, physical discomfort was the most significantly affected domain. In the entire study population, xerosis (dry skin) (22.3 %) and pruritus (itchy skin) (16.9 %) were reported as the most impactful AEs. For patients experiencing a papulopustular eruption (acneiform rash) pruritus (24.2 %), xerosis (18.9 %), and papulopustular eruption (6.3 %) were reported as the most impactful AEs. Papulopustular eruption, xerosis, and pruritus all showed a significant negative effect on HRQoL, displayed in FACT-EGFRI-18 scores.\n\n\nCONCLUSIONS\nIn addition to papulopustular eruption, xerosis and pruritus are major EGFRI-associated dermatological AEs with an impact on HRQoL, which warrant more attention in clinical practice and research.",
"affiliations": "Department of Clinical Oncology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. juliamkclabbers@gmail.com.;Department of Clinical Oncology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.;Department of Clinical Oncology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.;Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.;Department of Medicine, Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.;Department of Clinical Oncology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.;Department of Medical Psychology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.",
"authors": "Clabbers|Julia M K|JMK|;Boers-Doets|Christine B|CB|;Gelderblom|Hans|H|;Stijnen|Theo|T|;Lacouture|Mario E|ME|;van der Hoeven|Koos J M|KJM|;Kaptein|Adrian A|AA|",
"chemical_list": "D000970:Antineoplastic Agents; D066246:ErbB Receptors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-015-2781-y",
"fulltext": "\n==== Front\nSupport Care CancerSupport Care CancerSupportive Care in Cancer0941-43551433-7339Springer Berlin Heidelberg Berlin/Heidelberg 278110.1007/s00520-015-2781-yOriginal ArticleXerosis and pruritus as major EGFRI-associated adverse events Clabbers Julia M. K. juliamkclabbers@gmail.com Boers–Doets Christine B. Gelderblom Hans Stijnen Theo Lacouture Mario E. van der Hoeven Koos J. M. Kaptein Adrian A. Department of Clinical Oncology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands Department of Medicine, Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 USA Department of Medical Psychology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands 27 6 2015 27 6 2015 2016 24 513 521 17 11 2014 17 5 2015 © The Author(s) 2015\nOpen Access This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose\nThe objective of this sub-analysis of the BeCet study (NCT01136005) was to examine health-related quality of life (HRQoL) of patients experiencing dermatological adverse events (AEs) during the first 6 weeks of epidermal growth factor receptor inhibitor (EGFRI) treatment.\n\nMethods\nPatients (n = 85) treated with EGFRI completed five questionnaires during the first 6 weeks of treatment. 77 patients provided enough data for the sub-analysis. Experienced AEs were reported in the Dermatological Reactions Targeted Therapy–Patients (DERETT-P), a symptom experience diary for patients treated with targeted therapy. The impact of EGFRI-associated dermatological adverse events on HRQoL was examined using four HRQoL questionnaires; the Functional Assessment of Cancer Therapy–EGFRI (FACT-EGFRI-18), the Functional Assessment of Cancer Therapy–General (FACT-G), the 36-Item Short Form Health Survey (SF-36), and the Skindex-16.\n\nResults\nDuring the first 6 weeks of EGFRI treatment, physical discomfort was the most significantly affected domain. In the entire study population, xerosis (dry skin) (22.3 %) and pruritus (itchy skin) (16.9 %) were reported as the most impactful AEs. For patients experiencing a papulopustular eruption (acneiform rash) pruritus (24.2 %), xerosis (18.9 %), and papulopustular eruption (6.3 %) were reported as the most impactful AEs. Papulopustular eruption, xerosis, and pruritus all showed a significant negative effect on HRQoL, displayed in FACT-EGFRI-18 scores.\n\nConclusions\nIn addition to papulopustular eruption, xerosis and pruritus are major EGFRI-associated dermatological AEs with an impact on HRQoL, which warrant more attention in clinical practice and research.\n\nKeywords\nCancerQuality of lifeEpidermal growth factor receptor inhibitorPapulopustular eruptionXerosisPruritusissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2016\n==== Body\nBackground\nEpidermal growth factor receptor inhibitors (EGFRIs) are frequently used in treatment regimens of patients with solid tumors. Compared with cytotoxic chemotherapeutic agents, which may cause myelosuppression, nausea, vomiting, neuropathy, and alopecia, EGFRIs are associated with a lower incidence of systemic adverse events (AEs). However, patients treated with EGFRIs experience dermatological AEs (dAEs), such as papulopustular eruption (acneiform rash), xerosis (dry skin), pruritus (itchy skin), and paronychia (periungual inflammation), as well as mucosal and hair abnormalities [1, 2].\n\nThe most common AE of EGFRI treatment is a papulopustular eruption, occurring in 75 to 95 % of patients [1, 2]. The papulopustular eruption consists of acneiform follicular and perifollicular papules and sterile pustules, most pronounced on the face, scalp, upper back, and chest and is often accompanied by xerosis and pruritus. The papulopustular eruption is a relatively early-onset AE, usually occurring between 1 to 3 weeks after initiation of treatment. The incidence is higher with monoclonal antibodies like cetuximab and panitumumab (more than 88 %) than with tyrosine kinase inhibitors like gefitinib, erlotinib, lapatinib, and afatinib (43–75 %). In about 80 to 90 % of the skin reactions, the worst recorded severity is mild (grade 1) to moderate (grade 2), but in 10 % a more severe skin reaction (grade 3) is seen [1, 2]. In several studies, the presence and severity of the eruption has shown a correlation with a positive response to cancer treatment, as expressed in higher median survival rates [1–3]. However, patients reported that the papulopustular eruption interferes in their daily activities and in the appearance of their skin, because the EGFRI-associated dAEs, often in visible areas, make them worried, frustrated, and depressed and cause withdrawal from social activities [3, 4].\n\nThe physical discomfort caused by EGFRI treatment has been identified as having the most impact on health-related quality of life (HRQoL), especially the sensations of pain, burning, and skin sensitivity. The dAEs may lead to a decreased HRQoL and to dose reduction or discontinuation of anticancer treatment, even though the treatment might be effective in treating the cancer and reducing the dose may negatively affect cancer outcome [4]. At present, the consequence of the dAEs on HRQoL in patients with cancer receiving EGFRI treatment remains poorly understood.\n\nThis sub-analysis of the ongoing BeCet study (NCT01136005) is aimed to provide a better understanding of HRQoL in patients with cancer receiving EGFRI treatment, using five different questionnaires.\n\nPatients and materials\nPatients\nThe study population was derived from the ongoing BeCet study. This phase III randomized double-blinded trial compares Bepanthen against cetomacrogol cream on their preventive effect in decreasing the incidence of grade ≥2 EGFRI-associated papulopustular eruption and assesses the Dutch version of Functional Assessment of Cancer Therapy-EGFRI (FACT-EGFRI-18) for reliability and validity [5, 6]. The study has been approved by the Medical Ethics Review Committees of each participating hospital. Twelve Dutch centers are currently recruiting patients starting with an EGFRI treatment for any type of cancer (i.e., panitumumab, cetuximab, lapatinib, gefitinib, erlotinib, or afatinib). Patients need to have an Eastern Co-operative Oncology Group performance status ≤2 and need to be able to complete questionnaires.\n\nThe first 85 consecutive patients were included for this sub-analysis between July 2010 and May 2014. This analysis studies the impact of the dAEs on the HRQoL, while the main study analyses the appearance and severity of dAEs. There are no strict criteria for the sample size in HRQoL studies. Within a homogenous population there is lower variability in answers on HRQoL items, making a smaller sample size acceptable.\n\nMaterials\nDuring the 6-week study period, patients completed five different questionnaires. They completed the symptom experience diary Dermatological Reactions Targeted Therapy–Patients (DERETT-P) and the FACT-EGFRI-18 weekly. Within the BeCet trial, these two questionnaires are measured weekly to provide detailed information about the incidence and severity curve of dAEs. For this sub-analysis, fewer data than in the main study collected are of relevance. These are the data of weeks 0, 2, and 4.\n\nIn week 4, the Functional Assessment of Cancer Therapy–General (FACT-G), the 36-Item Short Form Health Survey (SF-36), and the Skindex-16 questionnaires were completed for validation purposes of the FACT-EGFRI-18. Week 4 of treatment was chosen, because then most patients will have experienced a papulopustular eruption [7]. In this analysis, scores of these generic questionnaires were compared with previously published articles, to put the HRQoL of cancer patients treated with EGFRIs in perspective to similar samples.\n\nDERETT\nThe Dermatological Reactions Targeted Therapy (DERETT) is available in two versions, for patients (DERETT-P) and healthcare professionals (DERETT-H), consisting of 61 and 50 items, respectively. These tools gather information such as area involved, severity and duration of the symptoms, products used to treat symptoms, effectiveness of the supportive care interventions, treatment adherence, and symptom-related distress [8]. DERETT provides a more precise and clinically relevant information on the patient’s condition than Common Terminology Criteria for Adverse Events (CTCAE) grading alone.\n\nFACT-EGFRI-18\nThe Functional Assessment of Cancer Therapy Questionnaire–EGFRI has been developed to assess HRQoL related to EGFRI-associated dAEs. The translation, linguistic validation, and qualitative assessment of the FACT-EGFRI-18 have been described [5, 6, 9]. The validations of the English and Dutch versions are ongoing. The FACT-EGFRI-18 consists of 18 items in three HRQoL domains: physical (7 items), social/emotional (6 items), and functional (5 items). Scores are rated on a numerical analogue scale (0 = not at all, 4 = very much). A high domain score reflects a low HRQoL. On the other hand, a high total score indicates a high HRQoL [10].\n\nFACT-G\nThe FACT-G version 4 is a patient reposted outcome (PRO) measure with numerical analogue scales (0 = not at all, 4 = very much). The FACT-G version 4 consists of 27 items in four HRQoL domains: physical (7 items), social/family (7 items), emotional (6 items), and functional well-being (7 items). High total scores indicate a high HRQoL. The FACT-G has been validated for patients with cancer in general [11].\n\nSF-36\nThe 36-Item Short Form Health Survey (SF-36) is a generic HRQoL survey. The questionnaire consists of 36 items, covering eight scales: physical functioning, role limitations due to physical health and due to emotional problems, energy/fatigue, emotional well-being, social functioning, pain, and general health. A high total scale score represents a high HRQoL. The SF-36 can be used to measure HRQoL in general and specific populations, and has been validated for Dutch citizens, and patients with cancer [12].\n\nSkindex-16\nThe Skindex-16 is a 16-item PRO assessing dermatological symptoms on a numerical analogue scale (0 = never bothered, 6 = always bothered), where high scores represent a low HRQoL. It contains three domains: symptoms (4 items), emotions (7 items), and functioning (5 items). The Skindex-16 is reliable and valid for general skin diseases. It has been used more often to assess HRQoL in patients receiving EGFRI treatment, but does not address symptoms related to hair, nails, or mucous membranes, that are specific targets for EGFRIs [13].\n\nStatistical analysis\nDescriptive statistics were used to describe the study population. In DERETT-P, the incidences of the AEs with the highest impact on HRQoL (Fig. 1) were determined per week and in total. The domain and total scores of FACT-EGFRI-18 during the first 6 weeks of EGFRI treatment are displayed in a time plot (Fig. 2). With a one-way ANOVA, item and domain scores during treatment were compared to baseline, followed by a Bonferroni procedure to correct for multiple testing. Using the Mann–Whitney test, FACT-EGFRI-18 scores during week 2 to 4 and Skindex-16 scores of week 4 were compared between different subgroups, i.e., gender, type of cancer, EGFRI agent, and age, as mainly in those weeks papulopustular eruption manifests [1]. To analyze HRQoL for patients experiencing a papulopustular eruption, their FACT-EGFRI-18 scores were compared with pre-treatment scores, also using the Mann–Whitney test. With manual two-sample t tests and one-sample Wilcoxon signed-rank tests, mean and median scores of FACT-G, SF-36, and Skindex-16 were both compared to scores in previously published articles, in order to determine how HRQoL relates to these populations. DERETT-P and FACT-EGFRI-18 scores have not been described before and could, therefore, not be compared. All data analysis was performed with the Statistical Package for Social Sciences (SPSS) version 20. Overall, p < 0.05 was accepted as a statistically significant result.\n\nResults\nDemographics\nBetween July 2010 and May 2014, a total of 85 patients were included. Eight patients (9.4 %) with disease progression were excluded as they stopped EGFRI treatment before week 4 and, consequently, did not complete FACT-G, SF-36, and Skindex-16. In total, 77 patients were evaluable. Six (7.79 %) of them stopped EGFRI treatment after week 4 because of disease progression and/or death, but produced enough data to be considered evaluable for this study. The mean age of the included study population (n = 77) was 65.0 years (SD 9.91). Forty-six patients (59.7 %) were male. The majority of the patients were of Caucasian origin (96.1 %) and three patients of other origin (Asian and Hindu) (Table 1). Patients were mainly diagnosed with non-small cell lung cancer (NSCLC) and colorectal cancer, 41.6 and 39.0 %, respectively. Panitumumab (37.7 %) and erlotinib (32.5 %) were the most prescribed EGFRI drugs. Of the DERETT-P, FACT-EGFRI-18, FACT-G, SF-36, and Skindex-16 questionnaires, 50, 47.4, 25.9, 25.9, and 23.5 %, respectively, were not completed. The main reasons for the uncompleted questionnaires were that the healthcare provider did not hand out the questionnaire in the uneven weeks (weeks 1, 3, and 5) and early discontinuation due to disease progression. Some patients did not complete the questionnaires because they did not feel the need to do so since their AEs stayed almost the same as during the previous measures, most prominent in patients with many or nearly none experienced AEs. Patient burden and burn out may also play a role.Table 1 Patient demographics (n = 77)\n\nCharacteristic\tNumber of patients (%)\t\nGender\t\n Male\t46 (59.7)\t\n Female\t31 (40.3)\t\nAge in years\t65.0 (9.91) [41–87]a\n\t\nRace\t\n Caucasian\t74 (96.1)\t\n Other\t3 (3.9)\t\nType of cancer\t\n NSCLC\t32 (41.6)\t\n Colorectal\t30 (39.0)\t\n HNC\t8 (10.4)\t\n Mamma\t3 (3.9)\t\n Pancreas\t3 (3.9)\t\n Osteosarcoma\t1 (1.3)\t\nEGFRI type\t\n Panitumumab\t29 (37.7)\t\n Erlotinib\t25 (32.5)\t\n Cetuximab\t10 (13.0)\t\n Gefitinib\t10 (13.0)\t\n Lapatinib\t3 (3.9)\t\n\nSD standard deviation, NSCLC non-small cell lung cancer, HNC head and neck cancer\n\n\naExpressed in mean (SD) [range]\n\n\n\nImpact of various adverse events\nThe DERETT-P questionnaire asks patients to report if they experienced certain AEs and in which severity. Secondly, the questionnaire asks from which AE they experienced the most hinder. Xerosis and pruritus were reported most often: mean 22.3 and 16.9 %, respectively. The remaining dAEs were reported by means less than 4.8 %. Fig. 1a displays the incidence of the four AEs which have the highest impact on HRQoL during the 6-week study period, while Fig. 1b displays the AEs with the highest impact on HRQoL over time. The peak of impact of xerosis on HRQoL was in week 5 (33.3 %), and at week 6 for pruritus (25.0 %). Papulopustular eruption was reported as having the most impact on HRQoL by 4.2 % of all patients, with a peak in week 4 (9.4 %).Fig 1 \na Adverse events that patients reported as present in DERETT-P compared to b adverse events as having most impact on HRQoL as measured by DERETT-P. In (a), papulopustular eruption is reported as the most common adverse event, while (b) displays that xerosis and pruritus have a more profound impact on HRQoL. HRQoL health-related quality of life\n\n\n\nSince a papulopustular eruption may overlap xerosis and pruritus and, therefore, the outcome may be different in patients who did develop a papulopustular eruption compared to those who did not, we explored the patients that experienced a papulopustular eruption separately. Even in this subgroup, AEs having most impact on HRQoL remained pruritus (24.2 %), xerosis (18.9 %), a burning sensation of the skin (8.4 %), and lastly a papulopustular eruption (6.3 %).\n\nQuality of life during EGFRI treatment\nTable 2 and Fig. 2 show the development of total and domain scores of FACT-EGFRI-18 over time. Scores on the physical domain were significantly higher during all 6 weeks compared to baseline (p < 0.001). The functional domain for all grades showed a significantly higher score in the sixth week compared to baseline (p = 0.039). In patients with grade 1/2, the dispersion in these domains is relatively low (Fig. 2c). However, the social-emotional domain did show significant changes within the grade 3/4 sample (Fig. 2d). What stands out is the large spread on the domains of “social-emotional” and “functional” in patients with grade 3/4 at weeks 0 and 1. This was also the case prior to the start of the EGFRI treatment; in week 0, the standard error is negative and as the weeks pass this spread decreases. For all domains and items, a higher score represents lower HRQoL. The total FACT-EGFRI-18 score decreased during treatment, reflecting decrease in HRQoL.Table 2 Domain and total scores FACT-EGFRI-18 per week\n\nWeek\tDomain scores\tTotal score\t\nPhysical\n7 items\tSocial-emotional\n6 items\tFunctional\n5 items\t\n0\t1.41 (1.80)\t0.490 (2.20)\t0.470 (1.69)\t69.5 (5.23)\t\n1\t2.90 (3.49)\t1.29 (2.80)\t0.760 (2.21)\t67.0 (8.03)\t\n2\t5.42 (4.13)\t1.45 (2.01)\t1.200 (1.86)\t63.8 (7.00)\t\n3\t5.32 (4.10)\t1.08 (2.10)\t0.970 (1.83)\t64.6 (6.95)\t\n4\t6.00 (5.14)\t1.57 (2.60)\t1.780 (3.27)\t62.6 (9.75)\t\n5\t5.41 (4.24)\t1.86 (3.02)\t1.410 (2.69)\t63.2 (8.97)\t\n6\t6.65 (5.01)\t1.70 (3.28)\t1.870 (3.13)\t61.6 (10.1)\t\nScores are presented in mean (standard deviation). Domain scores are calculated as the sum of all corresponding items, taking into account that at least 50 % of the items need to be answered for a reliable calculation. The total score is calculated by subtracting the domain scores from 72 (the maximum possible total score) and correct for the number of answered items. Therefore, a low HRQoL is reflected by a high domain score and a low total score\n\n\nFACT-EGFRI-18 Functional Assessment of Cancer Therapy–EGFRI\n\nFig. 2 \na Mean (standard error of the mean) FACT-EGFRI-18 total scores per week. b Mean (standard error of the mean) of all grade FACT-EGFRI-18 domain scores per week. c Mean (standard error of the mean) of grade 1/2 FACT-EGFRI-18 domain scores per week. d Mean (standard error of the mean) of grade 3/4 FACT-EGFRI-18 domain scores per week. FACT-EGFRI-18 Functional Assessment of Cancer Therapy–EGFRI, EGFRI epidermal growth factor receptor inhibitor\n\n\n\nThere were no significant differences between FACT-EGFRI-18 scores for gender (total score men 63.40, women 63.92) or cancer type (total scores ranging from 63.7 to 68.00). Patients younger than 50 years scored significantly (p = 0.015) lower on the functional domain (score 0.91 <50 years versus 1.61 61–70 years (mean age)). Patients above 81 years experienced more impact on the physical domain (p = 0.028) (2.94 versus 5.06 in the mean age group of 61–70) and total score (p = 0.020) (68.56 by >81; 63.84 by 61–70), compared to patients in the mean age range between 61 and 70 years.\n\nThe presence of papulopustular eruption during the study period significantly decreased HRQoL as measured by FACT-EGFRI-18 (p < 0.001). This was most prominent for the physical domain (Table 3). FACT-EGFRI-18 scores were also analyzed separately for xerosis and pruritus, showing a significant reduced HRQoL (p < 0.014).Table 3 HRQoL with papulopustular eruption displayed in FACT-EGFRI-18 scores\n\nWeek\tPapulopustular eruption\tDomain scores FACT-EGFRI-18\t\nPhysical\tSocial-emotional\tFunctional\t\n0\t\nn = 0\t1.41 (1.80)\t0.490 (2.20)\t0.470 (1.69)\t\n1\t\nn = 19\t4.58 (4.03)*\t2.21 (3.65)*\t1.42 (3.06)*\t\n2\t\nn = 31\t6.97 (3.70)*\t2.00 (2.21)*\t1.61 (1.94)*\t\n3\t\nn = 24\t6.54 (3.98)*\t1.50 (2.45)*\t1.42 (2.15)*\t\n4\t\nn = 30\t7.27 (5.75)*\t1.77 (2.85)*\t2.43 (3.95)*\t\n5\t\nn = 19\t6.79 (4.13)*\t2.37 (3.29)*\t1.84 (3.08)*\t\n6\t\nn = 24\t7.13 (4.16)*\t1.92 (2.80)*\t1.92 (2.21)*\t\nScores presented in mean (SD)\n\n\nFACT-EGFRI-18 Functional Assessment of Cancer Therapy–EGFRI, HRQoL Health-related quality of life\n\n*p < 0.05, a significantly lower HRQoL compared with week 0 (baseline)\n\n\n\nFACT-G scores were compared with the scores of Cella et al. [11], which included other types of cancer, i.e., leukemia, lymphoma, prostate cancer, and ovarian cancer without EGFRI treatment. Our study population scored significantly higher on the physical (p = 0.014) and emotional domains (p = 0.013), with higher scores indicating a higher HRQoL. Scores on the social-family and functional domains did not differ significantly.\n\nScores on SF-36 were first compared to scores of a sample of a Dutch healthy control population in order to examine the difference in HRQoL of EGFRI treated cancer patients with healthy individuals [14]. The current study population had a higher mean age and scored significantly lower on all domains (p < 0.028), meaning lower HRQoL. Secondly, SF-36 scores were compared with a group of cancer patients about to start chemotherapy or radiotherapy. The current study population was older, consisted of fewer females, had more patients with NSCLC and colorectal cancer, and fewer with breast cancer. Scores were similar for most SF-36 domains. Only for physical functioning (p = 0.042) and general health (p < 0.001), the current study population scored significantly lower, meaning a lower HRQoL [14].\n\nSkindex-16 separately identified a significant lower total score when papulopustular eruption was present (p < 0.002), but not for the presence of xerosis or pruritus. The Skindex-16 scores did not differ significantly between patients experiencing papulopustular eruption, xerosis, or pruritus (Table 4).Table 4 Comparison of mean and median Skindex-16 scores for patients experiencing dermatological adverse events\n\nSkindex-16 domains\tCurrent study\tCurrent study\tCurrent study\tJoshi et al.4\n\tRosen et al.14\n\tRosen et al.14\n\t\n\tPapulopustular eruption\tXerosis\tPruritus\tEGFRI\nAEs\tTargeted therapy AEs\tNon-targeted therapy AEs\t\n\t\nn = 30\t\nn = 24\t\nn = 21\t\nn = 67\t\nn = 163\t\nn = 120\t\nSymptoms\t\n Mean (SD)\t27.2 (26.4)\t22.9 (26.5)\t35.6 (28.9)\t45.3a,b,c\n\t\t\t\n Median (95 % CI)\t20.8 (12.5–33.3)\t16.7 (0.00–29.2)\t29.2 (20.8–37.5)\t\t37.5 (29.2–54.2)b,c\n\t39.6 (25.0–45.8)b,c\n\t\nEmotions\t\n Mean (SD)\t17.2 (21.9)\t14.7 (19.3)\t21.4 (24.2)\t50.0a,b,c,d\n\t\t\t\n Median (95 % CI)\t9.53 (4.77–21.4)\t9.53 (0.00–21.4)\t14.3 (4.77–26.2)\t\t50.0 (40.5–57.1)b,c,d\n\t38.1 (30.4–47.6)b,c,d\n\t\nFunctioning\t\n Mean (SD)\t10.0 (17.1)\t7.23 (14.3)\t10.5 (15.7)\t31.3a,b,c,d\n\t\t\t\n Median (95 % CI)\t0.00 (0.00-10.2)\t0.00 (0.00–3.34)\t3.34 (0.00–16.7)\t\t16.7 (8.2–26.7)b,c,d\n\t13.3 (3.3–20.0)b,c\n\t\nJoshi et al. [4] displayed mean scores while Rosen et al. [14] displayed median scores. Therefore, in the current study, both are displayed to make comparison possible\n\n\nAE adverse event\n\n\naNo standard deviations were given in Joshi et al. [4]\n\n\nbA statistically significant result compared with patients from the current study experiencing papulopustular eruption\n\n\ncA statistically significant result compared with patients from the current study experiencing xerosis\n\n\ndA statistically significant result compared with patients from the current study experiencing pruritus\n\n\n\nThe current Skindex-16 scores were compared with the data of Joshi et al. [4] and Rosen et al. [15], both a retrospective investigation of Skindex-16 scores of patients with dAEs due to cancer treatment in a specialty referral clinic. The study of Joshi et al. is the most comparable to the current study as they focused on patients treated with EGFRIs. Joshi et al. [4] analyzed more women, more patients younger than 50 years, and more patients treated with cetuximab and erlotinib. Rosen et al. [15] included patients with targeted as well as non-targeted therapy, who were generally younger, more often female, and less often of Caucasian ethnicity. Our study patients with papulopustular eruption and xerosis scored higher HRQoL on all Skindex-16 domains as patients in Joshi et al. [4] (p < 0.001) and in Rosen et al. [15] (p < 0.032). This was most marked on the emotional level. Our patients with pruritus had equal scores on the physical domain compared to both studies, and a comparable score on the functional domain with patients in Rosen et al. [15] receiving non-targeted therapy (Table 4). Even though not significant in the relatively small sample size, patients with pruritus showed a trend of higher scores on Skindex-16 and FACT-EGFRI-18 (indicating a lower HRQoL) than patients with papulopustular eruption or xerosis.\n\nDiscussion\nThe current results show that xerosis and pruritus have a major negative impact on HRQoL during the first 6 weeks of EGFRI treatment. This also applies for the patients affected by papulopustular eruption, from which only 6.3 % report the presence of papulopustular eruption as having the highest impact on HRQoL. These findings were confirmed also in the STEPP trial [16, 17].\n\nIn Gandhi et al. [18], patients reported xerosis as having the most negative impact on HRQoL and pruritus as the third most impactful of all dAEs. In addition, xerosis was reported as having the second most negative impact on HRQoL of all unexpected AEs due to cancer treatment. Since xerosis and pruritus are less frequent reported EGFRI-associated dAEs, not all patients are counseled about these possible dAEs before initiating treatment. Therefore, they cannot engage in anticipatory coping; a method to deal with anticipated AEs. In an interview study of Frith et al. [19], strategies were identified for patients to cope with anticipated cancer treatment AEs. First, patients try to foresee the amount of distress and accompanying emotions through “affective rehearsal,” followed by acceptance of possible AEs and gathering resources to manage them through “behavioral rehearsal,” a method to modify interpersonal skills and social interactions. The final strategy is finding ways to control the development of the AEs and the personal emotional reactions on them [19].\n\nSince this is the first report of FACT-EGFRI-18 scores, we are not able to compare our data to data from other trials. Our analysis showed that during the first 6 weeks of EGFRI treatment, patients experience influence on their HRQoL primarily due to physical symptoms, especially irritation, xerosis, pruritus, and nail sensitivity. The reversed FACT-EGFRI-18 scores of papulopustular eruption, xerosis and pruritus decreased significantly on the total scores (p < 0.014) indicating a high HRQoL. The non-reversed FACT-EGFRI-18 scores increased significantly on the domain scores (p < 0.012) reflecting a low HRQoL. Only patients experiencing xerosis in week 1 and patients experiencing pruritus in week 5 did not have a significant higher score on the functional domain, meaning a non-significant different score compared to before treatment.\n\nCella et al. [11] used the FACT-G questionnaire in a population with different cancer types and treatments, and EGFRI-treated patients were not included. EGFRI treatment is considered more tolerable compared to conventional cytotoxic treatments, because systemic AEs are less frequent [20]. This could explain the higher score on the physical and emotional domains in the current study population. Aaronson et al. [14] measured pre-treatment SF-36 scores, resulting in fewer AEs, which explain a higher physical functioning and general health.\n\nThe study of Joshi et al. [4] analyzed Skindex-16 scores at any time of AE development instead of the current fixed measurement at week 4 of treatment. In addition, the referral to a specialty clinic might have increased patients’ worry about the severity of the AEs. Rosen et al. [15] measured patients at any moment during all types of cancer treatment, causing a broader range of dAEs, which influences Skindex-16 scores. This could also explain a better HRQoL for patients with papulopustular eruption or xerosis. In addition, patients with pruritus had similar Skindex-16 scores on the physical domain as the patients in the specialty referral clinic in Joshi et al. [4] and Rosen et al. [15]. These findings suggest that the impact of pruritus on HRQoL might be larger than papulopustular eruption and xerosis. The similar score on the physical domain of Skindex-16 of patients with acne vulgaris suggests clinical similarities with EGFRI papulopustular eruptions. Patients with EGFRI-associated papulopustular eruption are generally more likely to accept the temporary eruption as part of their treatment for cancer, especially since they are usually informed about its association with effectiveness of treatment, which can clarify the different impact on emotions and functioning [17, 20, 21].\n\nThis study required a substantial effort for patients to complete consecutive questionnaires at the intended assessments. There might be a selection bias as missing data were from relatively sicker patients, which could result in overestimating the overall HRQoL and underestimating the impact of dAEs on HRQoL. Another cause may be the missing data from patients who did not experience noticeable AE changes and, therefore, did not complete the questionnaires in the weeks without AE changes. The incidence of dAEs might be reduced as all patients received close monitoring and preventive and reactive treatment. As all factors mentioned above are more likely to have improved HRQoL of patients, the expectation is that the current results are indeed realistic and may be even more profound when less confounding factors would be present. Because the study population consisted mainly of patients from Caucasian origin, with NSCLC or colorectal cancer, current results may not apply to all EGFRI-treated cancer patients.\n\nConclusion\nClinical and research endeavors in patients with various cancers who receive medical management consisting of EGFRIs have focused mainly on papulopustular eruption as an EGFRI-associated AE, which resulted in an important decrease in HRQoL. However, the current study shows that xerosis and pruritus are also important AEs with a major impact on HRQoL. This justifies more focus on HRQoL related to these symptoms and on their prevention and treatment in future research.\n\nIn clinical practice, xerosis and pruritus are infrequently discussed during patient counseling prior to treatment, as they are less visible than the more common papulopustular eruption. Providing patients adequate information about treatment and possible AEs has shown a positive result on patients’ emotional and physical well-being. Counseling patients prior to EGFRI treatment about potential xerosis and pruritus is therefore important, as well as taking preventive measures against these AEs [18, 19, 22, 23].\n\nJulia M. K. Clabbers and Christine B. Boers–Doets contributed equally to this work.\n\nConflict of interest\nMEL has consulted for Roche, BMS, BI, Genentech, AZ, and Merck. The other authors have no conflict of interest to declare in relation to this work.\n==== Refs\nReferences\n1. Lacouture ME Anadkat MJ Bensadoun RJ Bryce J Chan A Epstein JB Eaby-Sandy B Murphy BA Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities Support Care Cancer 2011 19 8 1079 1095 10.1007/s00520-011-1197-6 21630130 \n2. 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Boers-Doets CB Gelderblom H Lacouture ME Bredle JM Epstein JB Schrama NA Gall H Ouwerkerk J Brakenhoff JA Nortier JW Kaptein AA Translation and linguistic validation of the FACT-EGFRI-18 quality of life instrument from English into Dutch Eur J Oncol Nurs 2013 17 6 802 807 10.1016/j.ejon.2013.03.004 23571183 \n6. Boers-Doets CB Gelderblom H Lacouture ME Epstein JB Nortier JW Kaptein AA Experiences with the FACT-EGFRI-18 instrument in EGFRI-associated mucocutaneous adverse events Support Care Cancer 2013 21 7 1919 1926 10.1007/s00520-013-1752-4 23417565 \n7. Scope A Agero AL Dusza SW Myskowski PL Lieb JA Saltz L Kemeny NE Halpern AC Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption J Clin Oncol 2007 25 34 5390 5396 10.1200/JCO.2007.12.6987 18048820 \n8. Boers-Doets CB (2014) The Target System—approach to assessment, grading, and management of dermatological & mucosal side effects of targeted anticancer therapies. 1 ed. Wormer: IMPAQTT\n9. Wagner LI, Lai SE, Aneja M, LoRusso P, Perez-Soler R, O’Brien B et al. (2007) Development of a functional assessment of side-effects to therapy (FAST) questionnaire to assess dermatology-related quality of life in patients treated with EGFR inhibitors (EGFRI): the FAST-EGFRI. ASCO, Meeting Abstracts 25[18 Suppl], 19532.\n10. Wagner LI Berg SR Gandhi M Hlubocky FJ Webster K Aneja M Cella D Lacouture ME The development of a Functional Assessment of Cancer Therapy (FACT) questionnaire to assess dermatologic symptoms associated with epidermal growth factor receptor inhibitors (FACT-EGFRI-18) Support Care Cancer 2013 21 4 1033 1041 10.1007/s00520-012-1623-4 23128934 \n11. Cella DF Tulsky DS Gray G Sarafian B Linn E Bonomi A Silberman M Yellen SB Winicour P Brannon J The Functional Assessment of Cancer Therapy scale: development and validation of the general measure J Clin Oncol 1993 11 3 570 579 8445433 \n12. Newnham EA Harwood KE Page AC Evaluating the clinical significance of responses by psychiatric inpatients to the mental health subscales of the SF-36 J Affect Disord 2007 98 1-2 91 97 10.1016/j.jad.2006.07.001 16904752 \n13. Chren MM Lasek RJ Sahay AP Sands LP Measurement properties of Skindex-16: a brief quality-of-life measure for patients with skin diseases J Cutan Med Surg 2001 5 2 105 110 10.1007/BF02737863 11443481 \n14. Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R, Sprangers MA, Velde AtT, Verrips E (1998) Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 51(11):1055–1068\n15. Rosen AC Case EC Dusza SW Balagula Y Gordon J West DP Lacouture ME Impact of dermatologic adverse events on quality of life in 283 cancer patients: a questionnaire study in a dermatology referral clinic Am J Clin Dermatol 2013 14 4 327 333 10.1007/s40257-013-0021-0 23625802 \n16. Lacouture ME Mitchell EP Piperdi B Pillai MV Shearer H Iannotti N Xu F Yassine M Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer J Clin Oncol 2010 28 8 1351 1357 10.1200/JCO.2008.21.7828 20142600 \n17. Coleman S Jatoi A STEPP for the EGFR inhibitor-induced rash—definitely a step in the right direction Curr Oncol Rep 2010 12 4 223 225 10.1007/s11912-010-0102-7 20437117 \n18. Gandhi M Oishi K Zubal B Lacouture ME Unanticipated toxicities from anticancer therapies: survivors’ perspectives Support Care Cancer 2010 18 11 1461 1468 10.1007/s00520-009-0769-1 19956983 \n19. Frith H Harcourt D Fussell A Anticipating an altered appearance: women undergoing chemotherapy treatment for breast cancer Eur J Oncol Nurs 2007 11 5 385 391 10.1016/j.ejon.2007.03.002 17512251 \n20. White KJ Roydhouse JK Scott K Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor-inhibitor treatment Clin J Oncol Nurs 2011 15 1 88 96 10.1188/11.CJON.88-96 21278044 \n21. Balagula Y Garbe C Myskowski PL Hauschild A Rapoport BL Boers-Doets CB Lacouture ME Clinical presentation and management of dermatological toxicities of epidermal growth factor receptor inhibitors Int J Dermatol 2011 50 2 129 146 10.1111/j.1365-4632.2010.04791.x 21244375 \n22. Haley AC Calahan C Gandhi M West DP Rademaker A Lacouture ME Skin care management in cancer patients: an evaluation of quality of life and tolerability Support Care Cancer 2011 19 4 545 554 10.1007/s00520-010-0851-8 20336328 \n23. Siminoff LA Improving communication with cancer patients Oncology (Williston Park) 1992 6 10 83 87 1390017\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0941-4355",
"issue": "24(2)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Cancer; Epidermal growth factor receptor inhibitor; Papulopustular eruption; Pruritus; Quality of life; Xerosis",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D003875:Drug Eruptions; D066246:ErbB Receptors; D005076:Exanthema; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011537:Pruritus; D011788:Quality of Life; D011795:Surveys and Questionnaires",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "513-521",
"pmc": null,
"pmid": "26111953",
"pubdate": "2016-02",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "20437117;9817123;1390017;21630130;20142600;16904752;23128934;20336328;8445433;18048820;17512251;23625802;23417565;11443481;21244375;23571183;22997576;18154217;21278044;20564072;19956983",
"title": "Xerosis and pruritus as major EGFRI-associated adverse events.",
"title_normalized": "xerosis and pruritus as major egfri associated adverse events"
} | [
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{
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{
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{
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] |
{
"abstract": "BACKGROUND\nHaloperidol, 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone (HP), one of the most widely used antipsychotics in the treatment of schizophrenia, mania, and other psychiatric disorders, is frequently encountered in cases of unintentional pediatric intoxication because the ingestion of a small amount can cause significant toxic effects in children. For monitoring HP in suspected ingestions, a liquid chromatography-high-resolution mass spectrometry method has been developed and validated in urine, blood, and hair samples.\n\n\nMETHODS\nThe analyte was extracted from 1 mL blood or urine by liquid/liquid extraction and from 5 mg of hair by micropulverized extraction; gradient elution on an Atlantis T3 column was realized using HP-d4 as an internal standard. Positive ion electrospray ionization and high-resolution mass spectrometry determination were performed in an Orbitrap mass spectrometer.\n\n\nRESULTS\nThe method exhibited a r > 0.999 in the studied ranges (0.1-50 ng/mL in urine and blood and 0.1-50 ng/mg in hair) and a limit of quantification of 0.1 ng/mL for urine and blood and 0.1 ng/mg for hair; intra-assay and interassay relative SDs were always more than 18%. The method was applied to determine haloperidol in 3 children who were admitted to emergency departments. HP concentrations ranged from 2 to 21 ng/mL in urine, from not detected to 4.9 ng/mL in blood, and from 0.37 to 0.73 ng/mg in hair samples.\n\n\nCONCLUSIONS\nThe utilization of high-resolution/high-accuracy mass spectrometry in full scan mode allowed the identification of HP metabolites in urine and blood, thus unequivocally documenting the exposure to the drug. HP metabolites were structurally characterized by high-resolution multiple mass spectrometry. For the first time, a HP metabolite was detected in hair.",
"affiliations": "Department of Molecular Medicine, School of Medicine, University of Padova, I-35121 Padova, Italy.",
"authors": "Favretto|Donata|D|;Stocchero|Giulia|G|;Nalesso|Alessandro|A|;Vogliardi|Susanna|S|;Boscolo-Berto|Rafael|R|;Montisci|Massimo|M|;Ferrara|Santo D|SD|",
"chemical_list": "D006220:Haloperidol",
"country": "United States",
"delete": false,
"doi": "10.1097/FTD.0b013e3182892d11",
"fulltext": null,
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"issn_linking": "0163-4356",
"issue": "35(4)",
"journal": "Therapeutic drug monitoring",
"keywords": null,
"medline_ta": "Ther Drug Monit",
"mesh_terms": "D001826:Body Fluids; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring; D005260:Female; D006197:Hair; D006220:Haloperidol; D006801:Humans; D007223:Infant; D008297:Male; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "7909660",
"other_id": null,
"pages": "493-501",
"pmc": null,
"pmid": "23851906",
"pubdate": "2013-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Monitoring haloperidol exposure in body fluids and hair of children by liquid chromatography-high-resolution mass spectrometry.",
"title_normalized": "monitoring haloperidol exposure in body fluids and hair of children by liquid chromatography high resolution mass spectrometry"
} | [
{
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},
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"medicinalproduct": "HALOPERIDOL."
}
],
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"reaction": [
{
"reactionmeddrapt": "Sedation",
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},
{
"reactionmeddrapt": "Wrong patient received medication",
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},
{
"reactionmeddrapt": "Dystonia",
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{
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{
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}
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},
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"literaturereference": "FAVRETTO D, STOCCHERO G, NALESSO A, VOGLIARDI S, BOSCOLO-BERTO R, MONTISCI M, ET AL. MONITORING HALOPERIDOL EXPOSURE IN BODY FLUIDS AND HAIR OF CHILDREN BY LIQUID CHROMATOGRAPHY-HIGH-RESOLUTION MASS SPECTROMETRY. THER-DRUG-MONIT 2013; 35(4):493-501.",
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],
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"literaturereference": "FAVRETTO D, STOCCHERO G, NALESSO A, VOGLIARDI S, BOSCOLO-BERTO R, MONTISCI M, ET AL. MONITORING HALOPERIDOL EXPOSURE IN BODY FLUIDS AND HAIR OF CHILDREN BY LIQUID CHROMATOGRAPHY HIGH-RESOLUTION MASS SPECTROMETRY.. THERAPEUTIC DRUG MONITORING. 2013;35 (4):493-1",
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{
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},
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],
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},
{
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{
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{
"abstract": "Listeria rhombencephalitis is a rare cause of brain stem encephalitis. We report a case with a history of immunosupressive therapy due to Takayasu's arteritis that was treated with corticosteroids and linezolid for Listeria rhombencephalitis. A 63-year-old woman was admitted to the hospital with fever, headache, nausea, and vomiting. The patient's body temperature was 38°C, and she had a stiff neck. Listeria monocytogenes was isolated from the cerebrospinal fluid (CSF), and penicillin G and gentamicin treatment was initiated. Linezolid and dexamethasone were added. Due to hematuria and thrombocytopenia, the linezolid was discontinued. In immunocompromised patients with CNS infections, Listeria rhombencephalitis should be suspected. Linezolid can be used in combination with dexamethasone.",
"affiliations": "Ankara Numune Education and Research Hospital, Intensive Care Clinic, Turkey.;Ankara Numune Education and Research Hospital, Intensive Care Clinic, Turkey. Electronic address: mutlunm@gmail.com.;Ankara Numune Education and Research Hospital, Infectious Diseases and Clinical Microbiology Clinic, Turkey.;Ankara Numune Education and Research Hospital, Infectious Diseases and Clinical Microbiology Clinic, Turkey.;Ankara Numune Education and Research Hospital, Intensive Care Clinic, Turkey.;Ankara Numune Education and Research Hospital, Infectious Diseases and Clinical Microbiology Clinic, Turkey.",
"authors": "Yılmaz|Pakize Ö|PÖ|;Mutlu|Nevzat M|NM|;Sertçelik|Ahmet|A|;Baştuğ|Aliye|A|;Doğu|Cihangir|C|;Kışlak|Sümeyye|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D003907:Dexamethasone; D000069349:Linezolid",
"country": "England",
"delete": false,
"doi": null,
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"fulltext_license": null,
"issn_linking": "1876-0341",
"issue": "9(5)",
"journal": "Journal of infection and public health",
"keywords": "Dexamethasone; Linezolid; Listeria rhombencephalitis",
"medline_ta": "J Infect Public Health",
"mesh_terms": "D000900:Anti-Bacterial Agents; D020806:Central Nervous System Bacterial Infections; D003907:Dexamethasone; D005260:Female; D006801:Humans; D000069544:Infectious Encephalitis; D000069349:Linezolid; D008089:Listeria monocytogenes; D008088:Listeriosis; D008279:Magnetic Resonance Imaging; D012249:Rhombencephalon",
"nlm_unique_id": "101487384",
"other_id": null,
"pages": "670-4",
"pmc": null,
"pmid": "26860968",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Linezolid and dexamethasone experience in a serious case of listeria rhombencephalitis.",
"title_normalized": "linezolid and dexamethasone experience in a serious case of listeria rhombencephalitis"
} | [
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"primarysource": {
"literaturereference": "YILMAZ PO, MUTLU NM, SERT?ELIK A, BASTUG A, DOGU C, KISLAK S. LINEZOLID AND DEXAMETHASONE EXPERIENCE IN A SERIOUS CASE OF LISTERIA RHOMBENCEPHALITIS. JOURNAL OF INFECTION AND PUBLIC HEALTH. 2016;9(5):670-674.",
"literaturereference_normalized": "linezolid and dexamethasone experience in a serious case of listeria rhombencephalitis",
"qualification": "3",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20170124",
"receivedate": "20170124",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13144802,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20170428"
}
] |
{
"abstract": "Posterior reversible encephalopathy syndrome is a neurotoxic state accompanied by unique brain imaging patterns and neurologic abnormalities, typically associated with several complex clinical conditions such as preeclampsia/eclampsia, solid-organ transplant procedures, autoimmune diseases, and immunosuppressive agents. The detailed mechanism of posterior reversible encephalopathy syndrome is not known, and the current therapy is only supportive care. Here, we present a 33-year-old parturient woman with preeclampsia complicated with hemolysis, elevated liver enzymes, and low platelet syndrome, fulminant hepatitis B, acute fatty liver, and posterior reversible encephalopathy syndrome. The patient developed gross hepatic infarction soon after liver transplant. After several possible causes were excluded, we found that progression of underlying posterior reversible encephalopathy syndrome-induced endothelial damage by overdose of tacrolimus may have been the major cause for deteriorating hypoperfusion of the transplanted liver and fatal graft failure. In liver transplant recipients, severe posttransplant hypoperfusion of the grafted liver may result in loss of the liver allograft and even mortality. Poor control of underlying posterior reversible encephalopathy syndrome-associated endothelial damage because of tacrolimus overdose may lead to severe hypoperfusion of grafted hepatic vessels and subsequent hepatic infarction. This report highlights tacrolimus as a potential trigger of posterior reversible encephalopathy syndrome and may inform clinical decisions regarding tacrolimus administration in liver transplant recipients with preexisting or newly developed posterior reversible encephalopathy syndrome.",
"affiliations": "From the Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.",
"authors": "Tseng|Wei-Cheng|WC|;Lai|Hou-Chuan|HC|;Yeh|Chun-Chang|CC|;Fan|Hsiu-Lung|HL|;Wu|Zhi-Fu|ZF|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2017.0255",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "18(1)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000328:Adult; D065095:Calcineurin Inhibitors; D018450:Disease Progression; D062787:Drug Overdose; D017809:Fatal Outcome; D005260:Female; D000081011:Hepatic Infarction; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D019520:Living Donors; D009102:Multiple Organ Failure; D054038:Posterior Leukoencephalopathy Syndrome; D011247:Pregnancy; D016559:Tacrolimus",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "128-132",
"pmc": null,
"pmid": "30602365",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Overdose of Tacrolimus as the Trigger Causing Progression of Posterior Reversible Encephalopathy Syndrome and Subsequent Hepatic Infarction After Liver Transplant: A Case Report.",
"title_normalized": "overdose of tacrolimus as the trigger causing progression of posterior reversible encephalopathy syndrome and subsequent hepatic infarction after liver transplant a case report"
} | [
{
"companynumb": "TW-MYLANLABS-2019M1003053",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
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}
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"reaction": [
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Posterior reversible encephalopathy syndrome",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Hepatic infarction",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Transplant failure",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Multiple organ dysfunction syndrome",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TSENG WC, LAI HC, YEH CC, FAN HL, WU ZF. OVERDOSE OF TACROLIMUS AS THE TRIGGER CAUSING PROGRESSION OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME AND SUBSEQUENT HEPATIC INFARCTION AFTER LIVER TRANSPLANT: A CASE REPORT. EXP-CLIN-TRANSPLANT 2018?:.",
"literaturereference_normalized": "overdose of tacrolimus as the trigger causing progression of posterior reversible encephalopathy syndrome and subsequent hepatic infarction after liver transplant a case report",
"qualification": "3",
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},
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"receivedate": "20190121",
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},
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},
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"seriousnessdeath": 1,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190417"
},
{
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{
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},
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}
],
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"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Posterior reversible encephalopathy syndrome",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Hypoperfusion",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Hepatic infarction",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TSENG WC, LAI HC, YEH CC, FAN HL, WU ZF. OVERDOSE OF TACROLIMUS AS THE TRIGGER CAUSING PROGRESSION OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME AND SUBSEQUENT HEPATIC INFARCTION AFTER LIVER TRANSPLANT: A CASE REPORT. EXP CLIN TRANSPLANT. 2018 DEC 31.",
"literaturereference_normalized": "overdose of tacrolimus as the trigger causing progression of posterior reversible encephalopathy syndrome and subsequent hepatic infarction after liver transplant a case report",
"qualification": "3",
"reportercountry": "TW"
},
"primarysourcecountry": "TW",
"receiptdate": "20200318",
"receivedate": "20190118",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15841083,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "A 62-year-old man of North African descent presented with weight loss in the past year and diarrhea for three weeks. His medical history included erosive rheumatoid arthritis, treated with methotrexate and adalimumab. Histological examination of a duodenal biopsy showed foamy macrophages in the lamina propria, with PAS-positive cytoplasmatic inclusions. These findings are compatible with Whipple's disease, a rare chronic infectious disease caused by Tropheryma whipplei, an opportunistic bacterium. It is typically seen in middle-aged Caucasian men and the immunocompromised host. The classical presentation of Whipple's disease consists of intermittent migratory arthralgia, followed by intestinal symptoms which typically occur six to seven years later. The clinical image can be very variable, and this complicates the diagnostic process. PAS-staining and PCR are the diagnostic cornerstones. In our case, treatment consisted of a prolonged cure of antibiotics: intravenous ceftriaxone for two weeks, followed by an oral maintenance therapy of doxycycline and hydroxychloroquine for at least one year. A therapeutic dilemma arose as continued anti-TNF blockade was necessary to maintain remission of the rheumatoid arthritis. Lifelong follow-up is necessary because relapse is possible.",
"affiliations": "Faculty of Medicine, KU Leuven University, Belgium.;Faculty of Medicine, KU Leuven University, Belgium.;Department of Pathology, AZ Groeninge Hospital Kortrijk, Belgium.;Department of Internal Medicine, University Hospitals Leuven, Belgium.;Department of Gastroenterology, AZ Groeninge Hospital Kortrijk, Belgium.",
"authors": "Lenfant|M|M|;Callemeyn|J|J|;Alaerts|H|H|;Meersseman|W|W|;Van Moerkercke|W|W|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014409:Tumor Necrosis Factor-alpha; D006886:Hydroxychloroquine; D002443:Ceftriaxone; D004318:Doxycycline",
"country": "Belgium",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3227",
"issue": "82(1)",
"journal": "Acta gastro-enterologica Belgica",
"keywords": "Tropheryma whipplei; Whipple’s disease; clinical features; periodic acid-Schiff",
"medline_ta": "Acta Gastroenterol Belg",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D004318:Doxycycline; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D054851:Tropheryma; D014409:Tumor Necrosis Factor-alpha; D008061:Whipple Disease",
"nlm_unique_id": "0414075",
"other_id": null,
"pages": "83-86",
"pmc": null,
"pmid": "30888759",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Whipple's disease in a man of North African descent : case report and brief review of the literature.",
"title_normalized": "whipple s disease in a man of north african descent case report and brief review of the literature"
} | [
{
"companynumb": "BE-ACCORD-118741",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "040716",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "FOR FIVE YEARS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "RHEUMATOID ARTHRITIS",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "METHOTREXATE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
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"drugindication": "RHEUMATOID ARTHRITIS",
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"medicinalproduct": "ADALIMUMAB"
}
],
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"patientonsetage": "62",
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"patientsex": "1",
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"reaction": [
{
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"reactionmeddraversionpt": "22.0",
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},
{
"reactionmeddrapt": "Bacteraemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LENFANT M, CALLEMEYN J, ALAERTS H, MEERSSEMAN W, VAN MOERKERCKE W. WHIPPLE^S DISEASE IN A MAN OF NORTH AFRICAN DESCENT : CASE REPORT AND BRIEF REVIEW OF THE LITERATURE. ACTA GASTROENTEROL BELG. 2019 JAN-MAR?82(1):83-86.",
"literaturereference_normalized": "whipple s disease in a man of north african descent case report and brief review of the literature",
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},
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "Nocardial infections have been rare after allogeneic hematopoietic stem cell transplantation (HSCT). We report 10 recent cases of late-onset nocardiosis (median time of onset of 508 days after transplantation) primarily in patients on high doses of corticosteroids for graft-versus-host disease. All 10 patients had pulmonary infection caused by Nocardia species susceptible to trimethoprim-sulfamethoxazole (TMP-SMX). At time of diagnosis 8 of 10 patients were not receiving TMP-SMX for prophylaxis of Pneumocystis jiroveci pneumonia (PJP; 7 on atovaquone, 1 on i.v. pentamidine). After the initiation of atovaquone prophylaxis for PJP in place of TMP-SMX for many UCLA allogeneic HSCT patients in 2012, 9 cases of nocardiosis occurred in 411 patients (2.2%) over the next 6 years (2012 to 2017) compared with only 1 case in 575 patients (0.17%) during the previous 12 years (2000 to 2011). Although there were no deaths directly related to nocardial infection treated primarily with TMP-SMX, overall mortality in this group of patients was 40%. Based on this experience, the use of atovaquone for PJP prophylaxis in place of TMP-SMX may be associated with an increased risk for previously rare nocardial infections after allogeneic HSCT.",
"affiliations": "David Geffen School of Medicine, University of California, Los Angeles, California.;David Geffen School of Medicine, University of California, Los Angeles, California; Division of Hematology-Oncology, Department of Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, California. Electronic address: dwinston@mednet.ucla.edu.;David Geffen School of Medicine, University of California, Los Angeles, California.;David Geffen School of Medicine, University of California, Los Angeles, California; Division of Hematology-Oncology, Department of Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, California.",
"authors": "Molina|Alfonso|A|;Winston|Drew J|DJ|;Pan|Darren|D|;Schiller|Gary J|GJ|",
"chemical_list": "D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D053626:Atovaquone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2018.03.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "24(8)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Atovaquone prophylaxis; Nocardial infection; Stem cell transplantation",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D064591:Allografts; D053626:Atovaquone; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009617:Nocardia Infections; D011020:Pneumonia, Pneumocystis; D066027:Transplant Recipients; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1715-1720",
"pmc": null,
"pmid": "29555315",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Increased Incidence of Nocardial Infections in an Era of Atovaquone Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients.",
"title_normalized": "increased incidence of nocardial infections in an era of atovaquone prophylaxis in allogeneic hematopoietic stem cell transplant recipients"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-291980",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "089247",
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"drugindication": "Prophylaxis against graft versus host disease",
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}
],
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"patientonsetage": "36",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Nocardiosis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Molina A, Winston DJ, Pan D, Schiller GJ. Increased Incidence of Nocardial Infections in an Era of Atovaquone Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients. Biol Blood Marrow Transplant. 2018;24:1715-20",
"literaturereference_normalized": "increased incidence of nocardial infections in an era of atovaquone prophylaxis in allogeneic hematopoietic stem cell transplant recipients",
"qualification": "3",
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},
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},
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"sendertype": "2"
},
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"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220423"
},
{
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"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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},
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},
{
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"activesubstancename": "PENTAMIDINE"
},
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{
"abstract": "We report the case of a 66-year-old man with seropositive rheumatoid arthritis who developed neurologically asymptomatic rheumatoid meningitis (RM) revealed by MRI. RM worsened and chest CT showed pericardial effusion, pleural effusion, and bilateral consolidation, and his serum C3 level was decreased. We diagnosed systemic rheumatic vasculitis based on these findings. After a review of more than 20 previously reported cases of RM, this is the first case of RM without central nerve system symptoms.",
"affiliations": "a Department of Internal Medicine (I) , Osaka Medical College , Takatsuki City , Osaka , Japan.;a Department of Internal Medicine (I) , Osaka Medical College , Takatsuki City , Osaka , Japan.;a Department of Internal Medicine (I) , Osaka Medical College , Takatsuki City , Osaka , Japan.;a Department of Internal Medicine (I) , Osaka Medical College , Takatsuki City , Osaka , Japan.;a Department of Internal Medicine (I) , Osaka Medical College , Takatsuki City , Osaka , Japan.;a Department of Internal Medicine (I) , Osaka Medical College , Takatsuki City , Osaka , Japan.",
"authors": "Matsuda|Shogo|S|;Yoshida|Shuzo|S|;Takeuchi|Tohru|T|;Fujiki|Yohei|Y|;Yoshikawa|Ayaka|A|;Makino|Shigeki|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/14397595.2016.1232333",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1439-7595",
"issue": "29(2)",
"journal": "Modern rheumatology",
"keywords": "Central nervous system; Extra-articular manifestations; Malignant rheumatoid arthritis; Rheumatoid arthritis; Rheumatoid vasculitis",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D058070:Asymptomatic Diseases; D003937:Diagnosis, Differential; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008581:Meningitis; D056647:Systemic Vasculitis",
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "370-376",
"pmc": null,
"pmid": "27659704",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Asymptomatic rheumatoid meningitis revealed by magnetic resonance imaging, followed by systemic rheumatic vasculitis: A case report and a review of the literature.",
"title_normalized": "asymptomatic rheumatoid meningitis revealed by magnetic resonance imaging followed by systemic rheumatic vasculitis a case report and a review of the literature"
} | [
{
"companynumb": "JP-PFIZER INC-2015335899",
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"drugindication": "RHEUMATOID ARTHRITIS",
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],
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}
],
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},
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"literaturereference": "MATSUDA, S.. ASYMPTOMATIC RHEUMATOID MENINGITIS REVEALED BY MAGNETIC RESONANCE IMAGING, FOLLOWED BY SYSTEMIC RHEUMATIC VASCULITIS: A CASE REPORT AND A REVIEW OF THE LITERATURE. MODERN RHEUMATOLOGY. 2019?29 (2):370-376",
"literaturereference_normalized": "asymptomatic rheumatoid meningitis revealed by magnetic resonance imaging followed by systemic rheumatic vasculitis a case report and a review of the literature",
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},
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},
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},
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"transmissiondate": "20190417"
}
] |
{
"abstract": "The aim of this study is to determine the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) among adult patients treated with biologic agents or small molecules for chronic inflammatory rheumatic diseases, in particular for chronic inflammatory arthritides.\n\n\n\nTo this end, a population-based study, in the province of Udine (466,700 inhabitants, with age>15 years old, Friuli Venezia Giulia region, Italy) was planned. The primary outcome was the prevalence of COVID-19 in the first two months of the outbreak. All the rheumatic patients treated with biologic agents or small molecules in the last 6 months in our province were included (N=1051).\n\n\n\nFrom February 29 to April 25, 2020, 4 adult patients (4/1051, i.e. 3.8/1000, 95% Confidence Interval 1.5-9.7/1000) were registered as swab test positive by PCR for COVID-19. Overall, a total of 47/1051 (4.5%) cases were tested for COVID-19 by PCR in the same period, and 15 of them due to symptoms compatible with COVID-19. In the general population, the prevalence was 937 cases/466700 (2/1000, 95% Confidence Interval 1.9-2.1/1000, P-value=0.33, chi square test), and 20,179/466,700 (4.3%) swab tests for COVID-19 were performed.\n\n\n\nThe risk of COVID-19 in rheumatic patients under biologic agents or small molecules does not appear different from that observed in the general population. Patients should be informed to safely proceed with their treatment and follow the rules for self-protection to COVID-19.",
"affiliations": "Clinic of Rheumatology, Department of Medicine (DAME), ASUFC, University of Udine, Udine, Italy. Electronic address: luca.quartuccio@asufc.sanita.fvg.it.;Igiene ed Epidemiologia Clinica, ASUFC, Udine, Italy.;Service of Pharmacy, ASUFC, Udine, Italy.;Infectious Diseases Unit, ASUFC, Udine, Italy.;Clinic of Rheumatology, Department of Medicine (DAME), ASUFC, University of Udine, Udine, Italy.",
"authors": "Quartuccio|Luca|L|;Valent|Francesca|F|;Pasut|Enrico|E|;Tascini|Carlo|C|;De Vita|Salvatore|S|",
"chemical_list": "D018501:Antirheumatic Agents; D001685:Biological Factors",
"country": "France",
"delete": false,
"doi": "10.1016/j.jbspin.2020.05.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-319X",
"issue": "87(5)",
"journal": "Joint bone spine",
"keywords": "Biologic; COVID-19; Coronavirus; Rheumatic disease; Rheumatoid arthritis; Small molecule; Tumor necrosis factor",
"medline_ta": "Joint Bone Spine",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001685:Biological Factors; D000086382:COVID-19; D015331:Cohort Studies; D015897:Comorbidity; D016001:Confidence Intervals; D018352:Coronavirus Infections; D004196:Disease Outbreaks; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D015995:Prevalence; D011379:Prognosis; D012189:Retrospective Studies; D012216:Rheumatic Diseases; D018570:Risk Assessment; D016896:Treatment Outcome",
"nlm_unique_id": "100938016",
"other_id": null,
"pages": "439-443",
"pmc": null,
"pmid": "32445935",
"pubdate": "2020-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "32321635;32363212;32205186;32321633;32241793;32033941;32203977;32321634;32348641;32335513;32199494;32826129;32196933;32330277;29680581;32192578;31969328;30581616;32205856",
"title": "Prevalence of COVID-19 among patients with chronic inflammatory rheumatic diseases treated with biologic agents or small molecules: A population-based study in the first two months of COVID-19 outbreak in Italy.",
"title_normalized": "prevalence of covid 19 among patients with chronic inflammatory rheumatic diseases treated with biologic agents or small molecules a population based study in the first two months of covid 19 outbreak in italy"
} | [
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],
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"reaction": [
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "COVID-19",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2020"
}
},
"primarysource": {
"literaturereference": "QUARTUCCIO L, VALENT F, PASUT E, TASCINI C, DE VITA S. PREVALENCE OF COVID-19 AMONG PATIENTS WITH CHRONIC INFLAMMATORY RHEUMATIC DISEASES TREATED WITH BIOLOGIC AGENTS OR SMALL MOLECULES: A POPULATION-BASED STUDY IN THE FIRST TWO MONTHS OF COVID-19 OUTBREAK IN ITALY. JOINT BONE SPINE. 2020?87:439-43",
"literaturereference_normalized": "prevalence of covid 19 among patients with chronic inflammatory rheumatic diseases treated with biologic agents or small molecules a population based study in the first two months of covid 19 outbreak in italy",
"qualification": "1",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20201028",
"receivedate": "20201028",
"receiver": {
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"receivertype": "6"
},
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"transmissiondate": "20210114"
}
] |
{
"abstract": "BACKGROUND\nKey distinguishing characteristics of trabectedin in the treatment of advanced soft tissue sarcoma are its prolonged tumor control activity in multiple histological subtypes, positive outcomes in translocation-related sarcomas, maintenance of response, option to rechallenge after treatment interruption and lack of cumulative toxicity. Trabectedin is indicated for use in advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, or as front-line treatment in patients unsuited to receive these agents.\n\n\nMETHODS\nIn this review, cases studies are presented in which trabectedin was used according to its indication but in diverse clinical settings.\n\n\nRESULTS\nAs second-line treatment of uterine leiomyosarcoma, trabectedin produced prolonged tumor control with good quality of life. In treatment of recurrent synovial sarcoma, the best objective response (partial response) and longest disease control (37 months) was achieved under treatment with trabectedin. As neoadjuvant treatment of undifferentiated pleomorphic sarcoma in a patient unsuited to receive doxorubicin-based chemotherapy, trabectedin induced a pathological response with 85% of necrosis.\n\n\nCONCLUSIONS\nThese cases illustrate the broad range of indications for trabectedin in advanced soft tissue sarcoma and highlight how its unique characteristics can be optimized to achieve maximum clinical benefit.",
"affiliations": "1Medical Oncology Unit, Candiolo Cancer Institute - FPO, IRCCS, Italy.;2MUsculoSkeletal Tumor Board of Excellence Sevilla (MUSTBE SEVILLA), Virgen del Rocío University Hospital, Sevilla, Spain.;3Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.;4Department of Interdisciplinary Oncology, HELIOS Klinikum Berlin-Buch, Berlin, Germany.",
"authors": "Grignani|Giovanni|G|;Martín-Broto|Javier|J|;Schuler|Markus|M|;Reichardt|Peter|P|",
"chemical_list": "D018943:Anthracyclines; D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D003841:Deoxycytidine; D003606:Dacarbazine; C056507:gemcitabine; D000077606:Trabectedin; D007069:Ifosfamide",
"country": "England",
"delete": false,
"doi": "10.2217/fon.15.76",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6694",
"issue": "11(11 Suppl)",
"journal": "Future oncology (London, England)",
"keywords": "clinical case studies; dosing guidelines; neoadjuvant chemotherapy; synovial sarcoma; trabectedin rechallenge; undifferentiated pleomorphic sarcoma; uterine leiomyosarcoma",
"medline_ta": "Future Oncol",
"mesh_terms": "D018943:Anthracyclines; D018906:Antineoplastic Agents, Alkylating; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D000075202:Contraindications; D003606:Dacarbazine; D003841:Deoxycytidine; D004149:Dioxoles; D005260:Female; D005266:Femoral Neoplasms; D006801:Humans; D007044:Hysterectomy; D007069:Ifosfamide; D007890:Leiomyosarcoma; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011877:Radionuclide Imaging; D012074:Remission Induction; D016879:Salvage Therapy; D012509:Sarcoma; D013584:Sarcoma, Synovial; D012983:Soft Tissue Neoplasms; D044005:Tetrahydroisoquinolines; D013848:Thigh; D014057:Tomography, X-Ray Computed; D000077606:Trabectedin; D016896:Treatment Outcome; D014594:Uterine Neoplasms",
"nlm_unique_id": "101256629",
"other_id": null,
"pages": "15-24",
"pmc": null,
"pmid": "26043311",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trabectedin clinical cases: use according to indication in diverse clinical scenarios.",
"title_normalized": "trabectedin clinical cases use according to indication in diverse clinical scenarios"
} | [
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"drugindication": "SUPPORTIVE CARE",
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] |
{
"abstract": "Several classes of antidepressants can induce syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), thereby causing hyponatremia. Initial symptoms of hyponatremia include neuropsychiatric and gastrointestinal manifestations can mimic depression, especially in elderly people with multiple somatic complaints. Here we present a case of a 68-year-old man with treatment-refractory depression and general anxiety disorder who developed duloxetine-induced hyponatremia. His symptoms of hyponatremia including unsteady gait, dizziness, nausea, general malaise, and poor appetite subsided after discontinuing the offending medication. Our case illustrates that drug-induced SIADH and potential drug-drug interactions should be considered in elderly patients who develop hyponatremia following the initiation of antidepressants.",
"affiliations": "College of Medicine, China Medical University, Taichung, Taiwan.;Department of Psychiatry & Brain Disease Research Center, China Medical University Hospital, Taichung, Taiwan.;Department of Radiology, China Medical University Hospital, Taichung, Taiwan.;Division of Infectious Diseases, University of California San Diego, La Jolla, CA 92093, USA.;Division of Nephrology, Taichung Veterans General Hospital, Taichung, Taiwan.;Department of Psychiatry & Brain Disease Research Center, China Medical University Hospital, Taichung, Taiwan.",
"authors": "Sun|Ching-Fang|CF|0000-0001-5146-4575;Chen|Yeo-Lin|YL|;Li|Ying-Hsuan|YH|;Kumaraswamy|Monika|M|;Lo|Ying-Chih|YC|;Chen|Yi-Ting|YT|0000-0003-0730-7788",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/4109150",
"fulltext": "\n==== Front\nCase Rep PsychiatryCase Rep PsychiatryCRIPSCase Reports in Psychiatry2090-682X2090-6838Hindawi 10.1155/2019/4109150Case ReportDuloxetine-Induced Hyponatremia in an Elderly Male Patient with Treatment-Refractory Major Depressive Disorder http://orcid.org/0000-0001-5146-4575Sun Ching-Fang \n1\nChen Yeo-Lin \n2\nLi Ying-Hsuan \n3\nKumaraswamy Monika \n4\n\n5\nLo Ying-Chih \n6\nhttp://orcid.org/0000-0003-0730-7788Chen Yi-Ting ytclare@gmail.com\n2\n\n7\n\n1College of Medicine, China Medical University, Taichung, Taiwan\n2Department of Psychiatry & Brain Disease Research Center, China Medical University Hospital, Taichung, Taiwan\n3Department of Radiology, China Medical University Hospital, Taichung, Taiwan\n4Division of Infectious Diseases, University of California San Diego, La Jolla, CA 92093, USA\n5Infectious Diseases Section, VA San Diego Healthcare System, San Diego, CA 92161, USA\n6Division of Nephrology, Taichung Veterans General Hospital, Taichung, Taiwan\n7Graduate Institute of Biomedical Sciences, China Medical University, Taichung, TaiwanAcademic Editor: Toshiya Inada\n\n2019 13 5 2019 2019 410915026 1 2019 12 4 2019 28 4 2019 Copyright © 2019 Ching-Fang Sun et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Several classes of antidepressants can induce syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), thereby causing hyponatremia. Initial symptoms of hyponatremia include neuropsychiatric and gastrointestinal manifestations can mimic depression, especially in elderly people with multiple somatic complaints. Here we present a case of a 68-year-old man with treatment-refractory depression and general anxiety disorder who developed duloxetine-induced hyponatremia. His symptoms of hyponatremia including unsteady gait, dizziness, nausea, general malaise, and poor appetite subsided after discontinuing the offending medication. Our case illustrates that drug-induced SIADH and potential drug-drug interactions should be considered in elderly patients who develop hyponatremia following the initiation of antidepressants.\n==== Body\n1. Introduction\nDuloxetine and other serotonin-norepinephrine reuptake inhibitors reportedly induce hyponatremia in 5.7% of patients aged 60 or older [1]. Conversely, agomelatine has not been reported to induce hyponatremia [2, 3]. Furthermore, the interactions of drugs with newer antidepressants are insignificant [4]. Large-scale clinical studies evaluating the incidence of hyponatremia in patients utilizing duloxetine are lacking.\n\nThe initial symptoms of hyponatremia are primarily neuropsychiatric and gastrointestinal disturbances such as dizziness, clouding of consciousness, psychomotor retardation, confusion, gait impairment, falls, seizures, and nausea/vomiting/diarrhea [5]. Some of them can mimic depression especially in elderly patients with multiple somatic complaints. Herein, we describe a case of hyponatremia secondary to syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) associated with initiation of duloxetine and potentially exacerbated by agomelatine.\n\n2. Case Presentation\nA 68-year-old male with a history of treatment-refractory depression, general anxiety disorder, type 2 diabetes mellitus, and benign prostatic hyperplasia presented to our outpatient psychiatric clinic with worsening symptoms of depression including social withdrawal, problems with self-care and inattentiveness. Initially diagnosed with major depressive disorder and general anxiety disorder in 2001, his symptoms initially included depressive mood, anhedonia, psychomotor retardation, hopelessness, and suicidal ideation and were previously well managed with bupropion (150 mg/day) and lorazepam (0.5 mg/day). However, his treatment was ultimately modified to duloxetine (30 mg/day) and agomelatine (25 mg/day) given the signs and symptoms of worsening depression noted on presentation.\n\nFollowing 1 month of treatment with the modified regimen, the patient represented with complaints of unsteady gait, dizziness, nausea, general malaise, poor appetite, constipation, and insomnia. He was subsequently admitted to the hospital for a further workup. Upon interview and examination, he scored 35 on the Hamilton Depression Rating Scale; 91 on the Cognitive Abilities Screening Instrument, Chinese Version, and 35 on the Beck Anxiety Inventory, suggesting severe depression and anxiety without cognitive impairment. Admission laboratory findings were notable for a sodium level of 130 mmol/L (reference range: 135-147 mmol/L) and chloride level of 94 mmol/L (reference range: 98-107 mmol/L) as well as normal renal function: glomerular filtration rate 105 mL/min/1.73 m2 (reference range: >90 mL/min/1.73 m2); creatinine: 65.416μmol/L (reference range for male: 50-110μmol/L); blood urine nitrogen: 6 mmol/L (reference range: 2.9-7.1 mmol/L), thyroid function: thyroid-stimulating hormone: 2.21 mIU/L (reference range: 0.34-5.60 mIU/L); free thyroxine: 12.87 pmol/L (reference range: 6.94-18.01 pmol/L), and adrenal function: basal serum cortisol level: 563.66 nmol/L (reference range: 170-635 nmol/L). Over the course of the patient's hospitalization, his serum sodium level further decreased to 127 mmol/L and his baseline sodium level prior to the initiation of his latest medication regimen was noted to be 137 mmol/L. A hyponatremia workup was subsequently initiated. He was noted to have an effective serum osmolality of 260 mmol/kg (reference range: 285–300 mmol/kg), urine sodium level of 42 mmol/L (reference: variable), and urine osmolality of 557 mmol/kg (reference range: 300–900 mmol/kg). The patient's symptoms were ultimately attributed to duloxetine-induced hyponatremia associated with SIADH. As a consequence, the duloxetine was discontinued and he was initiated on a high-salt diet, leading to resolution of his hyponatremia (serum sodium: 135 mmol/L) and symptoms including unsteady gait, dizziness, nausea, general malaise, and poor appetite within 8 days (Figure 1). Due to his history and persistent symptoms of depression, he was started on escitalopram titrated from 5 mg/day to 15 mg/day. Ultimately, he was cross-titrated from the selective serotonin reuptake inhibitor (SSRI) escitalopram to the noradrenergic and specific serotonergic antidepressant mirtazapine given concern for the potential development of hyponatremia again while on a SSRI. After 6 weeks of hospitalization, the patient had less psychomotor retardation, dysphoria, and somatic complaints. With improvement in his depression and resolution of his hyponatremia, he was discharged.\n\n3. Discussion\nKnown risk factors for antidepressant-associated hyponatremia are advanced age, female sex, low body weight, low baseline serum sodium, and abnormal potassium level as well as other medical conditions such as heart failure, malignancy, liver disease, adrenal insufficiency, and possibly hypothyroidism [6, 7]. Our patient had several risk factors for hyponatremia including advanced age and low body weight (body mass index: 18.8 kg/m2). Generally, hyponatremia is most likely to develop within 2–4 weeks of initiating antidepressants. Thus, trending serum sodium during this time period in patients with known risk factors for hyponatremia is strongly recommended [8].\n\nUnlike those with symptoms of severe acute hyponatremia (serum sodium less than 120 mmol/L) including seizures, coma, and respiratory arrest, our patient presented with only mild symptoms. Unsteady gait is the most prevalent symptom of hyponatremia especially in cases of chronic or mild hyponatremia (serum sodium 130–135 mmol/L) [6]. Other common neuropsychiatric symptoms attributed to hyponatremia include confusion, dizziness/clouding of consciousness, and psychomotor retardation. Gastrointestinal symptoms such as nausea, vomiting, and diarrhea are also commonly observed [4].\n\nEvidence suggests serotonin (5-hydroxytryptamine, 5-HT) and 5-HTergic drugs can induce enhancement of both central 5-HT transmission and antidiuretic hormone (ADH) secretion at the level of the posterior pituitary, resulting in SIADH-associated hyponatremia. Multiple 5-HT receptors (5-HT2, 5-HT4, and 5-HT7 receptors) engage in the regulatory pathway, with 5-HT2 receptors being the predominant group [9]. Additionally, dopamine modulates the activity of ADH secretory cells responding to changes in osmolality and stimulates ADH release from the hypothalamus, predominantly via D2 receptors [9]. Duloxetine not only inhibits the reuptake of 5-HT and norepinephrine but also increases dopamine, specifically in the prefrontal cortex [10]. Duloxetine can affect multiple neuroendocrine pathways and thereby interfere with ADH secretion.\n\nTo objectively evaluate the adverse effect of the drugs administered to our patient, we applied the Naranjo Adverse Drug Reaction Probability Scale (Naranjo Scale) [11]. The score for duloxetine was 4, for agomelatine was 1, for aripiprazole was 0, and for bupropion was −1, suggesting duloxetine and possibly agomelatine were the primary offending medications. Agomelatine is not traditionally associated with hyponatremia but potentially contributed to our patient's SIADH [8, 10]. Agomelatine serves as a melatonin receptor agonist (MT1 and MT2) and elevates the release of norepinephrine and dopamine due to its 5-HT2C receptor antagonistic effect [12]. Additionally, agomelatine along with duloxetine is metabolized by enzyme CYP2A1 and coadministration of these drugs could prolong each other's half-life [13]. Consistent with both the pharmacokinetic effect and mechanism of action of agomelatine, it may serve as an aggravating factor for the unexpected adverse effect of duloxetine.\n\nA key component of managing drug-induced SIADH is to stop the offending agent. Other mainstays in treating hyponatremia include fluid restriction, a high-salt diet, and intravenous saline as well as the initiation of vaptan drugs in severe cases.\n\n4. Conclusion\nHyponatremia is a rare adverse effect of duloxetine; by contrast, agomelatine has not been reported to induce hyponatremia but has a 5-HT2C receptor antagonistic effect and the potential to prolong the half-life of duloxetine. Therefore, caution should be used when prescribing these drugs together given the potential for drug-drug interactions. Patients with risk factors for hyponatremia who are newly initiated on antidepressants should have their sodium levels closely monitored. Once diagnosed with antidepressant-induced SIADH, the potentially offending medications should be stopped immediately, and the patient should undergo a hyponatremia workup.\n\nData Availability\nThe authors confirm that the data supporting the findings of this study are available within the article.\n\nConflicts of Interest\nThere are no conflicts of interest regarding the publication of this article.\n\nFigure 1 Patient's serum sodium levels and antidepressant treatment regimen during hospitalization. Following discontinuation of agomelatine and duloxetine on the 6th and 7th day of hospitalization the patient's serum sodium level rose from 127 to 135 mmol/L. Ultimately, the patient's depression was well managed with mirtazapine and aripiprazole with tapering of escitalopram.\n==== Refs\n1 Viramontes T. S. Truong H. Linnebur S. A. Antidepressant-induced hyponatremia in older adults Consultant Pharmacist 2016 31 3 139 150 2-s2.0-84961678102 10.4140/TCP.n.2016.139 26975593 \n2 Taylor D. Paton C. Kapur S. The South London and Maudsley NHS Foundation Trust & Oxleas NHS Foundation Trust Prescribing Guidelines in Psychiatry 2015 12th London, UK \n3 Zajecka J. Schatzberg A. Stahl S. Shah A. Caputo A. Post A. Efficacy and safety of agomelatine in the treatment of major depressive disorder a multicenter, randomized, double-blind, placebo-controlled trial Journal of Clinical Psychopharmacology 2010 30 2 135 144 2-s2.0-77952156000 10.1097/JCP.0b013e3181d420a7 20520286 \n4 Lange-Asschenfeldt C. Kojda G. Cordes J. Epidemiology, symptoms, and treatment characteristics of hyponatremic psychiatric inpatients Journal of Clinical Psychopharmacology 2013 33 6 799 805 2-s2.0-84888132519 10.1097/JCP.0b013e3182a4736f 24052056 \n5 Spina E. Trifirò G. Caraci F. Clinically significant drug interactions with newer antidepressants CNS Drugs 2012 26 1 39 67 2-s2.0-83455178828 10.2165/11594710-000000000-00000 22171584 \n6 Greenblatt H. K. Greenblatt D. J. Antidepressant-associated hyponatremia in the elderly Journal of Clinical Psychopharmacology 2016 36 6 545 549 10.1097/JCP.0000000000000608 2-s2.0-84991510861 27755157 \n7 Egger C. Muehlbacher M. Nickel M. Geretsegger C. Stuppaeck C. A review on hyponatremia associated with SSRIs, reboxetine and venlafaxine International Journal of Psychiatry in Clinical Practice 2006 10 1 17 26 2-s2.0-33645156735 10.1080/13651500500410216 24926764 \n8 Lien Y.-H. H. Antidepressants and hyponatremia American Journal of Medicine 2018 131 1 7 8 2-s2.0-85032219634 \n9 Iovino M. Guastamacchia E. Giagulli V. A. Licchelli B. Triggiani V. Vasopressin secretion control: Central neural pathways, neurotransmitters and effects of drugs Current Pharmaceutical Design 2012 18 30 4714 4724 2-s2.0-84866398630 10.2174/138161212802651607 22794200 \n10 Stahl S. M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 2013 4th Cambridge University Press \n11 Naranjo C. A. Busto U. Sellers E. M. A method for estimating the probability of adverse drug reactions Clinical Pharmacology Therapeutics 1981 30 2 239 245 10.1038/clpt.1981.154 7249508 \n12 Valdoxan®(agomelatine) [Summary of product characteristics]. Laboratoires Servier ltd, 2009 \n13 Lobo E. D. Bergstrom R. F. Reddy S. In Vitro and In Vivo evaluations of cytochrome P450 1A2 interactions with duloxetine Clinical Pharmacokinetics 2008 47 3 191 202 2-s2.0-42949165178 10.2165/00003088-200847030-00005 18307373\n\n",
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"abstract": "Tracheobronchial stenoses (TBSs) are potentially severe manifestations of granulomatosis with polyangiitis (Wegener's) (GPA) that usually respond poorly to corticosteroids and immunosuppressive agents. We describe 26 GPA patients with ≥1 tracheal (mainly subglottic, SGS) and/or bronchial stenosis(ses) (BS(s)).Sixteen patients had solitary SGS and 10 had ≥1 BS(s). The male/female sex ratio was 9:17, and the median age at GPA diagnosis was 32 years (3:13 and 28 years, respectively, for SGS patients). Antineutrophil cytoplasm antibodies were proteinase 3-positive in 65.5% of the patients (50% of those with SGS).Despite conventional GPA therapy, 62% patients experienced ≥1 stenosis relapse(s) (81% of SGS patients, for a total of 1-8 relapses per patient). None of the several systemic or endoscopic treatments prevented future relapses. Cyclophosphamide induction therapy was effective in 4/6 patients with BS(s) and in 1 patient with SGS among the 7 treated. After many relapses, rituximab achieved remission in 3/4 SGS patients. Endoscopic treatments (dilation, laser, corticosteroid injection, etc.) had only transient efficacy. Other GPA manifestations relapsed independently of TBSs. One SGS patient died of acute respiratory distress syndrome.Our findings confirmed that TBSs are severe GPA manifestations that evolve independently of other organ involvements and do not respond to conventional systemic regimens. As previously described, our population was younger and comprised more females than usual GPA patients, especially those with SGS.The small number of patients and the wide variety of local and systemic treatments prevent us from drawing definitive conclusions about the contribution of each procedure. However, cyclophosphamide seemed to effectively treat BSs, but not SGS, and rituximab may be of interest for SGS management.",
"affiliations": "From the Department of Internal Medicine (CG, PaC, BT, GB, LG), National Referral Center for Rare Autoimmune and Systemic Diseases, Cochin Hospital; INSERM U1060 (CG, PaC, BT, GB, LG), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, University of Paris 5-René-Descartes, Paris; Department of Internal Medicine (CG), Department of Rheumatology, Mount Sinaï Hospital, Toronto, Ontario, Canada (CP), Edouard-Herriot University Hospital, Lyon; National Referral Center for Rare Pulmonary Diseases (VC, J-FC), Louis-Pradel Hospital, Lyon, France; and Department of Internal Medicine (PiC), Institut Mutualiste Montsouris, Paris.",
"authors": "Girard|Charlotte|C|;Charles|Pierre|P|;Terrier|Benjamin|B|;Bussonne|Guillaume|G|;Cohen|Pascal|P|;Pagnoux|Christian|C|;Cottin|Vincent|V|;Cordier|Jean-François|JF|;Guillevin|Loïc|L|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2626634410.1097/MD.0000000000001088010886900Research ArticleObservational StudyTracheobronchial Stenoses in Granulomatosis With Polyangiitis (Wegener's) A Report on 26 CasesGirard Charlotte MDCharles Pierre MDTerrier Benjamin MD, PhDBussonne Guillaume MDCohen Pascal MDPagnoux Christian MDCottin Vincent MD, PhDCordier Jean-François MD, PhDGuillevin Loïc MDPilar Brito Zeron. From the Department of Internal Medicine (CG, PaC, BT, GB, LG), National Referral Center for Rare Autoimmune and Systemic Diseases, Cochin Hospital; INSERM U1060 (CG, PaC, BT, GB, LG), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, University of Paris 5-René-Descartes, Paris; Department of Internal Medicine (CG), Department of Rheumatology, Mount Sinaï Hospital, Toronto, Ontario, Canada (CP), Edouard-Herriot University Hospital, Lyon; National Referral Center for Rare Pulmonary Diseases (VC, J-FC), Louis-Pradel Hospital, Lyon, France; and Department of Internal Medicine (PiC), Institut Mutualiste Montsouris, Paris.Correspondence: Loïc Guillevin, Department of Internal Medicine, Hôpital Cochin, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France (e-mail: loic.guillevin@cch.aphp.fr).\n8 2015 14 8 2015 94 32 e108810 12 2015 28 5 2015 8 6 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nTracheobronchial stenoses (TBSs) are potentially severe manifestations of granulomatosis with polyangiitis (Wegener's) (GPA) that usually respond poorly to corticosteroids and immunosuppressive agents. We describe 26 GPA patients with ≥1 tracheal (mainly subglottic, SGS) and/or bronchial stenosis(ses) (BS(s)).\n\nSixteen patients had solitary SGS and 10 had ≥1 BS(s). The male/female sex ratio was 9:17, and the median age at GPA diagnosis was 32 years (3:13 and 28 years, respectively, for SGS patients). Antineutrophil cytoplasm antibodies were proteinase 3-positive in 65.5% of the patients (50% of those with SGS).\n\nDespite conventional GPA therapy, 62% patients experienced ≥1 stenosis relapse(s) (81% of SGS patients, for a total of 1–8 relapses per patient). None of the several systemic or endoscopic treatments prevented future relapses. Cyclophosphamide induction therapy was effective in 4/6 patients with BS(s) and in 1 patient with SGS among the 7 treated. After many relapses, rituximab achieved remission in 3/4 SGS patients. Endoscopic treatments (dilation, laser, corticosteroid injection, etc.) had only transient efficacy. Other GPA manifestations relapsed independently of TBSs. One SGS patient died of acute respiratory distress syndrome.\n\nOur findings confirmed that TBSs are severe GPA manifestations that evolve independently of other organ involvements and do not respond to conventional systemic regimens. As previously described, our population was younger and comprised more females than usual GPA patients, especially those with SGS.\n\nThe small number of patients and the wide variety of local and systemic treatments prevent us from drawing definitive conclusions about the contribution of each procedure. However, cyclophosphamide seemed to effectively treat BSs, but not SGS, and rituximab may be of interest for SGS management.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nGranulomatosis with polyangiitis (Wegener's) (GPA) is a small-vessel necrotizing granulomatous vasculitis. Ear, nose and throat (ENT), lung, and kidney are the most frequently involved organs (90%, 90% and 80% patients, respectively).1 GPA can be life-threatening, but dramatic improvement has been obtained since corticosteroids and immunosuppressive or immunomodulating agents have been prescribed. Initial induction therapy now achieves GPA remission in ∼90% of the patients.\n\nTracheobronchial involvement, a less common GPA manifestation, comprises stenoses of the tracheobronchial tree, which can lead to upper airway obstruction and potentially severe functional but also life-threatening consequences.2 Subglottic stenosis (SGS) is the most frequent tracheobronchial stenosis (TBS) type that could be related to anatomic specificities and pathophysiological mechanisms.3 SGS treatment is not codified and is often less effective than that of other systemic manifestations. SGS occurrence and outcome can be independent of systemic GPA manifestations and their evolution.2,4 Little is known about bronchial stenoses (BSs) in terms of therapeutic response or evolution.5 Endoscopic treatments are frequently needed to improve airway flow.4,6\n\nThe objectives of this study were to describe patients managed for TBS(s) in 2 French medicine departments, and to compare the features and treatment responses of SGSs versus BSs.\n\nPATIENTS AND METHODS\nWe retrospectively identified GPA patients with ≥1 TBS(s) that had been followed and treated in 2 university hospitals (Paris and Lyon, France) during the past decade. GPA diagnosis was based on clinical, radiological, biological, and, sometimes, histological findings. Patients satisfied American College of Rheumatology classification criteria7 and Chapel Hill Nomenclature definitions.8 This study was conducted in compliance with good clinical practices and the Declaration of Helsinki principles. In accordance with French law, formal approval from an ethics committee is not required for this type of study.\n\nTracheal stenoses comprised SGSs (located at the level of cricoid cartilage and/or upper tracheal rings, 1.5–2 cm below the true vocal cords and above the trachea) or distal tracheal stenoses (dTSs).3,9 BSs affected the main or lobar bronchi (≥1). Tracheal and bronchial stenoses could coexist in the same patient. The diagnosis of stenosis was retained based on a persistent localized narrowing of the tracheal and/or bronchial lumen(s) during exploratory endoscopy or imaging. Each GPA patient identified in the databases of the 2 participating departments as having at least 1 of these stenoses was included in the study.\n\nWe paid particular attention to compare patients with isolated SGS versus those with BS(s) with or without SGS or dTS.\n\nPatients’ clinical, biological, histological, and radiological records were reviewed. Data concerning TBSs and systemic manifestations over time and responses to treatments were collected. In particular, each stenosis relapse was identified, and patient's characteristics at that time (systemic disease activity, antineutrophil cytoplasm antibody (ANCA) status, current medications, etc.), systemic and endoscopic treatments, and outcomes were recorded.\n\nStenosis remission was defined as the disappearance or regression of stenosis-related clinical symptoms (hoarseness, dyspnea, cough, etc.), associated with enlargement of the tracheal or bronchial lumen at the end of the endoscopic procedure or during exploratory endoscopy performed weeks after starting medical treatment. Relapse corresponded to each recurrence after remission of persistent, progressive, specific symptoms, concomitant with stenosis worsening compared to the last explorations.\n\nDisease activity was assessed with the Birmingham Vasculitis Activity Score (BVAS),10 whereas sequelae were evaluated with the Vasculitis Damage Index (VDI).11\n\nStatistical Analyses\nDescriptive statistics included numbers (percentages) for categorical variables and mean or median [range] for continuous variables. Categorical variables were compared with the nonparametric Fisher exact test. Continuous variables were compared using the nonparametric Mann–Whitney test. For all analyses, the α risk was set at 5%. All analyses were computed with the R v2.4.2 software package (http://www.R-project.org).\n\nRESULTS\nPatients\nTwenty-six patients were included (Figure 1). Their main characteristics are shown in Tables 1 and 2. They were 9 men and 17 women (male/female sex ratio, 0.53). Their median age at GPA onset was 32 (range 6–79) years. Figure 2 shows the patients’ distribution according to age and TBS type.\n\nFIGURE 1 Flow chart from diagnosis of GPA to remission of patients with a SGS or ≥1 BS. The solid black arrow represents the onset of stenosis treatment (and sometimes GPA) at diagnosis. The black-outline arrows are the treatments of each relapse. BS = bronchial stenosis, GPA = granulomatosis with polyangiitis (Wegener's), lost = lost sight, SGS = subglottic stenosis.\n\nTABLE 1 Stenosis Diagnosis and Initial Treatment(s) for Each Patient\n\nTABLE 2 Characteristics of Patients With SGS Versus Those With at Least 1 BS\n\nFIGURE 2 Age at diagnosis of GPA, according to stenosis type. BS = patients with ≥1 bronchial stenosis(ses), GPA = granulomatosis with polyangiitis (Wegener's), SGS = patients with single subglottic stenosis.\n\nSystemic Manifestations\nAmong the 26 patients, 25 (96%) had systemic GPA manifestations (Tables 1 and 2): 23/26 (88%) patients had ENT involvement (crusty rhinitis, chronic sinusitis, or otitis in most cases), 20 (77%) had associated pulmonary parenchymal manifestations, and 12 (46%) had renal disease. General symptoms (fever, weight loss, asthenia, etc.) were present in 19/26 (73%) patients.\n\nTBSs\nSixteen patients had isolated SGS (without BSs) and 10 had ≥1 BS(s). Multiple BSs were found in 7/10 patients (Table 1). All but 1 of the 10 BS patients had involvement of the left bronchi and 4/10 of the right bronchi. Left upper and lower lobar bronchi were the most often affected (5 patients each). No patient had isolated dTS, but BS patients 3 and 1, respectively, also had dTS and SGS.\n\nStenotic lesions were present at GPA onset (12 [46%] patients) or appeared subsequently (14 [54%] patients), after a median of 33 (5–113) months (39 [6–112] months for SGS, 30 [0–120] months for the others) (Table 1).\n\nPatient 1's first identified BS was diagnosed 3 months after his SGS. Patient 3's BS and dTS were diagnosed concomitantly after GPA.\n\nClinical SGS manifestations were dyspnea on exertion (8/16, 50%), stridor (3/16, 19%), or persistent cough or hoarseness (1 patient each, 6%). Initial BS symptoms were hemoptysis (2/10, 20%), dyspnea or cough (1 patient each, 10%). BSs were asymptomatic in 6 (60%) of the 10 patients, and SGS in 2 (13%) of the 16 patients. In those 8 asymptomatic patients, TBSs were diagnosed fortuitously during the initial GPA work-up or during its monitoring by computed tomography (CT) scan in patient 1, or bronchoscopy in the 7 other patients, which had been motivated by CT identification of pulmonary nodules in 6 patients, or exploration of an intraalveolar hemorrhage in the seventh patient.\n\nRelapses\nSixteen patients (62%) experienced ≥1 TBS relapse(s) (Figure 1, Table 3), for a total of 51 TBS relapses (42 SGS and 9 BS relapses). Eight (89%) of the 9 BS and 22/42 (52%) SGS relapses occurred while GPA was in remission. ENT disease was the only GPA manifestation during all the remaining TBS relapses, except 4 SGS relapses that were concomitant with eye (scleritis) or joint involvement.\n\nTABLE 3 Follow-Up and Relapse Features\n\nTen (63%; 1 with BSs and 9 with SGS) of the 16 TBS-relapsing patients remained in systemic GPA remission from TBS diagnosis until the end of follow-up. Six (23%) of the 26 patients suffered systemic disease relapses (mostly ENT) without any TBS recurrence.\n\nPatient 1, the only who had BSs and SGS, experienced 6 BS relapses (5 of them in the left main bronchus) and 6 SGS relapses, with 3 of the latter occurring without any concomitant BS relapse.\n\nAmong SGS patients, patient 17 was lost sight after 2 relapses, and patient 22 died after her first relapse, of acute respiratory distress caused by obstructive SGS.\n\nComplementary Investigations\nANCA\nTwenty-three (88%) patients were ANCA-positive at the time of GPA diagnosis (14 with cytoplasmic ANCA (c-ANCA)- and 4 with perinuclear-labeling patterns, 5 with undetermined specificities). Anti-proteinase-3 (PR3) ANCAs were detected in 17 (65.5%) patients, anti-myeloperoxidase (MPO) in 3 (11.5%), and no specificity in 3 (Table 2).\n\nANCAs were sought during 21/51 TBS flares (3/9 BS and 18/42 SGS relapses). They were never detected for patients with BS(s) and were negative during 8/18 (44%) SGS relapses. Among the 10 positive ANCA tests during SGS relapses, half had low titers.\n\nHistology\nSeventeen patients underwent ≥1 tracheal or bronchial biopsies at the time of TBS diagnosis (6/10 BSs, 7/16 SGSs), or at relapse (4/16 SGS patients). Distributions of histological findings are reported in Figure 3. Among the 26 biopsies performed, all but 2 were pathological (92%). Those latter 2 biopsies were obtained, a few months apart, from the same patient. Histological findings were never GPA-specific and never led to the diagnosis.\n\nFIGURE 3 Distributions of histological findings in the biopsies from 11/16 patients with SGS and 6/10 patients with ≥1 BS(s). The percentages indicate the frequency of each histological finding among SGSs, BSs, and all tracheobronchial stenoses (All). BSs = bronchial stenoses, SGS = subglottic stenosis.\n\nRadiological and Functional Tests used for TBS Management\nAs of TBS diagnosis, 14/16 SGS patients underwent ≥1 nasofibroscopic examination(s) and 5/10 patients with BS(s) underwent bronchoscopy at least once during their follow-up. CT scans were obtained for 11/16 SGS patients and 6/10 with BSs. Pulmonary function was assessed with flow-volume loop in 16 patients (11 with SGS and 5 with BS[s]). It showed flattening of both limbs of the loop, reflecting fixed upper airway obstruction. Patient 23 with SGS and patient 6 with BSs underwent positron-emission tomography (PET): no uptake was seen at the levels of the stenoses. Magnetic resonance imaging (MRI) was never done.\n\nAside from being used for monitoring, endoscopy was the investigation of choice for diagnosis (9/10 BSs and 12/16 SGSs). For patient 1 with multiple BSs, and SGS patients 11 and 13, this is CT scan that provided TBS diagnoses.\n\nTreatments\nInitial Treatment\nTable 1 shows the local and systemic treatments initiated when TBS(s) were diagnosed. Among the 14 patients whose TBS(s) had been diagnosed during the course of GPA, 10 (71%) were already on systemic therapy, comprising oral corticosteroids for all but patients 11 and 16, combined with cytotoxic drug(s). Patients 11 and 16 received cotrimoxazole alone (800 mg × 2 daily). Concerning the 12 patients whose TBS(s) were diagnosed at the same time as the first GPA flare, corticosteroids, and intravenous (IV) cyclophosphamide were prescribed for all but patients 17 and 23. Notably, patient 14 was already taken corticosteroids and cotrimoxazole at that time, for still misidentified ENT disease, as GPA had not yet been diagnosed.\n\nNine patients also received local treatment. Of the 2 patients who were not prescribed medical treatment, patient 20 underwent laser therapy for SGS and patient 9 was not treated because BS was asymptomatic and systemic GPA in remission at that time. The only initial local BS treatment was mechanical dilation, done for patients 1, 4, and 6. Seven patients received local treatment of their SGS: laser therapy for 5, mechanical granulation tissue removal for 2, and/or dilation or local corticosteroid injection for 1 each.\n\nSix (60%) of the 10 patients with BS(s) and 9/16 (56%) SGS patients were prescribed only medical treatments.\n\nSystemic Treatments for Relapses\nMedications were prescribed for 39/51 (76%) relapses (6/9 [67%] BS and 33/42 [79%] SGS relapses). The most frequently used were corticosteroids, IV or oral cyclophosphamide, azathioprine, and/or subcutaneous or oral methotrexate, which were, respectively, prescribed for 49%, 18% (IV [8%] as often as oral [10%]), 16%, and 14% of the relapses. IV immunoglobulins, infliximab, mycophenolate mofetil, cotrimoxazole, and rituximab were other systemic therapeutic options.\n\nLocal Treatments for Relapses\nLocal treatments were prescribed for 35/51 (69%) relapses (7/9 [78%] BSs and 28/42 [67%] SGSs relapses). Rigid bronchoscope dilation was done for 18/51 (35%) relapses (3/9 [33%] BSs and 15/42 [36%] SGSs), a stent was inserted for 7/51 (14%), and laser and/or local corticosteroid injection were used for 6/51 (12%) relapses. Stenting (silicone endoprosthesis) was only prescribed for BSs, and only SGSs were injected with corticosteroids. Laser was used for both TBS types (2/9 [22%] BS and 4/42 [10%] SGS relapses). Resection–anastomosis surgery, mechanical granulation tissue removal, or mitomycin C injection was done, respectively, only in 5, 3, or 2 SGS patients. Patient 16 underwent concomitant dilation and local corticosteroid injection twice. Nine other patients benefited from other local treatment combinations (dilation + stenting, laser + corticosteroid injection, etc.) so that combined local therapy was used for 11 (31%) of the 35 relapses treated locally.\n\nFinally, patients were prescribed concomitant local and medical treatments for 25/51 (49%) relapses.\n\nOutcomes\nTable 4 reports the efficacies of medical and local treatments, alone or combined, to achieve SGS or BS remission, or delay the next relapse. Remission rates after initial treatment or relapse management were 32% for all patients, 53% for BS, and 26% for SGS patients. Their respective mean intervals until the next relapse were 16, 8, and 18 months. Remission was achieved in 46% events treated only medically, without concomitant local procedure(s) (75% in case of BS, 35% in case of SGS). Combined therapies prevented further relapses in 24% cases, local treatment alone in 25%, and 0% in BS patients.\n\nTABLE 4 Influence of Treatment Type and Regimen on Attaining Remission or Time to Next Relapse\n\nCyclophosphamide or Rituximab Impact on TBSs\nIn SGS patients, cyclophosphamide allowed to achieve remission in 17% cases when used without associated local treatment, 20% when part of combined therapy. Seven of all the patients’ 51 relapses occurred under cyclophosphamide (mainly IV, for 5/7 relapses). SGS was diagnosed in patients 13 and 21 while they were receiving IV cyclophosphamide for induction therapy of their GPA. In BS patients, remission was achieved after cyclophosphamide treatment in 50% cases when associated with local procedure, 67% when not. Among the 10 patients with BSs, patient 1 was the only one receiving IV or oral cyclophosphamide at the time of TBS diagnosis.\n\nThe remission rate after rituximab infusion without combined local therapy was 80% (67% in SGS and 100% in BS patients). It was 67% when associated with local treatments. Rituximab achieved SGS remission in patients 11, 13, and 18, respectively, after their first, fourth, and eighth relapses, and for patient 15, remission was delayed, appearing only after the second rituximab infusion, given for her sixth relapse. For patient 1, rituximab was unable to prevent an early BS flare, but his SGS then remained asymptomatic for months.\n\nEffects of Concomitant Dilation and Local Corticosteroid Injection, Laser Therapy, or Resection–Anastomosis Surgery on SGSs\nFor patient 16, no subsequent relapse occurred after 2 successive dilation procedures combined with local corticosteroid injection. SGS-remission rates were 23% after any kind of endoscopic procedure (alone or combined with medical treatment), 37% after laser therapy, and 40% following surgical intervention, with respective means of 17 and 19 months before the next relapse for the latter 2 procedures.\n\nComplications\nEleven (42%) of the 26 patients developed ≥1 treatment or TBS complication(s). Acute respiratory distress was the most frequent, occurring in SGS patients 11, 12, 15, 18, 19, and 22, and patient 1 with BSs, and was the only complication recorded for SGS patients. In contrast, patients 1, 4, 5, and 9 with BS(s) developed bronchopulmonary infections. In patient 3, whose BS had been stented, the endoprosthesis migrated into the mediastinum. Tracheotomy was never performed. During follow-up, only patient 22 died (acute respiratory failure).\n\nDISCUSSION\nFew papers have focused on TBS in GPA.2–6,9,12–37 SGS is the most frequent stenosis type described, but the rare publications on SGS have mostly been case reports.2–4,6,12–14,16,18–21,24–25,27–33,35,37 Nonetheless, SGS frequency in larger series was estimated at 16% to 23% of GPA patients.4,18 BSs are even less studied and little is known about their epidemiology, clinical features, and therapeutic responses.2,5,15,17,22,23,26,31,34,36\n\nEvaluation of our sample confirmed that TBSs, especially SGSs, are unusual GPA manifestations, which do not follow the same evolution as other organ-system manifestations of this vasculitis.\n\nFirst, our population seems to differ demographically from the general GPA population described in literature. Indeed, the majority of our 26 patients were female, whereas the sex ratio for GPA is known to be 1:1.38 Furthermore, they were mostly young, while GPA usually affects patients in their fifth decade. These characteristics were especially true for SGS patients, who were even more frequently female and younger than patients with BS(s), who were demographically closer to the general GPA population. Intriguingly, females also predominated in pediatric GPA patients (male/female ratio of 1:4), with a relative SGS risk of 5 in this population.39 Our patients’ systemic manifestations also differed from those usually seen in GPA.1 Indeed, they had less frequent renal involvement, regardless of whether they had SGS or BS(s). On the contrary, ENT disease was frequent but pulmonary manifestations (other than BS(s)) were less common in SGS patients. Moreover, our SGS patients were less frequently ANCA-positive and more often MPO-positive than patients with BS(s), who, again, more closely resembled the general GPA population. Finally, tracheal and bronchial histological findings were never GPA-specific, with few granulomatous lesions and little vasculitis.\n\nOur findings agree with those previously reported, that is, the majority of cases were women and frequently young, especially those with SGS. For example, the largest cohort, described in 1998 by Langford et al,4 was composed of nearly twice as many women as men (27 vs 16) and the median age at diagnosis was 26 years. More recently, in 2008, Solans-Laque et al32 described 6 GPA patients with SGS, 5 of whom were women, whose average age was 33 years. Finally, in Schokkenbroek et al's9 retrospective study of the same year, the percentage of females and the mean age at GPA diagnosis, respectively, of the 9 patients investigated were significantly higher (P < 0.01) and lower (P < 0.05) than those of patients diagnosed with GPA at that institution during the same period. Fewer publications and no large series are available on GPA patients with BS(s). Similarly, our small population may not be representative of all GPA patients with BS(s).\n\nNotably, BSs have been described much less frequently than SGSs. Among our patients, those with BSs were a minority, with 2 patients also having tracheal stenoses. A possible explanation could be that BSs are frequently asymptomatic and discovered fortuitously, during bronchoscopy performed for pulmonary parenchymatous lesions, for example, unlike SGS which rapidly becomes symptomatic (voice changes, noisy breathing, dyspnea, etc.). Thus, BSs could actually be underdiagnosed among GPA patients.\n\nTBS patients’ clinical and immunological GPA characteristics are not well known. Schokkenbroek et al9 did not find any differences in other organ involvements between their 9 TBS patients and general GPA population. On the contrary, in accordance with our observations, Langford et al4 found renal and pulmonary manifestations to be less frequent in SGS patients. Among the 6 patients described by Solans-Laque et al,32 none had renal involvement but ENT disease was usually associated. Concerning ANCA titers, almost all patients reported were ANCA-positive, mostly with anti-PR3 c-ANCA (35/37 [95%]) in Langford et al's cohort.4 The somewhat weaker ANCA frequency of SGS patients in our series is surprising.\n\nOtherwise, the absence of TBS-histology specificity was previously described.2,4,12 However, according to our findings and those of Hervier et al,5 granuloma may be seen more often than vasculitis in bronchial biopsies, but its frequency remains to be confirmed in larger series.\n\nAll these observations may lead to considering GPA with TBSs, especially SGSs, particular forms of the vasculitis. Thus, our findings, like those of others, highlight the differences of BSs and SGSs, compared with other organ involvements, in terms of evolution and therapeutic responses.\n\nOur results confirmed that TBSs evolve independently of all other GPA manifestations. Indeed, in the case of secondary TBS diagnosis, GPA was otherwise in remission in half the patients. Above all, a large majority of TBS relapses occurred without any other evolutive GPA organ-system involvement. And, in 81% of the remaining patients with simultaneous GPA and TBS relapses, ENT disease was the only active GPA manifestation. Similarly, ANCA remained negative during half of the TBS relapses and all 3 BS relapses, when they had been sought. These findings are similar to those of other authors over the years,2,4,5,18 including for ANCA titers.2 For Schokkenbroek et al,9 95% of SGSs appeared when the disease was the less active.\n\nMoreover, TBS relapses were common and recurrent, suggesting the absence of response to classical GPA treatment. Indeed, when diagnosed secondary to GPA, TBSs mostly occurred under GPA therapy. Moreover, for our 26 patients, a large majority had recurrent TBSs, which were often multiple, whereas GPA remained in remission otherwise in 63% of these patients, as previously described.2,18,19 However, SGSs and BSs have not yet been compared.\n\nAlthough the mean number of relapses was the same for our SGS and BS patients, SGSs may be at higher risk of relapse than BSs. Indeed, among our 10 patients with BS(s), only 3 relapsed and 2/3 relapsed only once or twice. The mean number of relapses for this group was biased because of the third, patient 1, who had 6 relapses. Pertinently, he had a particular disease phenotype, with both BSs and SGS, and was thus perhaps closer to patients with only SGS, especially because the latter also relapsed 6 times. This unusual phenotype has been much less described in the literature than the association of BS(s) and dTS(s). Concerning isolated BS(s), which are much more common, relapses are possible but usually few in number. For example, only 2 of the 7 BS patients reported by Hervier et al5 relapsed, and only once for both. On the contrary, Tiernan et al26 described a 19-year-old woman whose BS relapsed >10 times in 7 years. To compare this mixed-TBS phenotype to patients with only SGS in a large cohort would be of interest to determine whether they exhibit the same demographic, clinical, immunological, and histological features or therapeutic responses.\n\nAssessing the benefit of the different treatment options for SGS and BS management in our study was difficult because of the numerous therapeutic strategies (many systemic and local treatments) which were frequently combined, leading to multiple different associations. The small size of our sample precluded relevant statistical analyses. However, exclusively medical treatments seemed to be more effective, at achieving remission and/or delaying the next relapse, than exclusively local or combined local and medical therapies, especially for BSs. These surprising findings that contradict those of previous large studies should be interpreted with caution. Indeed, the TBSs managed with local or, a fortiori, local and systemic treatment were probably more severe lesions, having more dismal vital and functional prognoses, than those treated only medically, for whom achieving rapid remission was less urgent.\n\nInterestingly, herein, neither laser therapy nor resection–anastomosis surgery was attributed an increased risk of SGS relapse, as was sometimes advanced in the literature.3–6 Indeed, it had never been subjected to statistical analyses until now, and some authors even recommended those treatments.16,18,19,26 However, prudence is necessary because of the small size of our population and the frequently combined local and medical treatments that, again, do not allow definitive conclusions to be drawn about the safety of laser and surgery to manage SGS.\n\nUnfortunately, dilation combined with local corticosteroid injection, which is highly recommended in the literature,4,6,21,29,32 was prescribed for only 1 patient, so we cannot conclude about its contribution to TBS, especially SGS, management. Nonetheless, it was quite effective in our patient 16 who has been in SGS remission since the second procedure, after a long series of relapses. Also, in our cohort, only 7 local corticosteroid injections, without concomitant dilation, were given.\n\nEven though our sample is too small, and the different treatment types too numerous and frequently combined to enable subgroup analyses, we would like to temper the dogma that TBSs do not respond to conventional GPA therapeutic agents. Indeed, cyclophosphamide, which seemed useless against SGSs, may be effective against BSs, again making it more similar to other classical GPA manifestations. Furthermore, rituximab may be of interest for SGS management, as it achieved remission after multiple relapses in our 4 SGS patients for whom it was prescribed. Two different teams had, to date, extolled the virtues of rituximab as treatment for SGS, but each in a single GPA patient.37,40\n\nTherefore, whereas endoscopic treatments of TBSs are being supported more-and-more often in the literature, particularly dilation combined with local corticosteroid injection for SGS, they were not associated with better clinical outcomes herein, compared to a more classical medical strategy. Indeed, although cyclophosphamide seems to be poorly effective at treating SGSs, it remains useful for BS management, and rituximab may prove to be an attractive option for SGSs. Of course, these therapeutic assumptions should be viewed with caution, in light of the above-mentioned lack of statistical analyses. Large, prospective, randomized studies are necessary to determine the best management strategy for TBSs, but difficult to achieve because of the rarity of GPA and, a fortiori, of these manifestations.\n\nConcerning SGS follow-up, as previously proposed, flow-volume-loop pulmonary function assessment was shown to be an easy and sensitive technique.27,29 PET scan was not considered useful (but was performed on only 2 patients) and MRI was never used. However, the latter was recently shown to be a more informative tool for the management of SGSs, both for morphological follow-up and noninvasive assessment of the status of inflammatory activity.41\n\nCONCLUSION\nTBSs are not-so-uncommon GPA manifestations of which physicians should be aware given their marked functional and life-threatening risks. Our observations seem to confirm their specificities of evolving independently of other GPA manifestations and circulating ANCA titers, which may be especially true for SGSs that do not respond to most immunosuppressive regimens and for which local endoscopic management could be particularly contributive, especially for life-threatening disease. Moreover, SGS patients seem to differ markedly from the usual GPA population, with a higher percentage of females, younger age at GPA onset and less frequent PR3-ANCA-positivity. These differences might be explained by a particular pathophysiological process responsible for SGS, whose study may help us better understand and treat this severe GPA manifestation. Concerning rituximab use for TBS management, more and larger prospective studies are needed to determine whether it could be a valid option for the treatment of this challenging condition.\n\nAcknowledgments\nThe authors thank Ms. Janet Jacobson for her friendly and painstaking proofreading. This work could not have been done without the help of the devoted secretaries of Cochin Internal Medicine and Louis-Pradel Pulmonology units in retrieving patients’ medical records. The authors are grateful to all those who, in one way or another, contributed to the elaboration of this article.\n\nAbbreviations: ANCAs = antineutrophil cytoplasm antibodies, BS(s) = bronchial stenosis(ses), BVAS = Birmingham Vasculitis Activity Score, c-ANCA = cytoplasmic ANCA, CT = computed tomography, dTS(s) = distal tracheal stenosis(ses), ENT = ear, nose and throat, GPA = granulomatosis with polyangiitis (Wegener's), IV = intravenous, MPO = myeloperoxidase, MRI = magnetic resonance imaging, PET = positron-emission tomography, PR3 = proteinase-3, SGS(s) = subglottic stenosis(ses), TBS(s) = tracheobronchial stenosis(ses), VDI = Vasculitis Damage Index.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Jennette JC Falk RJ \nSmall-vessel vasculitis . N Engl J Med \n1997 ; 337 :1512 –1523 .9366584 \n2. Daum TE Specks U Colby TV \nTracheobronchial involvement in Wegener's granulomatosis . 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Interact Cardiovasc Thorac Surg \n2009 ; 9 :530 –531 .19491126 \n35. Daijo H Takabuchi S Ohigashi T \nUnexpectedly difficult intubation caused by subglottic stenosis in Wegener's granulomatosis . J Anesth \n2010 ; 24 :284 –286 .20094734 \n36. Hernandez-Rodriguez J Hoffman GS Koening CL \nSurgical interventions and local therapy for Wegener's granulomatosis . Curr Opin Rheumatol \n2010 ; 22 :29 –36 .19910793 \n37. Garcia-Valladares I Espinoza LR \nSubglottic stenosis is a form of limited Wegener's granulomatosis . J Rheumatol \n2011 ; 38 :2268 .21965697 \n38. Mohammad AJ Jacobsson LT Westman KW \nIncidence and survival rates in Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and polyarteritis nodosa . Rheumatology (Oxford) \n2009 ; 48 :1560 –1565 .19797309 \n39. Rottem M Fauci AS Hallahan CW \nWegener granulomatosis in children and adolescents: clinical presentation and outcome . J Pediatr \n1993 ; 122 :26 –31 .8419611 \n40. Seo P Specks U Keogh KA \nEfficacy of rituximab in limited Wegener's granulomatosis with refractory granulomatous manifestations . J Rheumatol \n2008 ; 35 :2017 –2023 .18688911 \n41. Klink T Holle J Laudien M \nMagnetic resonance imaging in patients with granulomatosis with polyangiitis (Wegener's) and subglottic stenosis . MAGMA \n2013 ; 26 :281 –290 .23086288\n\n",
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}
],
"summary": null
},
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},
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},
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{
"abstract": "To report cancer control rates and adverse events (AEs) of curative-intent, extended-field chemoradiation therapy administered to patients with squamous cell carcinoma (SCC) of the anal canal presenting with distant metastasis limited to the para-aortic (PA) lymph nodes.\n\n\n\nThis was a retrospective review of patients with SCC of the anal canal metastatic to the PA lymph nodes at initial diagnosis who were treated with curative-intent, extended-field chemoradiation therapy between September 2002 and February 2016 at two tertiary care centers. Outcomes assessed included treatment-related AEs (Common Terminology Criteria for Adverse Events, version 4.0), disease control (cumulative incidence estimates), and survival (Kaplan-Meier estimates).\n\n\n\nThirty patients were included. Involved and elective PA nodes were treated to median doses of 51 Gy (range 45-57.6) and 45 Gy (range 30.6-50.4) in 29 fractions (range 17-32). All patients received one of these concomitant regimens: 6 weekly cycles of cisplatin with 5-fluoruracil/capecitabine (5-FU) (n = 22), 2 cycles of mitomycin-C with 5-FU (n = 7), or daily capecitabine (n = 1). After a median follow-up period of 3.1 years, 18 patients (60%) remained alive and 17 patients were without evidence of anal cancer after definite and salvage treatments. Overall and disease-free survival at 3 years was 67% (95% CI 49%-89%) and 42% (95% CI 25%-69%). Fifteen (50%) patients experienced a recurrence at a median of 0.9 year (range 0.5-3.5 years). The predominant site of recurrence was distant metastases, with a 3-year cumulative incidence of 50% (95% CI 20%-68%). There was no acute grade 5 AE. Grade 3 to 4 gastrointestinal, dermatologic, and hematologic AEs occurred in 30%, 27%, and 20% of patients respectively.\n\n\n\nExtended-field chemoradiation therapy is a potentially curative treatment option for patients presenting with SCC of the anal canal with metastases limited to the PA lymph nodes.",
"affiliations": "Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.;Department of Biostatistics, Mayo Clinic, Rochester, Minnesota.;Department of Gastrointestinal Oncology, MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.;Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas. Electronic address: Hallemeier.Christopher@mayo.edu.",
"authors": "Holliday|Emma B|EB|;Lester|Scott C|SC|;Harmsen|W Scott|WS|;Eng|Cathy|C|;Haddock|Michael G|MG|;Krishnan|Sunil|S|;Das|Prajnan|P|;Hallemeier|Christopher L|CL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijrobp.2018.04.076",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "102(1)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000328:Adult; D000368:Aged; D001005:Anus Neoplasms; D001011:Aorta; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012449:Safety; D016019:Survival Analysis",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "102-108",
"pmc": null,
"pmid": "29907489",
"pubdate": "2018-09-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Extended-Field Chemoradiation Therapy for Definitive Treatment of Anal Canal Squamous Cell Carcinoma Involving the Para-Aortic Lymph Nodes.",
"title_normalized": "extended field chemoradiation therapy for definitive treatment of anal canal squamous cell carcinoma involving the para aortic lymph nodes"
} | [
{
"companynumb": "US-ROCHE-2173148",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
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},
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},
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],
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"reaction": [
{
"reactionmeddrapt": "Lymphopenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Small intestinal obstruction",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rectal haemorrhage",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dermatitis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stomatitis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HOLLIDAY E, LESTER S, HARMSEN W, ENG C, HADDOCK M, KRISHNAN S, DAS P AND HALLEMEIER C. EXTENDED?FIELD CHEMORADIATION THERAPY FOR DEFINITIVE TREATMENT OF ANAL CANAL SQUAMOUS CELL CARCINOMA INVOLVING THE PARA?AORTIC LYMPH NODES. INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 2018?102 (1):102?108.",
"literaturereference_normalized": "extended field chemoradiation therapy for definitive treatment of anal canal squamous cell carcinoma involving the para aortic lymph nodes",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180823",
"receivedate": "20180823",
"receiver": {
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},
"reporttype": "2",
"safetyreportid": 15309123,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20181010"
}
] |
{
"abstract": "Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.\nThe patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.\nThe diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.\nTopical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.",
"affiliations": "Department of Ophthalmology, Nassau University Medical Center, East Meadow, NY, 11554, USA.;Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.;Division of Cornea and Refractive Surgery, Ophthalmic Consultants of Long Island, Rockville Centre, NY, 11570, USA.;Department of Ophthalmology, Nassau University Medical Center, East Meadow, NY, 11554, USA.",
"authors": "Chang|Eileen L|EL|;Chu|Rachel L|RL|;Wittpenn|John R|JR|;Perry|Henry D|HD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2021.101030",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(21)00021-9\n10.1016/j.ajoc.2021.101030\n101030\nCase Report\nNocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus\nChang Eileen L. echang324@gmail.comeileen.chang@yale.edua∗ Chu Rachel L. b Wittpenn John R. c Perry Henry D. ac a Department of Ophthalmology, Nassau University Medical Center, East Meadow, NY, 11554, USA\nb Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA\nc Division of Cornea and Refractive Surgery, Ophthalmic Consultants of Long Island, Rockville Centre, NY, 11570, USA\n∗ Corresponding author. Department of Ophthalmology Nassau University Medical Center East Meadow, New York, 11554, USA. echang324@gmail.comeileen.chang@yale.edu\n13 2 2021 \n6 2021 \n13 2 2021 \n22 10103012 5 2020 8 12 2020 1 2 2021 © 2021 The Authors. Published by Elsevier Inc.2021This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nNocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.\n\nObservation\nThe patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.\n\nConclusion\nThe diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.\n\nImportance\nTopical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.\n\nKeywords\nNocardiaCorneaInfectionKeratitisHSVSLK\n==== Body\n1 Introduction\nNocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.\nNocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2\nNocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8\n\nThis unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.\n\n2 Case presentation\nA 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.\n\nOn two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.\n\nThe patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.\n\nFig. 1\n\nAfter returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.\n\nOne week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.\n\nFig. 2\n\n3 Discussion\nThe usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10\n\nDiagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1\n\nNocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15\n\nAnother confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.\n\nNocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.\n\nNocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.\n\n4 Conclusions\nNocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.\n\nPatient consent\nThe patient consented to publication of the case in writing and orally.\n\nCRediT authorship contribution statement\nEileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.\n\nAcknowledgments and Disclosures\nNo funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship.\n==== Refs\nReferences\n1 Sridhar M.S. Gopinathan U. Garg P. Sharma S. Rao G.N. Ocular Nocardia infections with special emphasis on the cornea Surv Ophthalmol 45 5 2001 361 378 10.1016/s0039-6257(00)00207-1 11274691 \n2 Perry H.D. Nauheim J.S. Donnenfeld E.D. Nocardia asteroides keratitis presenting as a persistent epithelial defect Cornea 8 1 1989 41 44 2647409 \n3 Sridhar M.S. Sharma S. Reddy M.K. Mruthyunjay P. Rao G.N. Clinicomicrobiological review of Nocardia keratitis Cornea 17 1 1998 17 22 10.1097/00003226-199801000-00003 9436875 \n4 Lalitha P. Nocardia keratitis Curr Opin Ophthalmol 20 4 2009 318 323 10.1097/ICU.0b013e32832c3bcc 19387343 \n5 Parsons M.R. Holland E.J. Agapitos P.J. Nocardia asteroides keratitis associated with extended-wear soft contact lenses Can J Ophthalmol 24 3 1989 120 122 2659153 \n6 Enzenauer R.W. Cornell F.M. Brooke J.D. Butler C.E. Nocardia asteroides keratitis: a case associated with soft contact lens wear CLAO J 15 1 1989 71 73 2645066 \n7 Garg P. Sharma S. Vemuganti G.K. Ramamurthy B. A cluster of Nocardia keratitis after LASIK J Refract Surg 23 3 2007 309 312 17385300 \n8 Patel N.R. Reidy J.J. Gonzalez-Fernandez F. Nocardia keratitis after laser in situ keratomileusis: clinicopathologic correlation J Cataract Refract Surg 31 10 2005 2012 2015 10.1016/j.jcrs.2005.02.049 16338576 \n9 Hirst L.W. Merz W.G. Green W.R. Nocardia asteroides corneal ulcer Am J Ophthalmol 94 1 1982 123 124 10.1016/0002-9394(82)90208-2 7046451 \n10 Hirst L.W. Harrison G.K. Merz W.G. Stark W.J. Nocardia asteroides keratitis Br J Ophthalmol 63 6 1979 449 454 10.1136/bjo.63.6.449 380634 \n11 Srinivasan M. Sharma S. Nocardia asteroides as a cause of corneal ulcer Arch Ophthalmol 105 4 1987 464 10.1001/archopht.1987.01060040034016 \n12 Behaegel J. Ni Dhubhghaill S. Koppen C. Diagnostic challenges in Nocardia keratitis Eye Contact Lens 44 2018 S370 S372 10.1097/ICL.0000000000000462 \n13 Theodore F.H. Ferry A.P. Superior limbic keratoconjunctivitis. Clinical and pathological correlations Arch Ophthalmol 84 4 1970 481 484 10.1001/archopht.1970.00990040483016 5492455 \n14 Kymionis G.D. Klados N.E. Kontadakis G.A. Mikropoulos D.G. Treatment of superior limbic keratoconjunctivitis with topical tacrolimus 0.03% ointment Cornea 32 11 2013 1499 1501 10.1097/ICO.0b013e318295e6b9 23770977 \n15 Passons G.A. Wood T.O. Conjunctival resection for superior limbic keratoconjunctivitis Ophthalmology 91 8 1984 966 968 10.1016/s0161-6420(84)34207-5 6493706 \n16 Lalitha P. Tiwari M. Prajna N.V. Gilpin C. Prakash K. Srinivasan M. Nocardia keratitis: species, drug sensitivities, and clinical correlation Cornea 26 3 2007 255 259 10.1097/ICO.0b013e318033d853 17413948 \n17 Patel R. Sise A. Al-Mohtaseb Z. Nocardia asteroides keratitis resistant to amikacin Cornea 34 12 2015 1617 1619 10.1097/ICO.0000000000000634 26418432\n\n",
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"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Photophobia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Eye disorder",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Visual impairment",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHANG EL, CHU RL, WITTPENN JR, PERRY HD. NOCARDIA KERATITIS MIMICKING SUPERIOR LIMBIC KERATOCONJUNCTIVITIS AND HERPES SIMPLEX VIRUS. AM J OPHTHALMOL CASE REP. 2021?22:101030",
"literaturereference_normalized": "nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210601",
"receivedate": "20210601",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19356229,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210717"
}
] |
{
"abstract": "A 71-year-old man presented with sudden abdominal pain. He had past history of atrial fibrillation, cerebral infarction and heart-valve replacement and received anticoagulant therapy with warfarin. Computed tomography of the abdomen revealed bloody ascites and a huge mass in contact with the third portion of the duodenum. The mass was encapsulated and consisted of a solid component with calcification and hematoma. Under the preoperative diagnosis of gastrointestinal stromal tumor with intra-abdominal bleeding, laparotomy was performed. Intraoperative findings revealed the tumor arising from the right mesocolon and excision of the tumor with right hemicolectomy was performed. Histologic examination confirmed a diagnosis of mixed type liposarcoma. No postoperative complication was observed and he was discharged home on the 8th postoperative day. He remains alive and well with no evidence of disease 52 months after resection.",
"affiliations": "Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences.",
"authors": "Miura|Yohei|Y|;Sakata|Jun|J|;Ando|Takuya|T|;Soma|Daiki|D|;Yuza|Kizuki|K|;Hirose|Yuki|Y|;Ishikawa|Hirosuke|H|;Miura|Kohei|K|;Takizawa|Kazuyasu|K|;Kobayashi|Takashi|T|;Ichikawa|Hiroshi|H|;Nagahashi|Masayuki|M|;Shimada|Yoshifumi|Y|;Kameyama|Hitoshi|H|;Wakai|Toshifumi|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D015746:Abdominal Pain; D000368:Aged; D004379:Duodenal Neoplasms; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008080:Liposarcoma; D008297:Male; D011379:Prognosis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1155-1157",
"pmc": null,
"pmid": "29394565",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mixed Type Liposarcoma with Intra-Abdominal Bleeding - Report of a Case.",
"title_normalized": "mixed type liposarcoma with intra abdominal bleeding report of a case"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1044032",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
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"medicinalproduct": "WARFARIN"
}
],
"patientagegroup": null,
"patientonsetage": "71",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Intra-abdominal haemorrhage",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Liposarcoma",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MIURA Y, SAKATA J, ANDO T, SOMA D, YUZA K, HIROSE Y, ET AL. [MIXED TYPE LIPOSARCOMA WITH INTRA-ABDOMINAL BLEEDING - REPORT OF A CASE]. GAN-TO-KAGAKU-RYOHO 2017?44(12):1155-1157.",
"literaturereference_normalized": "mixed type liposarcoma with intra abdominal bleeding report of a case",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20180625",
"receivedate": "20180625",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15061334,
"safetyreportversion": 1,
"sender": {
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
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"transmissiondate": "20180711"
}
] |
{
"abstract": "Checkpoint inhibition is the mainstay of treatment in metastatic melanoma. More recently combined cytotoxic T-lymphocyte antigen-4 and programmed-death-1 blockade has resulted in improved response rates and overall survival in treatment naïve patients compared to monotherapy albeit with increased rates of adverse events. Dermatologic toxicities are an emerging consequence of the use of checkpoint inhibitors and have reportedly been more prevalent with the use of combined therapy. However, grade 3 and 4 adverse event rates are still less than 5%. Here, we report a case of a 63-year-old Caucasian male with metastatic melanoma treated with first line combined ipilimumab and nivolumab who then developed a steroid refractory, biopsy confirmed pityriasis lichenoides-like, drug related rash that resolved with cyclosporine. Time of onset was 24 days and presenting symptoms demonstrated a maculopapular rash presenting over the back and chest with pruritus. Unfortunately, the patient subsequently had multi-organ failure with acute kidney injury requiring dialysis, hypotension requiring vasopressor support, hepatic dysfunction, and bilateral lung infiltrates resulting in a fatal outcome. This case report highlights the effective use of cyclosporine as an immunomodulatory agent in the management of severe dermatological toxicity due to combination immunotherapy.",
"affiliations": "Department of Medical Oncology, The Canberra Hospital, Garran, Australian Capital Territory, Australia.;Department of Medical Oncology, The Canberra Hospital, Garran, Australian Capital Territory, Australia.;Department of Medical Oncology, The Canberra Hospital, Garran, Australian Capital Territory, Australia.;Dermatology Clinic, The Canberra Hospital, Garran, Australian Capital Territory, Australia.;Department of Anatomical Pathology, The Canberra Hospital, Garran, Australian Capital Territory, Australia.;Department of Medical Oncology, The Canberra Hospital, Garran, Australian Capital Territory, Australia.;Department of Medical Oncology, The Canberra Hospital, Garran, Australian Capital Territory, Australia.",
"authors": "Randhawa|Manreet|M|;Archer|Christine|C|https://orcid.org/0000-0003-0389-3791;Gaughran|Gregory|G|;Miller|Andrew|A|;Morey|Adrienne|A|;Dua|Divyanshu|D|;Yip|Desmond|D|",
"chemical_list": "D000911:Antibodies, Monoclonal",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajco.13136",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-7555",
"issue": "15(4)",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": "cutaneous toxicity; cyclosporine; immune therapy; ipilimumab; metastatic melanoma; nivolumab; steroid-refractory rash",
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D003872:Dermatitis; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D060787:Neoplasm Grading",
"nlm_unique_id": "101241430",
"other_id": null,
"pages": "262-265",
"pmc": null,
"pmid": "30809956",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Combined immune therapy grade IV dermatitis in metastatic melanoma.",
"title_normalized": "combined immune therapy grade iv dermatitis in metastatic melanoma"
} | [
{
"companynumb": "PHHY2019AU179505",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
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"medicinalproduct": "HYDROCORTISONE."
},
{
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"activesubstancename": "PREDNISOLONE"
},
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"medicinalproduct": "PREDNISOLONE."
},
{
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{
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"medicinalproduct": "LORATADINE."
},
{
"actiondrug": "2",
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},
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"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugstartdateformat": null,
"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "007",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CICLOSPORIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
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"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "RASH",
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"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DEXAMETHASONE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash maculo-papular",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nephropathy toxic",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Confusional state",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Metabolic acidosis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia aspiration",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Hyperkalaemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Disease progression",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Generalised oedema",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "RANDHAWA M, ARCHER C, GAUGHRAN G, MILLER A, MOREY A, DUA D ET AL.. COMBINED IMMUNE THERAPY GRADE IV DERMATITIS IN METASTATIC MELANOMA. ASIA-PAC. J. CLIN. ONCOL.. 2019?15:262-5",
"literaturereference_normalized": "combined immune therapy grade iv dermatitis in metastatic melanoma",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20190802",
"receivedate": "20190802",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16664154,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20191004"
},
{
"companynumb": "AU-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-025195",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "3 MILLIGRAM/KILOGRAM, Q3WK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "METASTATIC MALIGNANT MELANOMA",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "201711",
"drugstartdateformat": "610",
"drugstructuredosagenumb": "3",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "IPILIMUMAB"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "125554",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1 MILLIGRAM/KILOGRAM, Q3WK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "METASTATIC MALIGNANT MELANOMA",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "201711",
"drugstartdateformat": "610",
"drugstructuredosagenumb": "1",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "NIVOLUMAB"
}
],
"patientagegroup": null,
"patientonsetage": "63",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lichenoid keratosis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "RANDHAWA M, ARCHER C, GAUGHRAN G, MILLER A, MOREY A, DUA D, ET AL.. COMBINED IMMUNE THERAPY GRADE IV DERMATITIS IN METASTATIC MELANOMA. ASIA?PACIFIC JOURNAL OF CLINICAL ONCOLOGY. 2019?1?4",
"literaturereference_normalized": "combined immune therapy grade iv dermatitis in metastatic melanoma",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20210330",
"receivedate": "20190315",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16076712,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210419"
}
] |
{
"abstract": "Fludarabine is a highly effective chemotherapeutic agent for chronic lymphocytic leukemia/small lymphocytic lymphoma and is also active in other B-cell lymphoproliferative disorders. Although highly efficacious in destroying the malignant B-cells, fludarabine also causes T-cell lymphopenia and immunosuppression. We present five patients given fludarabine for low-grade B-cell lymphoproliferative disorders who showed transformation of the primary neoplasm to a higher grade tumor. Immunohistologic antibody studies were performed on paraffin-embedded tissue sections of the initial tissue (when available) and on the follow-up biopsy specimens for CD20, CD3, CD45RO, CD43, CD30, CD15, and latent membrane protein (LMP-1) for Epstein-Barr virus (EBV). The initial diagnoses in these five patients included chronic lymphocytic leukemia/small lymphocytic lymphoma (three cases), follicle center lymphoma (one case), and Waldenstrom's macroglobulinemia (one case). All of the follow-up biopsy specimens showed scattered Hodgkin's-like cells, and two of the five also showed foci of large-cell transformation. The Hodgkin's-like cells showed CD30 immunoreactivity in four of the five cases and CD15 immunoreactivity in three of the five. Strong immunoreactivity of the large, atypical, Hodgkin's-like cells for LMP-1 of EBV was noted in four cases; in the remaining case, this finding was equivocal. In situ hybridization for EBV-encoded RNA was positive in four of the five cases. Molecular studies by polymerase chain reaction (PCR) showed the presence of EBV in three of the five cases. PCR for detection of immunoglobulin heavy chain demonstrated identical monoclonal rearrangements in the original lymphoma and transformation in one case with available material. The CD4 lymphocyte count in each patient was less than 550/microL, indicating cellular dysfunction. Transformation of low-grade non-Hodgkin's lymphomas after fludarabine therapy might be associated with EBV and severe immunosuppression.",
"affiliations": "Department of Pathology, Walter Reed Army Medical Center, Washington, D.C., USA.",
"authors": "Shields|D J|DJ|;Byrd|J C|JC|;Abbondanzo|S L|SL|;Lichy|J H|JH|;Diehl|L F|LF|;Aguilera|N I|NI|",
"chemical_list": "D015703:Antigens, CD; D000956:Antigens, Viral; D000970:Antineoplastic Agents; D017931:DNA Primers; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D012367:RNA, Viral; D014763:Viral Matrix Proteins; D014740:Vidarabine; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"literaturereference": "SHIELDS, D.. DETECTION OF EPSTEIN- BARR VIRUS IN TRANSFORMATIONS OF LOW-GRADE B-CELL LYMPHOMAS AFTER FLUDARABINE TREATMENT. MODERN PATHOLOGY. 1997?10 (11):1151-1159",
"literaturereference_normalized": "detection of epstein barr virus in transformations of low grade b cell lymphomas after fludarabine treatment",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190318",
"receivedate": "20190318",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 16084703,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190418"
}
] |
{
"abstract": "Background and Purpose- There are limited data on intravenous thrombolysis treatment in patients with ischemic stroke who have received prophylactic doses of low molecular weight heparins (LMWHs). We aimed to evaluate the safety and outcomes of intravenous thrombolysis treatment in stroke patients taking thromboprophylactic doses of LMWH. Methods- We analyzed 109 291patients treated with intravenous thrombolysis, recorded in the Safe Implementation of Treatments in Stroke International Thrombolysis Register between 2003 and 2017 not taking oral anticoagulants or therapeutic doses of heparin at stroke onset. One thousand four hundred eleven patients (1.3%) were on prophylactic LMWH for deep venous thrombosis prevention. Outcome measures were symptomatic intracerebral hemorrhage, parenchymal hematoma, death within 7 days and 3 months, and functional dependency at 3 months. Results- Patients on LMWH were older, had more severe strokes, more prestroke disability, and comorbidities than patients without LMWH. There was no significant increase in adjusted odds ratios (aOR) for symptomatic intracerebral hemorrhage (aOR, 1.02 [95% CI, 0.48-2.17] as per Safe Implementation of Treatments in Stroke -MOST, aOR, 0.95 [0.59-1.53] per ECASS II]), nor for 7-day mortality (aOR, 1.14 [0.82-1.59]), in the prophylactic LMWH group. The LMWH group had a higher aOR for 3-month mortality (aOR, 1.94 [1.49-2.53]) and functional dependency, aOR, 1.44 (1.10-1.90). Propensity score analysis matching patients on baseline characteristics removed differences between groups on all outcomes except 3-month mortality. Conclusions- Intravenous thrombolysis in patients with acute ischemic stroke on treatment with prophylactic doses of LMWH at stroke onset is not associated with an increased risk of symptomatic intracerebral hemorrhage or early death.",
"affiliations": "From the Department of Clinical Neurosciences, Karolinska Institutet and Department of Neurology Karolinska University Hospital, Stockholm, Sweden (C.C., M.M., N.A.).;From the Department of Clinical Neurosciences, Karolinska Institutet and Department of Neurology Karolinska University Hospital, Stockholm, Sweden (C.C., M.M., N.A.).;International Clinical Research Center and Neurology Department, St Anne's University Hospital in Brno, Masaryk University, Czech Republic (R.M.).;Neurocentre, Regional Hospital Liberec, Czech Republic (L.J.).;Faculty Hospital Nitra, Constantine Philosopher University, Slovakia (M.B.).;Department of Neurology, Heidelberg University Hospital, Germany (P.R.).;University of Newcastle upon Tyne and Newcastle upon Tyne Hospitals NHS Foundation Trust (A.D.).;Emergency Department Stroke Unit, Hospital Policlinico Umberto I, Department of Neurology and Psychiatry, Sapienza University, Rome, Italy (D.T.).;From the Department of Clinical Neurosciences, Karolinska Institutet and Department of Neurology Karolinska University Hospital, Stockholm, Sweden (C.C., M.M., N.A.).",
"authors": "Cooray|Charith|C|;Mazya|Michael|M|;Mikulik|Robert|R|;Jurak|Lubomir|L|;Brozman|Miroslav|M|;Ringleb|Peter|P|;Dixit|Anand|A|;Toni|Danilo|D|;Ahmed|Niaz|N|",
"chemical_list": "D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight",
"country": "United States",
"delete": false,
"doi": "10.1161/STROKEAHA.118.024575",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0039-2499",
"issue": "50(5)",
"journal": "Stroke",
"keywords": "cerebral hemorrhage; comorbidities; hematoma; heparin; thrombosis",
"medline_ta": "Stroke",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000925:Anticoagulants; D005260:Female; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D008297:Male; D065129:Pre-Exposure Prophylaxis; D020521:Stroke; D015912:Thrombolytic Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "0235266",
"other_id": null,
"pages": "1149-1155",
"pmc": null,
"pmid": "30943884",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety and Outcome of Intravenous Thrombolysis in Stroke Patients on Prophylactic Doses of Low Molecular Weight Heparins at Stroke Onset.",
"title_normalized": "safety and outcome of intravenous thrombolysis in stroke patients on prophylactic doses of low molecular weight heparins at stroke onset"
} | [
{
"companynumb": "SE-ROCHE-2345723",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": "3",
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"drugindication": "CEREBROVASCULAR ACCIDENT PROPHYLAXIS",
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"medicinalproduct": "LOW MOLECULAR WEIGHT HEPARIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "103172",
"drugbatchnumb": "UNKNOWN",
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"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": null,
"drugenddate": null,
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"drugindication": "ISCHAEMIC STROKE",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "ALTEPLASE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Haematoma",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cerebral haemorrhage",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "COORAY C, MAZYA M, MIKULIK R, JURAK L, BROZMAN M, RINGLEB P, DIXIT, A, TONI D AND AHMED N. SAFETY AND OUTCOME OF INTRAVENOUS THROMBOLYSIS IN STROKE PATIENTS ON PROPHYLACTIC DOSES OF LOW MOLECULAR WEIGHT HEPARINS AT STROKE ONSET.. STROKE 2019?50 (5):1149-1155.",
"literaturereference_normalized": "safety and outcome of intravenous thrombolysis in stroke patients on prophylactic doses of low molecular weight heparins at stroke onset",
"qualification": "1",
"reportercountry": "SE"
},
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"receiptdate": "20190703",
"receivedate": "20190703",
"receiver": {
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"receivertype": "6"
},
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"safetyreportversion": 1,
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191004"
}
] |
{
"abstract": "Since lacosamide was approved as an adjuvant agent for the treatment of medically refractory focal epilepsy over ten years ago, it is becoming more widely used for the treatment of idiopathic (genetic) generalized epilepsies. Several studies have demonstrated efficacy in reducing primary generalized tonic-clonic seizures (GTCS), but efficacy is less well-characterized for myoclonic and absence seizures. A 29-year-old man with juvenile myoclonic epilepsy and medically refractory GTCS on a combination of levetiracetam and topiramate was started on lacosamide adjunctive therapy with the plan to replace topiramate. While his GTCS became controlled, he was witnessed to have confusional episodes, with waxing and waning responsiveness, lasting a few days, several times a month. After eight months of adjunctive lacosamide therapy, he was admitted to the epilepsy monitoring unit, where paroxysms of generalized spike-and-wave complexes, lasting for 30-90 minutes, were recorded, interrupted only by sleep. During these periods, he demonstrated psychomotor slowing and disorientation on examination. The absence status was successfully broken by lorazepam, and lacosamide was discontinued. The patient had no further confusional episodes at the most recent follow-up visit, four months after discharge.",
"affiliations": "Department of Neurology and South Texas Comprehensive Epilepsy Center, UT Health San Antonio, San Antonio, Texas.;Department of Neurology and South Texas Comprehensive Epilepsy Center, UT Health San Antonio, San Antonio, Texas.;Department of Neurology and South Texas Comprehensive Epilepsy Center, UT Health San Antonio, San Antonio, Texas.;Department of Neurology and South Texas Comprehensive Epilepsy Center, UT Health San Antonio, San Antonio, Texas.",
"authors": "Ákos Szabó|Charles|C|;Morgan|Lola C|LC|;Sonnenberg|Suzanne|S|;Karkar|Kameel M|KM|",
"chemical_list": "D000927:Anticonvulsants; D000078334:Lacosamide",
"country": "France",
"delete": false,
"doi": "10.1684/epd.2019.1032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "21(1)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "absence status; antiepileptic medications; idiopathic generalized epilepsy; lacosamide; seizure aggravation",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D000069279:Drug Resistant Epilepsy; D004359:Drug Therapy, Combination; D006801:Humans; D000078334:Lacosamide; D008297:Male; D020190:Myoclonic Epilepsy, Juvenile; D012640:Seizures; D013226:Status Epilepticus",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "97-101",
"pmc": null,
"pmid": "30782579",
"pubdate": "2019-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Absence status induced by lacosamide adjunctive therapy.",
"title_normalized": "absence status induced by lacosamide adjunctive therapy"
} | [
{
"companynumb": "US-TEVA-2019-US-1081335",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "ETHOSUXIMIDE"
},
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"drugindication": "PETIT MAL EPILEPSY",
"drugintervaldosagedefinition": "804",
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"drugstructuredosagenumb": "500",
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"medicinalproduct": "ETHOSUXIMIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
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"drugindication": "GENERALISED TONIC-CLONIC SEIZURE",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "LEVETIRACETAM."
},
{
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"medicinalproduct": "ETHOSUXIMIDE."
},
{
"actiondrug": "5",
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},
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{
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{
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"drugdosagetext": "INITIAL DOSE UNKNOWN; FURTHER TITRATED TO 500MG DAILY",
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"drugindication": "GENERALISED TONIC-CLONIC SEIZURE",
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"medicinalproduct": "LACOSAMIDE."
},
{
"actiondrug": "5",
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"activesubstancename": "FENOFIBRATE"
},
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"drugenddateformat": null,
"drugindication": "HYPERLIPIDAEMIA",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "FENOFIBRATE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
"drugadministrationroute": "065",
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"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "UNKNOWN INITIAL DOSAGE",
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"drugindication": "GENERALISED TONIC-CLONIC SEIZURE",
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"medicinalproduct": "LEVETIRACETAM."
}
],
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"patientonsetage": "29",
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Drug intolerance",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hiccups",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "AKOS SZABO C, MORGAN LC, SONNENBERG S, KARKAR KM. ABSENCE STATUS INDUCED BY LACOSAMIDE ADJUNCTIVE THERAPY. EPILEPTIC-DISORD 2019?21(1):97-101.",
"literaturereference_normalized": "absence status induced by lacosamide adjunctive therapy",
"qualification": "3",
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},
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"receiptdate": "20190724",
"receivedate": "20190724",
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"receivertype": "6"
},
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"safetyreportversion": 1,
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"sendertype": "2"
},
"serious": 2,
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"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191004"
},
{
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},
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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},
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"medicinalproduct": "FENOFIBRATE."
},
{
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"activesubstancename": "TRAZODONE HYDROCHLORIDE"
},
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"medicinalproduct": "TRAZODONE"
},
{
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},
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{
"abstract": "The clinical spectrum of Neisseria meningitidis can range from nasopharyngeal colonization to life-threatening invasive diseases such as meningitis. However, its etiologic role in invasive pyomyositis (PM) has never been reported before in the English language. In this study, we report the first case of PM in the English language and the second case in the literature caused by N meningitidis.",
"affiliations": "Division of Gastroenterology & Hepatology.;Division of Infectious Disease & Geographic Medicine.;Department of Medicine.;Department of Radiology.;Department of Medicine.;Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Toxoplasma Serology Laboratory, National Reference Center for the Study and Diagnosis of Toxoplasmosis, Palo Alto, California.",
"authors": "Barakat|Monique T|MT|;Gajurel|Kiran|K|;Fischer|Katrina|K|;Stevens|Kathryn|K|;Ozdalga|Errol|E|;Montoya|José G|JG|",
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"fulltext": "\n==== Front\nOpen Forum Infect DisOpen Forum Infect DisofidofidsOpen Forum Infectious Diseases2328-8957Oxford University Press 10.1093/ofid/ofw087ofw087Review ArticlesA Case of Meningococcal Pyomyositis in an Otherwise Healthy Adult Barakat Monique T. 1Gajurel Kiran 2Fischer Katrina 3Stevens Kathryn 4Ozdalga Errol 3Montoya José G. 561 Division of Gastroenterology & Hepatology2 Division of Infectious Disease & Geographic Medicine3 Department of Medicine4 Department of Radiology5 Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine6 Toxoplasma Serology Laboratory, National Reference Center for the Study and Diagnosis of Toxoplasmosis, Palo Alto, CaliforniaCorrespondence: M. T. Barakat, Division of Gastroenterology & Hepatology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 (barakat@stanford.edu).9 2016 29 6 2016 3 3 ofw08720 1 2016 29 4 2016 © The Author 2016. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.2016This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.The clinical spectrum of Neisseria meningitidis can range from nasopharyngeal colonization to life-threatening invasive diseases such as meningitis. However, its etiologic role in invasive pyomyositis (PM) has never been reported before in the English language. In this study, we report the first case of PM in the English language and the second case in the literature caused by N meningitidis.\n\ncellulitismeningococcusmyositisNeisseria meningitidispyomyositis cover-dateSummer 2016\n==== Body\nBacterial pyomyositis (PM) is an infection of the skeletal muscle and is an uncommon complication of bacteremia [1, 2]. Also called tropical PM, it is primarily reported in the tropics, where it accounts for up to 4% hospitalizations [3]. It is usually caused by Staphylococcus aureus [4–6]. Pyomyositis caused by Gram-negative bacteria is rare, but it is thought to be more common in temperate climates, especially in people with underlying comorbid conditions [5]. In an extensive review of Gram-negative bacteria-associated PM, 180 cases were described between 1979 and 2011, with Escherichia coli, Salmonella, and Klebsiella species being the predominant pathogens [7]. To the best of our knowledge, PM caused by Neisseria meningitidis (meningococcus), a Gram-negative bacterium, has never been described in the English language. In this study, we report the first case of invasive meningococcal PM in the English language.\n\nINITIAL PRESENTATION AND HOSPITAL COURSE\nThe patient is a 45-year-old man who developed a cough, rhinorrhea, and sore throat after his children and wife had developed similar symptoms. His past medical history included hypertension. His symptoms gradually improved over the course of 10 days, when he spiked a fever to 103°F and developed profound pain in the lower back and left thigh. He was urgently evaluated and found to be tachycardic with a pulse rate of 115 per minute, a blood pressure of 109/65 millimeter mercury, an oxygen saturation of 98% on room air, and fever of 103.2°F. There was tenderness and faint erythema over the lumbar paraspinal muscles and medial aspect of his left thigh, with overlying edema. He had a limited range of motion of the left leg due to muscle weakness and pain.\n\nHe did not report headache, neck stiffness, or confusion. There was no significant history of tobacco or alcohol use. He denied the use of illicit drugs or supplements. He had recently visited Hawaii but had not traveled outside the United States for the past several years. There was no exposure to animals other than his family dog and cat, and he denied recent insect bites. His family history was noncontributory.\n\nHe was admitted to a hospital, blood cultures were drawn, and he was started on vancomycin, clindamycin, and piperacillin/tazobactam. His fever improved with ibuprofen and acetaminophen, but it consistently recurred within 6 hours of dosing each of these agents. Blood cultures grew N meningitidis, and antibiotic coverage was narrowed to penicillin G 3 days after presentation. After this transition, his white blood cell count (WBC) rose from 11 000/mm3 to 14 000/mm3 and he remained febrile, with fevers up to 103°F multiple times per day. The following day, he developed worsening erythema and pain in the left thigh and back and new erythema and pain on the dorsum of his left hand. A magnetic resonance imaging (MRI) study of the thoracic spine was performed and showed edema and enhancement of the left paraspinal muscles compatible with myositis (Figure 1). An MRI scan of the thigh demonstrated edema and enhancement in the anterior and medial muscle compartments of the left thigh (Figure 2). The vastus medialis muscle in particular was enlarged and edematous. There were a few ill-defined areas of patchy nonenhancement in the vastus medialis, but no rim-enhancing fluid collections to suggest abscess. At this time, the patient requested a transfer to a tertiary referral center for more specialized care.\nFigure 1. Axial T2 (A) and T1-weighted (B) images with fat saturation through the thoracolumbar region after intravenous gadolinium administration demonstrating high T2 signal and enhancement in the left paraspinal muscles (arrows), and there is prominent edema in the overlying soft tissues.\n\n\nFigure 2. Axial T2 (A) and T1-weighted (B) images with fat saturation through the left mid-thigh after intravenous gadolinium administration demonstrate edema and enhancement in the anteromedial thigh musculature, with a swollen and edematous vastus medialis (VM) muscle. High T2 signal and enhancement also tracks along the interfascial planes, most marked around the sartorius muscle (S) (arrows).\n\n\n\nUpon presentation to Stanford University Hospital, the patient had received 5 days of antibiotic therapy (3 days with vancomycin, clindamycin, and piperacillin/tazobactam and 2 days with penicillin G). His WBC was 15 400/mm3 (65% polymorphonuclear cells, 10% bands), and erythrocyte sedimentation rate was 112 millimeter per hour. The patient had mild elevation of the transaminases at presentation, which was thought to be due to muscle involvement, but had a normal creatine kinase. The left thigh was erythematous and edematous from the groin to the knee, nontender, with significant progression of erythema beyond the demarcation line drawn at the local hospital (Figure 3). He also had nonerythematous swelling of the left knee, but no joint effusion or pain with range of motion, and no evidence of hip joint involvement. Nontender erythema was also noted over the bilateral paraspinal muscles from L1 extending down to the gluteal cleft. His clinical presentation was thought to be due to PM from N meningitidis. He shortly became febrile to 101°F, and his antibiotic regimen was broadened to ceftriaxone and vancomycin due to presumed lack of response. The following day, there was significant improvement of erythema over the left thigh and back, and the leukocytosis had decreased to 11 800/mm3. A MRI of the thoracolumbar spine again revealed diffuse edema and enhancement in the left paraspinal musculature, with no rim-enhancing fluid collections. There was marked edema in the subcutaneous tissues of the lower back, measuring at least 20 cm in the transverse dimension and 26 cm craniocaudally. A follow-up MRI examination of the thigh again revealed edema and enhancement in the anterior and medial compartment musculature of the thigh. However, small foci of nonenhancing muscle with peripheral enhancement were now seen within the vastus medialis muscle, compatible with discrete areas of muscle necrosis (Figure 4). There was decreased edema and enhancement in the overlying subcutaneous tissues and along the interfascial planes compared with the earlier scan. General surgery was consulted and, given the absence of frank abscess, opted to defer surgical management. He remained intermittently febrile throughout the next 24 hours, and ceftriaxone was increased to 2 grams every 12 hours. He also began to describe intermittent pain and swelling of his right groin. On examination, he had mild right inguinal fullness but was nontender, with minimal overlying erythema.\nFigure 3. Cellulitis is seen over sites of radiologically documented muscle inflammation in the medial thigh (A and B) and paraspinal regions (C and D), clearly progressing beyond the previously marked margins. Cellulitis is also seen over the dorsum of the left hand (E), in a distribution clinically thought to reflect underlying tenosynovitis.\n\n\nFigure 4. Follow-up magnetic resonance imaging (MRI) 4 days later. Axial T2 (A) and T1-weighted (B) images with fat saturation through the left mid-thigh after intravenous gadolinium administration demonstrate persistent edema and enhancement in the anteromedial thigh musculature, with a swollen and edematous vastus medialis (VM). However, there is now a small focus of nonenhancing muscle in the vastus medialis muscle (arrow) but no corresponding high signal intensity fluid collection on the T2-weighted image (arrow). Decreased edema and enhancement is seen in the subcutaneous tissues compared with the MRI scan 4 days earlier.\n\n\n\nOn hospital day 8, the patient remained afebrile, his leukocytosis steadily decreased, erythema and edema continued to improve, and knee swelling resolved. Vancomycin was discontinued on hospital day 8. Repeat blood cultures were negative, and he was discharged home to complete a 2-week course of ceftriaxone. The patient recovered completely and almost 1 year later after the illness he is doing well without any local or systemic sequelae. His initial blood cultures were sent to the Microbial Diseases Laboratory of the California Department of Public Health, eventually returning as N meningitidis capsular group C. Of note, the patient's children spontaneously recovered from their illnesses, but the patient's wife developed respiratory distress and epiglottitis for which she was hospitalized, and she was also found to have N meningitidis, isolated from a pharyngeal swab.\n\nDISCUSSION\nNeisseria meningitidis can present with a wide spectrum of clinical manifestation ranging from colonization in the nasopharynx to devastating invasive diseases. Even in the antibiotic era, invasive meningococcal disease carries a high case fatality rate of 10%–15%, and another 10%–20% of survivors experience long-term complications that include amputation and neurologic deficits [8–10]. Meningitis and meningococcemia are the most common forms of invasive disease. Other less commonly reported clinical presentations are pneumonia, septic arthritic, pericarditis, conjunctivitis, sinusitis, epiglottitis, urethritis, and proctitis [11]. Although petechial and ecchymotic lesions have been commonly associated with invasive meningococcal disease, PM and cutaneous infections such as abscesses and cellulitis are uncommon and are not mentioned even in standard reference textbooks of infectious diseases. There is only 1 reported case of a cutaneous abscess associated with thyroglossal duct cyst that was successfully treated with drainage and antimicrobials [12]. Seventeen cases of meningococcal cellulitis have been described to date, and 13 of them were recently reviewed by Ozaki et al [13–16]. Thirteen of the 17 cases were described in females. Almost 60% had bacteremia detected. Nine cases occurred in children and 8 in adults. Children typically presented with periorbital cellulitis, whereas extremity involvement was more common in males. Sixty-seven percent of adults and none of the children had underlying comorbidities. The outcome was generally good, with only 1 attributed death. However, none of these cases were reported to have PM, although it is possible that some patients could have had unrecognized underlying muscle inflammation [17]. In fact, no cases of primary invasive meningococcal PM have been reported in the English language, even though proinflammatory cytokine-induced myositis (as evidenced by myalgia and elevated creatinine kinase) has been described [18]. We are aware of only 1 prior case of meningococcal PM reported in the French literature [19]. It describes a 7-year-old male child with right hip septic arthritis with associated osteomyelitis of the acetabulum who developed bilateral pelvic muscle abscesses. The blood, right hip synovial fluid, and left pelvic muscle cultures were sterile, but a polymerase chain reaction analysis of right hip synovial fluid confirmed capsular group B N meningitidis.\n\nWe believe our patient had early invasive PM rather than cytokine-induced myositis based on the fact that there was cellulitis overlying sites of radiologically documented muscle inflammation in the thigh and paraspinal muscles. The vastus medialis muscle in particular was diffusely swollen and edematous, with mildly heterogeneous enhancement at initial presentation. Edema and enhancement was also seen in the adjacent fascial planes and overlying subcutaneous tissues. Antibiotic therapy was commenced at this point, and it probably prevented the development of abscesses. It should be acknowledged that the confirmation of the etiology of PM was not obtained directly from the soft tissue and was assumed on the basis of positive blood cultures.\n\nThe patient likely developed primary meningococcemia followed by bacterial seeding of the skeletal muscles in the thigh, paraspinal region, and dorsum of the hand in a pattern of multifocal involvement that has been described in up to 43% of cases [6]. Similar to most other cases of bacterial PM, our patient was male and had prominent involvement of the thigh muscles without any history of trauma. Creatinine kinase was also normal, as can be seen in more than 75% cases of bacterial PM [5]. In contrast to other Gram-negative bacteria associated PM, our patient did not have significant medical comorbidities except for hypertension.\n\nCONCLUSIONS\nMeningococcal capsular group C, along with capsular groups B and Y, is responsible for the vast majority of meningococcal disease in the United States [9]. In a recent Canadian Study of invasive meningococcal disease, group C was associated with a worse outcome compared with other capsular groups, but this association was not found to be statistically significant in their multivariate analysis [8]. Meningococcal vaccination against capsular groups A, C, Y, and W is recommended for adolescents and people with risk factors for invasive meningococcal disease. Recently, vaccination against capsular group B has also been recommended for high-risk individuals more than 10 years of age in the United States. It may also be used in adolescents and young adults aged 16–23 without high risk factors for short-term protection [20]. However, it should be noted that different countries have varying schedules of different meningococcal vaccines dependent on local epidemiology, with vaccines currently available for capsular groups A, B, C, W, and Y.\n\nAcknowledgments\nPotential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1 Fowler VG Jr, Olsen MK , Corey GR et al \nClinical identifiers of complicated Staphylococcus aureus bacteremia . Arch Intern Med \n2003 ; 163 :2066 –72 .14504120 \n2 Smith IM , Vickers AB \nNatural history of 338 treated and untreated patients with staphylococcal septicaemia (1936–1955) . Lancet \n1960 ; 1 :1318 –22 .13831996 \n3 Chauhan S , Jain S , Varma S , Chauhan SS \nTropical pyomyositis (myositis tropicans): current perspective . Postgrad Med J \n2004 ; 80 :267 –70 .15138315 \n4 Christin L , Sarosi GA \nPyomyositis in North America: case reports and review . Clin Infect Dis \n1992 ; 15 :668 –77 .1420680 \n5 Crum NF \nBacterial pyomyositis in the United States . Am J Med \n2004 ; 117 :420 –8 .15380499 \n6 Chiedozi LC \nPyomyositis: review of 205 cases in 112 patients . Am J Surg \n1979 ; 137 :255 –9 .426186 \n7 Gousseff M , Lanternier F , Ferroni A et al \nEnterobacter cloacae pyomyositis complicating chronic granulomatous disease and review of Gram-negative bacilli pyomyositis . Eur J Clin Microbiol Infect Dis \n2013 ; 32 :729 –34 .23370968 \n8 Sadarangani M , Scheifele DW , Halperin SA et al \nOutcomes of invasive meningococcaldisease in adults and children in Canada between 2002 and 2011: a prospective cohort study . Clin Infect Dis \n2015 ; 60 :e27 –35 .25605282 \n9 Cohn AC , MacNeil JR , Clark TA et al \nPrevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP) . MMWR Recomm Rep \n2013 ; 62 :1 –28 .23515099 \n10 Cohn AC , MacNeil JR , Harrison LH et al \nChanges in Neisseria meningitidis disease epidemiology in the United States, 1998–2007: implications for prevention of meningococcal disease . Clin Infect Dis \n2010 ; 50 :184 –91 .20001736 \n11 Stephens DS , Bennett JE , Dolin R eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases . 8th ed \nNew York: Elsevier & Saunders , Vol 213 : pp 2425 –2445.e6 .\n12 Gupta R , Levent F , Healy CM , Edwards MS \nUnusual soft tissue manifestations of Neisseria meningitidis infections . Clin Pediatr (Phila) \n2008 ; 47 :400 –3 .18424564 \n13 Ozaki B , Kittai A , Chang S \nNeisseria meningitidis as a cause of facial cellulitis . BMJ Case Rep \n2014 ; 2014 :doi:10.1136/bcr-2014-203774 .\n14 Porras MC , Martinez VC , Ruiz IM et al \nAcute cellulitis: an unusual manifestation of meningococcal disease . Scand J Infect Dis \n2001 ; 33 :56 –9 .11234980 \n15 Guarner J , Greer PW , Whitney A et al \nPathogenesis and diagnosis of human meningococcal disease using immunohistochemical and PCR assays . Am J Clin Pathol \n2004 ; 122 :754 –64 .15491972 \n16 Kennedy KJ , Roy J , Lamberth P \nInvasive meningococcal disease presenting with cellulitis . Med J Aust \n2006 ; 184 :421 .16618247 \n17 Cartolano GL , Barbier C , Arnoult L et al \nFatal acute cellulitis due to Neisseria meningitidis . J Clin Microbiol \n2003 ; 41 :3996 –7 .12904440 \n18 Carrol ED , Thomson AP , Mobbs KJ et al \nMyositis in children with meningococcal disease: a role for tumour necrosis factor-alpha and interleukin-8? \nJ Infect \n2002 ; 44 :17 –21 .11972413 \n19 Rousseau V , Descours G , Chaker M et al \n[Primary meningococcal B osteomyelitis and arthritis with multifocal pyomyositis in a child: a case report] . Arch Pediatr \n2012 ; 19 :1330 –3 .23044033 \n20 Folaranmi T , Rubin L , Martin SW et al \nUse of serogroup B meningococcal vaccines in persons aged >/=10 years at increased risk for serogroup B meningococcal disease: recommendations of the advisory committee on immunization practices, 2015 . MMWR Morb Mortal Wkly Rep \n2015 ; 64 :608 –12 .26068564\n\n",
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"keywords": "Neisseria meningitidis; cellulitis; meningococcus; myositis; pyomyositis",
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"abstract": "Nicotine is the psychoactive agent involved in nicotine dependence. However, nicotine as a drug, and its effects on human psychology are largely under-investigated in genetic studies. In this study, we recruited 208 current non-smokers to evaluate the effect of nicotine and its relationship to genetic risks to nicotine dependence. Exploratory and confirmatory factor analyses, as well as measurement invariance testing, were conducted to evaluate the latent factor structures of the POMS, PANAS and DEN questionnaires across 3 nicotine doses. Structural models were used to examine the effects of nicotine and their relationship to genetic risks of nicotine dependence. We found that nicotine administration led to the change of both measurement construct and factor means, indicating the causal effect of nicotine on the psychological responses. The genotypes of rs588765 predicted the scores of the DEN Confused and Dizzy factors (p = 0.0003 and 0.001 respectively), and rs16969968 and rs588765 were associated with the PANAS Nervous factor (p = 0.006 and 0.007 respectively). Our study suggested that genetic risk of nicotine dependence is associated with acute psychological responses. The integration of psychometric analyses and dose effects could be a powerful approach for genetic study of nicotine dependence.",
"affiliations": "1] Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University [2] Department of Human and Molecular Genetics, Virginia Commonwealth University.;Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University.;Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University.;Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University.;1] Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University [2] Department of Human and Molecular Genetics, Virginia Commonwealth University.;Department of Psychology, West Virginia University.;Department of Psychology and Center for the Study of Tobacco Products, Virginia Commonwealth University.",
"authors": "Chen|Xiangning|X|;Aggen|Steven H|SH|;Chen|Jingchun|J|;Li|Lingxi|L|;Kendler|Kenneth S|KS|;Blank|Melissa|M|;Eissenberg|Thomas|T|",
"chemical_list": "D009538:Nicotine",
"country": "England",
"delete": false,
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"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group srep0952110.1038/srep0952125826680ArticleGenetic Risks to Nicotine Dependence Predict Negative Mood and Affect in Current Non-Smokers Chen Xiangning a12Aggen Steven H. 1Chen Jingchun 1Li Lingxi 1Kendler Kenneth S. 12Blank Melissa 3Eissenberg Thomas 41 Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University2 Department of Human and Molecular Genetics, Virginia Commonwealth University3 Department of Psychology, West Virginia University4 Department of Psychology and Center for the Study of Tobacco Products, Virginia Commonwealth Universitya xchen@vcu.edu31 03 2015 2015 5 952112 10 2014 10 03 2015 Copyright © 2015, Macmillan Publishers Limited. All rights reserved2015Macmillan Publishers Limited. All rights reservedThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Nicotine is the psychoactive agent involved in nicotine dependence. However, nicotine as a drug, and its effects on human psychology are largely under-investigated in genetic studies. In this study, we recruited 208 current non-smokers to evaluate the effect of nicotine and its relationship to genetic risks to nicotine dependence. Exploratory and confirmatory factor analyses, as well as measurement invariance testing, were conducted to evaluate the latent factor structures of the POMS, PANAS and DEN questionnaires across 3 nicotine doses. Structural models were used to examine the effects of nicotine and their relationship to genetic risks of nicotine dependence. We found that nicotine administration led to the change of both measurement construct and factor means, indicating the causal effect of nicotine on the psychological responses. The genotypes of rs588765 predicted the scores of the DEN Confused and Dizzy factors (p = 0.0003 and 0.001 respectively), and rs16969968 and rs588765 were associated with the PANAS Nervous factor (p = 0.006 and 0.007 respectively). Our study suggested that genetic risk of nicotine dependence is associated with acute psychological responses. The integration of psychometric analyses and dose effects could be a powerful approach for genetic study of nicotine dependence.\n==== Body\nIn the last several years, genetic studies of smoking and nicotine dependence have made significant progress, exemplified by the identification of the CHRNA5-CHRNA3-CHRNB4 locus. Genetic variants at this locus have been shown to be associated with a number of smoking phenotypes such as the number of cigarettes smoked per day1234, nicotine dependence as defined by DSM IV56 and the Fagerström Test for Nicotine Dependence78, age of smoking onset5910 and plasma cotinine concentration11. This locus includes the CHRNA5, CHRNA3 and CHRNB4 genes. While a non-synonymous SNP, rs16969968, in the CHRNA5 gene has emerged as a functional candidate, it may not be the one tagging the strongest association signal12. Further analyses reveal that there are multiple statistically independent association signals at this locus, represented by SNPs rs16969968, rs588765 and rs57877613.\n\nNicotine, the primary psychoactive substance in cigarette smoke, has broad psychological effects on humans14. When first exposed to nicotine, either by smoking or other routes of administration, some people feel pleasant and relaxed, while others feel dizzy and nauseous. These initial responses to nicotine have significant impacts on sustained smoking and subsequent development of nicotine dependence15161718. However, in a typical genetic study, the psychological effects of nicotine are rarely utilized and included in association testing. This omission is due, in part, to the fact that little is known of the relationship between these effects and genetic risks of nicotine dependence. In the literature, there are a few reports on the association between subjective measures and genetic variants in the nicotinic receptors, and some nominal associations are found in the CHRNB3/CHRNA619 and CHRNB220 genes. These studies use the scores of individual items or several items that contribute to a common factor, but these studies do not control for measurement errors and correlations between items, and do not have nicotine dose effect information.\n\nPsychometric analysis with structural equation modeling provides a framework for constructing latent factor structures that can take into account measurement errors, item residual correlations and the degree of invariance across multiple waves of data simultaneously. In theory, it can identify and differentiate “true” treatment responses from confounding effects, attribute responses directly to experimental treatments (nicotine administration and dosage), and permit the test of genetic effects on these responses. Thus, integration of structural modeling with association testing may improve statistical power when well targeted hypotheses are postulated. To demonstrate the utility and advantage of this approach, we conducted a pilot study to evaluate the relationship between genetic risks of nicotine dependence and the subjective responses resulting from nicotine administration. We hypothesized that genetic risks of nicotine dependence contributed to subjective responses, and that by integrating psychometric modeling of psychological effects and dose effects we could improve statistical power to detect this genetic association. In a lab setting, we recruited 208 non-smokers, and measured their psychological responses via self-report by the Profile of Mood State (POMS)21, the Positive and Negative Affect Scale (PANAS)22, and the Direct Effects of Nicotine scale (DEN)23 after administration of each of a series of nicotine doses. We used the 3 SNPs (rs16969968, rs588765 and rs578776) that were shown to be associated independently with smoking quantity at the CHRNA5-CHRNA3-CHRNB4 locus13 as an example. In this article, we report the results of this pilot study.\n\nResults\nOur primary goals were to evaluate how nicotine administration influenced subject's mood and affect as measured by the POMS, PANAS and DEN, and whether mood states and affect were influenced by genetic risks of nicotine dependence using the established markers from the CHRNA5-CHRNA3-CHRNB4 locus. Towards these goals, we needed first to examine the latent factor structures of the items of the instruments, and to evaluate whether the latent measurement factor structures remained equivalent (i.e. statistically invariant) after the administration of different nicotine doses using measurement invariance (MI) testing procedures. A failure in the MI testing would provide evidence that the latent factor(s) and the individual differences they represent were not constructed equivalently across the nicotine administrations, i.e., individual differences on the latent factors were not calibrated in the same way across administrations, presumably due to differential item responses attributable to the administration of different amounts of nicotine. Second, given the factor structures, we could test the association between the factors and genetic variants, and compare effects of the association across different dosage.\n\nExploratory factor analyses of the POMS, PANAS and DEN\nAfter removing poorly responded to items, we conducted exploratory factor analyses (EFA) for the POMS, PANAS and DEN item sets. In the analyses of the POMS, 24 items were included. Specifically, we conducted exploratory analyses for the 0 mg, 2 mg and 4 mg gum sessions separately, extracting 3-, 4-, 5- and 6-factor solutions respectively. A 5-factor solution fit the data adequately as judged by the root mean square of the residuals (RMSR), root mean square error of approximation (RMSEA), Tucker-Lewis Index (TLI) and χ2 test collectively (Table S1). For example, for the 0 mg nicotine administration, compared to the 4-factor solution, the 5-factor solution had better χ2\nP value (0.0028 vs. 1.0E-6), RMSEA (0.045 vs. 0.057) and TLI (0.968 vs. 0.945), while the RMSR (0.03 vs. 0.03) was comparable. EFAs of the 2 and 4 mg of nicotine administration showed the same results. Further examination revealed that while the items consistently loaded onto the same factors (configural invariance), some loadings displayed differences across the 3 nicotine dosages (Table S2). The 5-factor solution included 3 positive and 2 negative factors. The first positive factor, labeled Friendly, consisted of 7 items (Friendly, Considerate, Efficient, Helpful, Cheerful, Good Natured and Trusting). The second positive factor, labeled Active, consisted of the items of Lively, Active, Energetic, Full of Pep and Vigorous. The third positive factor, labeled Clear Headed, was contributed by 3 items (Clear Headed, Unable to Concentrate (negative loading), and Alert). The negative factors were called On Edge (Tense, On Edge, Uneasy, Restless and Unable to Concentrate) and Fatigued (Worn out, Fatigued and Sluggish). It appeared that the loadings for the Friendly and Active factors changed significantly across the 3 nicotine gum doses while the Clear Headed, Uneasy and Fatigued factors remained stable (Table S2). In the literature, there was a report of a 5-factor structure of the POMS among smokers and non-smokers24. Generally, the POMS items typically are reported to have 6 distinct factors2125. In our EFA using 6-factor solutions, Sympathetic and Care Free had substantial loadings (~0.5) on the 6th factors, but other item's loadings on this sixth factor were below 0.2. For this reason, they were excluded from further analyses.\n\nSimilar analyses were done for the PANAS. The EFA results pointed to a 3-factor structure based on the RMRS, RMSEA, TLI and χ2 test (Table S3). The 3-factor model, after the administration of 0 mg of nicotine, had reasonable absolute fit (RMRS, 0.04) and comparative fit (TLI, 0.075). While the 4-factor model had better absolute and comparative fits comparing to the 3-factor model, no indicator had a reasonable factor loading (maximal λ = 0.42 for all indicators) on the fourth factor. The models for the 2 and 4 mg of nicotine showed the same pattern. Therefore, we decided on the 3-factor solution. The first positive affect factor, labeled Inspired, included the following items: Interested, Excited, Enthusiastic, Proud, Strong, Determined, Inspired and Active. The second positive factor, Attentive, had strong loadings for the items of Interested, Alert, Attentive and Active. Two items, Interested and Active, had substantial cross loading on both factors. The negative factor, Nervous, consisted of the items Distressed, Nervous, Jittery, Afraid and Irritable. The loadings of individual items were also consistent across the 3 nicotine doses (Table S4). Typically, the PANAS shows a 2-factor structure, but in different type of samples, latent structures of more than 2 factors have been reported26. We did not find any report of structural analysis of PANAS with smokers or with nicotine treatment.\n\nThe EFAs of the DEN suggested a 2-factor structure (Table S5). All 10 items had significant loadings (range from 0.23 ~ 0.78) on the first factor. Two items, Dizzy and Light Headed, had significantly higher loadings (0.82–0.94) on a second factor. The cross loadings between the two factors were substantial (Table S6). When forcing a single factor structure, the overall fit was worse than that of a two-factor solution (for example, for the models after administration of 0 mg of nicotine, 1-factor model: RMRS 0.06, TLI 0.873, and χ2 p value 1.9E-14; 2-factor model: RMRS 0.03, TLI 0.964, and χ2 p value 5.8E-3, Table S5). For this reason, we choose the 2-factor model in the subsequent analyses. The 2 factors were Confused and Dizzy. The Confused factor had 7 items (Nauseous, Nervous, Sweaty, Headache, Salivation, Heart Pound, and Confused), and the Dizzy factor had 3 items (Dizzy, Lite Headed and Weak).\n\nInvariance tests for the POMS, PANAS and DEN models\nBased on the results of EFA, confirmatory measurement models were constructed for each of the 3 nicotine administrations for the POMS, PANAS and DEN instruments. Since our sample size was modest, to avoid over parameterization, models for the positive and negative factors were modeled separately. In these common factor models for each administration, correlations among the same item's residuals were allowed across the 3 nicotine doses since assessments were obtained within relatively short time intervals leaving open the possibility of memory carry over. Inter-factor correlations across the doses and between different affect factors (since POMS had 3 positive factors and 2 negative factors, and PANAS had 2 positive factors) were also included. A path diagram of the general measurement model is shown in Figure 1 using the PANAS Nervous factor as an example.\n\nFollowing general guidelines for MI testing, configural invariance was first examined using the confirmatory factor analyses (CFA). Based on the factor models derived from the EFAs, metric (factor loadings) and scalar (thresholds/intercepts) invariance were imposed across the 3 nicotine doses sequentially, and compared to the saturated baseline model using RMSEA, TLI, BIC and χ2 test. The results of the MI tests for the POMS were summarized in Tables 1. The overall model fits of the configural models for POMS were reasonable (three positive factors, CFI 0.994, TLI 0.993, RMSEA from 0.078; two negative factors, CFI 0.999, TLI 0.999, RMSEA 0.024). When the factor loadings were forced to be invariant across the 3 nicotine doses, the change of χ2 was insignificant for the positive factors (Δ χ2 10.5, Δ DF 29, p = 0.9993), and the change of χ2 was nominally significant (Δ χ2 32.2, Δ DF 18, p = 0.0208) for the negative factors. Further constraining the thresholds led to highly significant misfits for both positive and negative factors (positive factors, Δ χ2 397.1, Δ DF 116, p < 2.2E-16; negative factors, Δ χ2 444.5, Δ DF 52, p < 2.2E-16). The overall fit indices were reasonable (CFI 0.988–0.999, TLI 0.988–0.999, RMSEA 0.024–0.078).\n\nSimilar results for the PANAS and DEN were observed (Tables 2 and 3). For the PANAS items, the positive factors model also failed the metric invariance test (Δ χ2 57.9, Δ DF 24, p = 1.24E-4). Overall, the failure of MI tests in all instruments at the metric and/or scalar levels indicated that nicotine administration resulted in differential item functioning for the mood and affect factors measured by the POMS, PANAS and DEN. In other words, we found evidence that volunteers responded differentially to some of the items in these instruments after administration of different doses of nicotine, resulting in the change of factor structure of these instruments. These results provided a solid foundation for testing the association of these nicotine specific effects with genetic variants associated with nicotine dependence.\n\nThe association of genetic risks of nicotine dependence and latent factors\nHaving shown that nicotine administration was related to differential influences on subjects' mood and affect, we proceeded to test if known genetic risks to developing nicotine dependence could predict variation in these psychological measures. We selected 3 SNPs from the CHRNA5-CHRNA3-CHRNB4 locus to test the association between the latent factors identified in our item level analyses and the genotypes of these SNPs. In these models, the factor loadings and thresholds/intercepts of all items were held invariant across the 3 nicotine doses (i.e., as in scalar invariance test, Figure 2A), forcing the effects of nicotine administration to be represented at the latent factors. Under these conditions, we regressed the latent factors onto the SNP genotypes, testing whether SNP genotypes could linearly predict variation in the latent mood factors. The results were summarized in Tables 4–6 for POMS, PANAS and DEN respectively. Regression results suggested that the positive factors and negative factors had different patterns. For the POMS positive factors, the Active factor demonstrated nominally significant association with rs16969968, the most significant finding at the CHRNA5-CHRNA3-CHRNB4 locus. For the negative factors, most of them showed an association with genotypes, although the strength of association was modest. SNP rs588765 was associated with 4 of the 5 negative factors identified in this study. Rs16969968 had association with 3 of the 5 factors. These results indicated that genetic markers associated with nicotine dependence predicted variations in negative mood and affect in current non-smokers, the cohort used in this study. To visualize the results, we computed the Nervous factor scores for the PANAS dataset and plotted them against the genotypes of rs16969968 (Figure 2B). A similar plot was made for the DEN Confused factor and rs588765 (Figure 2C). Of note, subjects carrying the risk alleles (the A allele of rs16969968 and the C allele of rs588765) had lower negative factor scores, indicating that these subjects tended to be less negative on nicotine ingestion as compared to subjects not carrying the risk alleles.\n\nIn these analyses, we tested the association of 3 SNPs with the latent factors identified in our measurement models across 3 nicotine doses. The factors from the POMS, PANAS and DEN measured different aspects of mood and affect, but they were not independent. For example, the correlation between the factors varied from 0.3 to 0.9 for the DEN. The effects of nicotine on these factors were most likely accumulative, i.e. the effects observed at 4 mg were the sum of 2 and 4 mg of nicotine, because it took 30–45 min to reach maximal plasma nicotine concentration after gum administration2728. How to correct for multiple testing was an important issue in evaluating the significance of these tests. If we combined all positive and negative factors in each instrument, and considered the 3 SNPs independent, we needed to correct for 15 tests (2 positive factors and 3 negative factors, for 3 SNPs). Under these conditions, rs588765 was associated with DEN factors (Confused at 4 mg, p = 0.0003 and Dizzy at 0 mg, p = 0.001). rs588765 and rs16969968 showed a trend for the PANAS Nervous at 4 mg (p = 0.006 and 0.007 respectively). None of the positive factors survived this correction.\n\nTo evaluate how nicotine dose influenced the mood and affective states of volunteers, we conducted post hoc analyses for the DEN factors that showed significant association with genotypes. In these analyses, we compared the fit indices between two models: the SNP model, with scalar invariance and SNP as exogenous predictor (Figure 2A), and a constrained SNP model, which added constraints on the regression coefficients of SNP prediction by setting paths a, b, and c in Figure 2A to be invariant. The results were summarized in Table 7. When the regression coefficients were forced to be equal across the 3 nicotine doses, it caused significant misfit of the constrained model for SNP rs588765, the marker showing significant association with the factors in this study. These results implied that the regression coefficients (effect sizes) for rs588765 on DEN factors were statistically different across the nicotine doses. Since the coefficients increased from 0 mg to 4 mg (Table 6), it could be interpreted that the change of effect sizes was proportional to the amount of nicotine administered.\n\nDiscussion\nIn this study, current non-smokers were recruited to examine the effects of nicotine administration on their responses to the POMS, PANAS and DEN instruments. Our objectives were to evaluate whether previously identified genetic risks for nicotine dependence (i.e., SNPs at the CHRNA5 locus) predicted variation of self-reported subjective states using psychometric analyses with structural equation modeling. We performed exploratory and confirmatory factor analyses to determine the factor structures of these instruments. Based on these structures, we carried out MI testing to evaluate if the administration of increasing levels of nicotine had an impact on the structures. We further tested whether known genetic variants were associated with these affective factors. The main findings of our study were two-fold: 1) Using increasing nicotine doses and repeated measures with standard instruments, we found that nicotine administration had significant differential impacts on the mood measurement structures for both positive and negative affect in current non-smokers, implying that nicotine dose had direct and measurable effects on items assessing mood and affect; and 2) Variation in mood and affect states under forced MI models were predicted by previously identified genetic risk factors of nicotine dependence, suggesting that the effects of nicotine on mood and affect were linked to genetic risks of nicotine dependence. Furthermore, post hoc analyses of rs588765 suggested that the effect might be proportional to the amount of nicotine administered.\n\nOur findings have important implications. Traditionally, genetic studies of nicotine dependence use smokers (current smokers and/or ex-smokers), and phenotype ascertainments focus on behavioral outcomes (e.g., number and/or duration of cigarette use). The effects of nicotine as a drug on mood and affect are rarely incorporated. Our study is the first, to our knowledge, to provide direct evidence that psychological effects of nicotine can be used for genetic studies of nicotine dependence in current non-smokers. When we designed the study, we decided to use current non-smokers to avoid the complication of neuroadaptive changes associated with cigarette smoking29. We reasoned that subjects with minimal exposure would be better to measure the psychological effects of nicotine. Can we use these same psychological effects from smokers for genetic studies of nicotine dependence? A few reports in the literature suggest yes193031. However, we do not know whether the effects on smokers are more or less informative compared to that of current non-smokers. Therefore, a similar study in smokers would be of interest.\n\nInterestingly, we were able to detect consistent association signals in a sample of 208 subjects that might otherwise require a sample size several times larger in a typical genetic association study. This indicates that the integration of the drug effects of nicotine with psychometric structural modeling can be a powerful approach in genetic studies of nicotine dependence. In genetic studies, several factors influence the power. In addition to sample size, the reliability and accuracy of phenotype measurements are one of the most important, but often overlooked, factors to improve power for a given trait. In a typical study of psychiatric trait, phenotypic data are normally based on self-reports and the accuracy of these self-reports are far from satisfactory. For this reason, researchers have used psychometric models to obtain factor scores to serve as the phenotype3233. In the studies of other complex diseases such as cardiovascular diseases, researchers use biologically relevant surrogates (i.e. endophenotypes)34 to improve power. Specific to nicotine dependence study, cotinine, a major metabolite of nicotine, has been used as a surrogate, and the study has demonstrated tremendous improvement in statistical power11. In our study, we used psychometric analyses of multiple waves of data to control for measurement errors and confounding effects, achieving experiment-wide significance for rs588765. In a study with 789 nicotine dependence cases and 811 controls19, subjective responses similar to the DEN were used as phenotypes. Although the study found associations between the CHRNB3 gene and the “dizziness” phenotype, no associations were found for any markers typed in the CHRNA5-CHRNA3-CHRNB4 locus, including rs16969968 and rs578776, despite the much larger sample size. In contrast, with only 208 subjects, we found nominal association between rs16969968 and the Dizzy factor. The gains in power in our study, we believe, is partly due to the integration of psychometric modeling of item level data for multiple waves of measurement which effectively accounts for measurement errors and confounding effects. Another advantage of integration of psychometric modeling with experimentally generated data is that it provides a much stronger basis for interpreting the results. What the modeling effects might be attributed to is more clearly defined and circumscribed, i.e. the controlled administration of nicotine in this study.\n\nWe also notice that while there are quantifiable differences for both positive and negative effects across increasing doses of nicotine, genetic associations are observed largely on the negative factors. This may be due to the fact that our subjects are non-smokers, or because negative affect factors have larger effect sizes. In the literature, there is a suggestion that non-smokers (including both never smokers and ex-smokers) react to smoking more negatively than smokers do24. In this study, we did find that ever smokers had higher negative factor scores than the never smokers, although the differences were not statistically significant (data not shown). This greater negative affect among the ever smokers toward nicotine administration may play a role in their persistent abstinence.\n\nThis study has some limitations. Given the relatively small sample size, while modest genetic effects are detected, most estimates do not survive corrections for multiple comparisons. However, the observed effects of SNPs are consistent across all doses of nicotine and for all three subjective instruments; therefore, our modest associations are more likely due to a small sample size rather than Type II error. Nonetheless, further studies are needed to replicate and verify our findings. The small sample size also prevents us from expanding to more complex models to estimate the trajectory of the effects of nicotine intake, and to test if the amount of change is proportional to nicotine doses and if it is influenced by genetic risks of nicotine dependence. These are of great interest for the research community, and we hope to extend the study to address these questions.\n\nIn summary, in this study, we provide the first evidence linking established genetic risk factors for nicotine dependence to mood states and affect of non-smokers under controlled laboratory conditions. These results demonstrate that the psychological effects of nicotine as a drug can, and should be utilized in genetic studies of smoking addiction and nicotine dependence. Study designs incorporating these effects may be more powerful than typical studies using only smoking behaviors as phenotypes.\n\nMethods\nSubjects\nNon-smokers of European ancestry between the ages of 18 and 50 years old were recruited to participate in the study. We defined non-smokers as those individuals who reported not smoking in the last 3 months and also smoking less than 100 cigarettes during their lifetime. The cutoff of 100 cigarettes smoked in one's lifetime is commonly used to differentiate between “smokers” and “nonsmokers”3536. Current smoking status was verified by breath carbon monoxide (CO) level (7 ppm or lower, BreathCO; Vitalograph, Lenexa, KS), and by urine cotinine concentration (2 ng/mL or less). Individuals were excluded if they reported a history of chronic health problems or psychiatric conditions, were pregnant or breastfeeding, or had other major medical conditions. The total number of subjects included for the study was 208, with an average age of 26 years (standard error, se 0.49) and average years of education of 15.5 (se 0.14). One hundred and eight were females (52.7%), and 102 (49.2%) reported having smoked some cigarettes (i.e. these subjects smoked some cigarettes in their lifetime, but they did not smoke in the last 3 months and the total number of cigarettes smoked was less than 100 cigarettes). The study was reviewed and approved by the IRB of Virginia Commonwealth University. All subjects provided informed consent to participate in this study. The experiments were conducted in accordance with procedures approved by the IRB.\n\nLab procedures\nAfter providing informed consent, all volunteers participated in a single laboratory session that included the administration of three doses of nicotine gum in ascending dose order (0, 2, and 4 mg) and measurement of self-reported mood and affect responses. Upon arrival to the laboratory, subjects were connected to a physiological monitor (Model 507E, Criticare Systems) for continuous recording of heart rate and blood pressure. Baseline self-report ratings using the POMS, PANAS and DEN were also obtained. Participants were then administered the first piece of nicotine gum (0 mg) and instructed to follow a computer-guided pacer to chew the gum for 15 minutes3738. Immediately after the gum was discarded, participants again were asked to respond to the subjective questionnaire items. This same procedure (15 minute standardized gum chewing period followed by subjective questionnaires) was repeated for the 2 and 4 mg doses of nicotine gum, with 45 minutes in between each administration. Blood samples were drawn prior to the first gum administration for genotype analyses.\n\nOutcome measures\nWe used the POMS, PANAS and DEN questionnaires to evaluate the effects of nicotine administration on mood and affect. In this study, we used POMS, a 65-item, single-word questions to assess each subject's current mood states21. For each question, a 5-level Likert type response format was used to record the level of his/her affect at the time. The PANAS is a 20-item single-word questionnaire designed to obtain positive and negative affect responses using a 5-level response format22. The DEN is a 10-item single-word instrument tapping more physiologically based aspects of nicotine effects (e.g., “dizzy”)23. Participants indicated their response to each item on a computerized scale ranging from 0 to 100 (whole numbers) using the computer pointer.\n\nDNA extraction and genotyping\nDNAs were extracted from blood samples using a kit (Qiagen, QiaAmp DNA Blood Midi kit, Valencia, CA 91355) and manufacture provided protocol. After the extraction, DNA samples were quantified and stored at −80°C. Genotypes for the subjects for rs16969968, rs588765 and rs578776 were obtained using the TaqMan method39. The genotype and allele frequencies of the 3 markers were in Hardy-Weinberg equilibrium.\n\nData analyses\nThe POMS and PANAS items, and SNP genotype data were modeled as ordered categorical (ordinal) variables. For the POMS and PANAS, items that showed limited variability with more than 90% of subjects using only one of the response categories were dropped from further analyses. Twenty four items of the POMS and 15 items of the PANAS were retained and included in this analysis. For the 10 DEN items, a log 10 transformation was performed in an attempt to normalize their distributions. All 10 items were included in the analyses. First, exploratory item factor analyses were conducted for the POMS, PANAS and DEN item sets using the R packages PSYCH and POLYCOR with oblimin rotation to determine the appropriate dimensionality of the latent structures of each set of items. Second, measurement invariance (MI) testing of the POMS, PANAS and DEN structures were performed with the R packages LAVAAN40 and SemTools. MI testing was carried out to evaluate if the affect factor measurement structures remained invariant across the different nicotine gum administrations. Third, the associations of SNPs with the psychological latent factors were tested within models where the loadings and thresholds/intercepts of the indicators of each latent factor were constrained to be equal across the 3 nicotine administrations. This approach tests whether changes in factor scores are confounded with any differential item functioning that may be present. Therefore, the tests of association of the SNPs with the psychological factors provide estimates of unambiguous effects indicating whether the genetic risk factors (i.e., SNPs) predict variation and changes in psychological status in the context of the effects of different doses of nicotine administration.\n\nSupplementary Material\nSupplementary Information\nSupplementary information\n\n We thank the volunteers for their participation in this study, as well as Janet Austin and Barbara Kilgalen for their data collection efforts. This study is supported by NIH grant R03DA027619 and Virginia Commonwealth University bridge funds to X.C.\n\nAuthor Contributions X.C. conceptualized the study, analyzed the data and wrote the paper. K.K. and T.E. advised the study design, data analyses, and revised the paper. M.B. and J.C. performed the experiments and collected the data. S.A., L.L. and J.C. analyzed the data. All authors had reviewed and agreed on the contents of the paper.\n\nFigure 1 Configural latent variable measurement model for testing invariance across nicotine doses.\nThe figure is shown using the PANAS Nervous factor.\n\nFigure 2 Measurement model based association testing between SNP genotypes and the means of latent factors.\n(A). The invariant base model used in the testing. (B). The association between rs16969968 genotypes and the scores of the PANAS Nervous factor. (C). The association between rs588765 genotypes and the scores of the DEN Confused factor.\n\nTable 1 Summary of measurement invariance test of the POMS models\nModel\tDF\tχ2\tΔ χ2\tΔ DF\tΔ χ2 P\tCFI\tTLI\tRMSEA\t\nPOMS Positive Factors (“Friendly”, “Active” and “Clear Headed”)\t\nConfigural model\t879\t1990.5\t \t \t \t0.994\t0.993\t0.078\t\nMetric Invariance\t908\t2043.9\t10.5\t29\t0.9993\t0.994\t0.994\t0.078\t\nScalar Invariance\t1024\t2229.3\t397.1\t116\t<2.2E-16\t0.994\t0.994\t0.076\t\nPOMS Negative Factors (“On Edge” and “Fatigued”)\t\nConfigural model\t218\t242.9\t \t \t \t0.999\t0.999\t0.024\t\nMetric Invariance\t236\t297.8\t32.2\t18\t0.0208\t0.997\t0.997\t0.036\t\nScalar Invariance\t288\t577.6\t444.5\t52\t<2.2E-16\t0.988\t0.988\t0.070\t\nCFI: comparative fit index.\n\nTable 2 Summary of measurement invariance test of the PANAS models\nModel\tDF\tχ2\tΔ χ2\tΔ DF\tΔ χ2 P\tCFI\tTLI\tRMSEA\t\nPANAS Positive Factors (Inspired and Attentive)\t\nConfigural model\t364\t707.9\t \t \t \t0.997\t0.997\t0.068\t\nMetric Invariance\t388\t832.5\t57.9\t24\t1.24E-04\t0.996\t0.996\t0.075\t\nScalar Invariance\t468\t904.7\t175.6\t80\t3.98E-09\t0.997\t0.997\t0.067\t\nPANAS Negative Factor (Nervous)\t\nConfigural model\t77\t121.2\t \t \t \t0.991\t0.988\t0.053\t\nMetric Invariance\t85\t142.5\t10.3\t8\t0.2458\t0.989\t0.986\t0.057\t\nScalar Invariance\t107\t267.0\t197.6\t22\t<2.2E-16\t0.969\t0.969\t0.085\t\nTable 3 Summary of measurement invariance test of the DEN models\nModel\tDF\tAIC\tBIC\tχ2\tΔ χ2\tΔ DF\tΔ χ2 P\tCFI\tTLI\tRMSEA\t\nConfigural model\t409\t7779.7\t8267.0\t1000.9\t \t \t \t0.873\t0.846\t0.083\t\nMetric Invariance\t428\t7777.6\t8201.4\t1036.7\t26.8\t13.5\t0.0168\t0.869\t0.849\t0.083\t\nScalar Invariance\t444\t7845.2\t8215.7\t1136.4\t99.1\t16.7\t9.97E-14\t0.851\t0.834\t0.087\t\nAIC: Akaiki information criterion.\n\nTable 4 Association of POMS factors with SNPs*\n \tPlacebo (0 mg)\tNicotine Gum (2 mg)\tNicotine Gum (4 mg)\t\nSNP\tBeta\tSe\tZ\tP\tBeta\tSe\tZ\tP\tBeta\tSe\tZ\tP\t\nFriendly\t\nrs16969968\t0.065\t0.110\t0.593\t0.5530\t0.071\t0.108\t0.655\t0.5120\t0.065\t0.114\t0.569\t0.5690\t\nrs578776\t0.126\t0.110\t1.146\t0.2520\t0.181\t0.109\t1.671\t0.0950\t0.155\t0.111\t1.397\t0.1620\t\nrs588765\t−0.023\t0.102\t−0.22\t0.8230\t−0.038\t0.100\t−0.375\t0.7080\t−0.039\t0.103\t−0.380\t0.7040\t\nActive\t\nrs16969968\t0.189\t0.110\t1.720\t0.0850\t0.261\t0.110\t2.378\t0.0170\t0.228\t0.115\t1.977\t0.0480\t\nrs578776\t0.095\t0.110\t0.866\t0.3870\t0.205\t0.110\t1.856\t0.0630\t0.155\t0.118\t1.320\t0.1870\t\nrs588765\t0.011\t0.102\t0.110\t0.9130\t0.031\t0.100\t0.308\t0.7580\t0.049\t0.105\t0.466\t0.6420\t\nClear Headed\t\nrs16969968\t−0.106\t0.125\t−0.85\t0.3970\t−0.061\t0.130\t−0.472\t0.6370\t0.002\t0.126\t0.019\t0.9850\t\nrs578776\t0.082\t0.130\t0.636\t0.5250\t0.083\t0.115\t0.721\t0.4710\t0.115\t0.127\t0.907\t0.3640\t\nrs588765\t−0.111\t0.116\t−0.957\t0.3390\t−0.041\t0.116\t−0.348\t0.7270\t0.004\t0.121\t0.031\t0.9750\t\nUneasy\t\nrs16969968\t0.164\t0.134\t1.220\t0.2220\t0.166\t0.123\t1.349\t0.1770\t0.132\t0.120\t1.099\t0.2720\t\nrs578776\t−0.188\t0.138\t−1.366\t0.1720\t−0.017\t0.126\t−0.134\t0.8930\t−0.218\t0.119\t−1.830\t0.0670\t\nrs588765\t0.236\t0.129\t1.822\t0.0690\t0.109\t0.126\t0.861\t0.3890\t0.243\t0.121\t2.013\t0.0440\t\nFatigued\t\nrs16969968\t0.132\t0.128\t1.032\t0.3020\t−0.013\t0.124\t−0.107\t0.9150\t−0.045\t0.123\t−0.368\t0.7130\t\nrs578776\t0.090\t0.121\t0.750\t0.4530\t−0.065\t0.126\t−0.517\t0.6050\t−0.109\t0.126\t−0.865\t0.3870\t\nrs588765\t0.056\t0.114\t0.491\t0.6230\t0.048\t0.120\t0.398\t0.6900\t0.037\t0.115\t0.321\t0.7480\t\n*P values ≤ 0.05 were highlighted by bold fonts, and p values ≤ 0.1 were highlighted by italic fonts and underscored.\n\nTable 5 Association of PANAS factors with SNPs\n \tPlacebo (0 mg)\tNicotine Gum (2 mg)\tNicotine Gum (4 mg)\t\nSNP\tBeta\tSe\tZ\tP\tBeta\tSe\tZ\tP\tBeta\tSe\tZ\tP\t\nInspired\t\nrs16969968\t0.074\t0.110\t0.673\t0.5010\t0.154\t0.111\t1.389\t0.1650\t0.148\t0.115\t1.286\t0.1990\t\nrs578776\t0.104\t0.113\t0.916\t0.3600\t0.151\t0.112\t1.340\t0.1800\t0.141\t0.111\t1.268\t0.2050\t\nrs588765\t−0.044\t0.102\t−0.44\t0.6630\t−0.005\t0.104\t−0.04\t0.9650\t0.046\t0.106\t0.430\t0.6670\t\nAttentive\t\nrs16969968\t0.053\t0.123\t0.433\t0.6650\t0.108\t0.115\t0.939\t0.3480\t0.082\t0.122\t0.677\t0.4980\t\nrs578776\t0.095\t0.113\t0.843\t0.3990\t0.130\t0.106\t1.218\t0.2230\t0.139\t0.113\t1.230\t0.2190\t\nrs588765\t0.002\t0.104\t0.023\t0.9820\t−0.001\t0.104\t−0.013\t0.9900\t−0.017\t0.109\t−0.159\t0.8740\t\nNervous\t\nrs16969968\t0.121\t0.146\t0.830\t0.4060\t0.406\t0.169\t2.394\t0.0170\t0.414\t0.149\t2.768\t0.0060\t\nrs578776\t−0.150\t0.155\t−0.966\t0.3340\t0.082\t0.14\t0.587\t0.5570\t−0.062\t0.135\t−0.460\t0.6460\t\nrs588765\t0.240\t0.136\t1.763\t0.0780\t0.218\t0.148\t1.471\t0.1410\t0.367\t0.136\t2.690\t0.0070\t\nTable 6 Association of DEN factors with SNPs\n \tPlacebo (0 mg)\tNicotine Gum (2 mg)\tNicotine Gum (4 mg)\t\nSNP\tBeta\tSe\tZ\tP\tBeta\tSe\tZ\tP\tBeta\tSe\tZ\tP\t\nConfused\t\nrs16969968\t−0.119\t0.078\t−1.528\t0.1270\t−0.158\t0.082\t−1.941\t0.0520\t−0.213\t0.101\t−2.103\t0.0350\t\nrs578776\t−0.123\t0.076\t−1.608\t0.1080\t−0.134\t0.092\t−1.446\t0.1480\t−0.165\t0.103\t−1.591\t0.1120\t\nrs588765\t0.186\t0.082\t2.266\t0.0230\t0.203\t0.082\t2.472\t0.0130\t0.339\t0.094\t3.598\t0.0003\t\nDizzy\t\nrs16969968\t−0.198\t0.079\t−2.498\t0.0120\t−0.267\t0.092\t−2.884\t0.0040\t−0.118\t0.105\t−1.121\t0.2620\t\nrs578776\t−0.096\t0.080\t−1.204\t0.2280\t0.146\t0.090\t1.616\t0.1060\t−0.019\t0.089\t−0.212\t0.8320\t\nrs588765\t0.247\t0.075\t3.276\t0.0010\t0.152\t0.087\t1.744\t0.0810\t0.183\t0.090\t2.035\t0.0420\t\nTable 7 Post hoc analyses of nicotine dose on the DEN factors\nSNP\tModel*\tDf\tχ2\tΔ χ2\tΔ DF\tΔ χ2 P\tCFI\tTLI\tRMSEA\t\nrs16969968\tSNP\t476\t1275.7\t \t \t \t0.828\t0.811\t0.090\t\nConstrained SNP\t480\t1280.3\t5.0\t3.8\t0.2650\t0.828\t0.812\t0.090\t\nrs578776\tSNP\t476\t1291.3\t \t \t \t0.826\t0.808\t0.091\t\nConstrained SNP\t480\t1299.4\t7.2\t3.7\t0.1056\t0.825\t0.808\t0.091\t\nrs588765\tSNP\t476\t1279.5\t \t \t \t0.828\t0.810\t0.090\t\nConstrained SNP\t480\t1288.8\t9.6\t3.7\t0.0396\t0.827\t0.810\t0.090\t\n*see text for full description of the models.\n==== Refs\nBerrettini W. \net al.\nAlpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking . 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"fulltext_license": "CC BY",
"issn_linking": "2045-2322",
"issue": "5()",
"journal": "Scientific reports",
"keywords": null,
"medline_ta": "Sci Rep",
"mesh_terms": "D000328:Adult; D000339:Affect; D000483:Alleles; D005163:Factor Analysis, Statistical; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine; D020641:Polymorphism, Single Nucleotide; D011594:Psychometrics; D014029:Tobacco Use Disorder; D055815:Young Adult",
"nlm_unique_id": "101563288",
"other_id": null,
"pages": "9521",
"pmc": null,
"pmid": "25826680",
"pubdate": "2015-03-31",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24961312;20418890;17226798;22438940;20700436;18783506;20955488;19132693;16085500;16366815;14732415;22585541;21279447;22241830;19760673;15498787;22534784;22868939;22102629;22071378;21280952;25390645;10084106;3391001;18385739;16756416;14668070;23212062;17135278;16380569;17553635;20418889;18227835;19060906;17555378;20854418;17908753;3397865",
"title": "Genetic risks to nicotine dependence predict negative mood and affect in current non-smokers.",
"title_normalized": "genetic risks to nicotine dependence predict negative mood and affect in current non smokers"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2015054671",
"fulfillexpeditecriteria": "1",
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"actiondrug": "5",
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"reaction": [
{
"reactionmeddrapt": "Confusional state",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Irritability",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
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"reactionmeddraversionpt": "18.0",
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{
"abstract": "Trihexyphenidyl is an anticholinergic medication that is routinely used for the management of extrapyramidal symptoms in patients who receive antipsychotic medications. Trihexyphenidyl has been reported to be abused by some patients, who start to take it in increasing doses and tend to report a sensation of relaxation or pleasure with this medication. Hence, whether trihexyphenidyl should be considered a psychoactive substance and whether nonprescription misuse of this medication should be considered under the purview of substance use disorders need further clarity. We present here two cases of trihexyphenidyl misuse which developed in the context of persistent delusional disorders and highlight the challenges in diagnosis in such a situation.",
"affiliations": "Department of Psychiatry and NDDTC, All India Institute of Medical Sciences, New Delhi, India.;Department of Psychiatry and NDDTC, All India Institute of Medical Sciences, New Delhi, India.;Department of Psychiatry and NDDTC, All India Institute of Medical Sciences, New Delhi, India.;Department of Psychiatry and NDDTC, All India Institute of Medical Sciences, New Delhi, India.;Department of Psychiatry and NDDTC, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Mahal|Pankaj|P|;Nishanth|K N|KN|;Mahapatra|Ananya|A|;Sarkar|Siddharth|S|;Balhara|Yatan Pal Singh|YPS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/jnrp.jnrp_569_17",
"fulltext": "\n==== Front\nJ Neurosci Rural PractJ Neurosci Rural PractJNRPJournal of Neurosciences in Rural Practice0976-31470976-3155Medknow Publications & Media Pvt Ltd India 30069107JNRP-9-42810.4103/jnrp.jnrp_569_17Case ReportTrihexyphenidyl Misuse in Delusional Disorder Mahal Pankaj Nishanth K. N. Mahapatra Ananya Sarkar Siddharth Balhara Yatan Pal Singh Department of Psychiatry and NDDTC, All India Institute of Medical Sciences, New Delhi, IndiaAddress for correspondence: Dr. Siddharth Sarkar, Department of Psychiatry and NDDTC, All India Institute of Medical Sciences, 4th Floor, Teaching Block, Ansari Nagar, New Delhi - 110 029, India. E-mail: sidsarkar22@gmail.comJul-Sep 2018 9 3 428 430 Copyright: © 2018 Journal of Neurosciences in Rural Practice2018This 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.Trihexyphenidyl is an anticholinergic medication that is routinely used for the management of extrapyramidal symptoms in patients who receive antipsychotic medications. Trihexyphenidyl has been reported to be abused by some patients, who start to take it in increasing doses and tend to report a sensation of relaxation or pleasure with this medication. Hence, whether trihexyphenidyl should be considered a psychoactive substance and whether nonprescription misuse of this medication should be considered under the purview of substance use disorders need further clarity. We present here two cases of trihexyphenidyl misuse which developed in the context of persistent delusional disorders and highlight the challenges in diagnosis in such a situation.\n\nDelusional disorderdependencemisusetrihexyphenidyl\n==== Body\nINTRODUCTION\nTrihexyphenidyl is an anticholinergic medication that is routinely used for the management of extrapyramidal symptoms in patients who receive antipsychotic medications. Trihexyphenidyl has been reported to be abused by some patients, who start to take it in increasing doses and tend to report a sensation of relaxation or pleasure with this medication.[12] Hence, whether trihexyphenidyl should be considered a psychoactive substance and whether nonprescription misuse of this medication should be considered under the purview of substance use disorders need further clarity. We present here two cases of trihexyphenidyl misuse which developed in the context of persistent delusional disorders and highlight the challenges in diagnosis in such a situation.\n\nCASE REPORTS\nCase 1\nA 32-year-old married male presented to our center with a history of multiple prescription medications misuse, which started after his marriage around 10 years back. The illness started with a doubt on the character of his wife, leading to tension, headache, anger outburst towards wife, following which he was put on combination of trifluoperazine (5 mg) and trihexyphenidyl (2 mg) by a private practitioner. Within few months, the conviction on doubt toward his spouse reached a delusional level. Gradually, he kept on increasing the dose of the medication (up to 20 tablets/day) to be relaxed, free from tension, and have a sense of well-being. He would get these medications from shops showing his old medical prescriptions, and sometimes, even without prescriptions. He showed the features of intense desire to take the medication, diminished control, tolerance, preoccupation with the substance, and withdrawal in the form of restlessness, tachycardia, irritability, aggressiveness, headache, sweating, and sleep disturbances on cessation. In addition, he was also using tobacco and sedative hypnotic (clonazepam or alprazolam) in a dependent pattern. He was prescribed amitriptyline when he approached health-care providers with tension-type headache around 4 years back but did not reveal the use of other medications then. Subsequently, he would alternate between amitriptyline and sedatives depending on availability. He also used tramadol for 2 years which started due to an episode of abdominal pain which subsided after few days, but he continued taking it later with features of dependence in the form of craving, tolerance, and preoccupation with the substance and impaired control. Hence, when he approached our center, he was taking multiple tablets of trihexyphenidyl (with trifluoperazine), amitriptyline, tramadol, and tobacco.\n\nCase 2\nA 32-year-old married male presented with nicotine dependence for 20 years, alcohol dependence for 18 years, opioid dependence syndrome in the form of injection pentazocine for 15 years, and benzodiazepines abuse for 15 years. Along with it, he was using combination of trifluoperazine (5 mg) and trihexyphenidyl (2 mg) about 20–30 tablets per day which he took over the course of 14 years and had stopped a year back. It was started by a private practitioner after he had symptoms of delusion of infidelity. He reported that this combination medication increased the “high” of other substances. Hence, he continued using it in increasing dose and would arrange these medications from local chemists without valid prescription and developed features of dependence in the form of craving, tolerance, preoccupation with substance, impaired control, and symptoms such as restlessness, irritability, sleep disturbance, and anxiety.\n\nDISCUSSION\nMany centrally acting anticholinergic drugs such as biperiden, benztropine, procyclidine, and trihexyphenidyl are used in clinical practice for control of extrapyramidal side effects induced by neuroleptics.[3] These anticholinergics, especially trihexyphenidyl, have been related to two types of psychotropic effects: mood elevating, euphorigenic, and stimulating effect and toxic psychosis effect. Few risk factors such as advanced age, history of sedative-induced confusion, concurrent use of tricyclics or neuroleptics, and narcotic drug abuse have been reported to increase the likelihood of such effects.[4] In a study of 50 patients with chronic psychosis, the prevalence of anticholinergic misuse was 34%, and trihexyphenidyl was the most common anticholinergic implicated due to its propensity to produce a “high.”[5]\n\nHere, in both the cases, patients were misusing many prescription medications among which combination medication misuse of trifluoperazine and trihexyphenidyl was prominent. The combination medication exists as trihexyphenidyl negates the extrapyramidal side effects of trifluoperazine, a typical antipsychotic agent. Although both the patients took combination medication, it is likely that trihexyphenidyl was the medication that produced the euphoric effect due to its anticholinergic properties. The withdrawal symptoms were not specific though some of them were similar to the withdrawal symptoms mentioned in published literature which include tachycardia, restlessness, aggressiveness, lethargy, giddiness, sweating, anxiety, body ache, headache, and photophobia.[126]\n\nThe exact biochemical explanation regarding the misuse of these anticholinergic agents is still unclear. Although mesolimbic dopaminergic system (formed by the ventral tegmental area, the nucleus accumbens, and the prefrontal cortex) is the common final reward pathway for drug abuse, the cholinergic system may interfere in this reward pathway. Activation of muscarinic receptors can facilitate dopaminergic transmission which leads to release of dopamine in the nucleus accumbens. Hence, by inhibiting these muscarinic receptors, the anticholinergics may inhibit dopamine reuptake and storage. This mechanism could explain the euphoric effect of these anticholinergics.[7] A double-blind study in healthy volunteers found improvement in emotional status with biperiden, the effect being related to the personality features of the volunteers.[8]\n\nNeuroleptic drugs have been shown to disrupt the reward pathway motivated by many positive reinforcers. The neuroleptics blunt the euphoric impact of reinforcers by selective attenuation of motivational arousal which is required for goal-directed behavior for subjective experience of pleasure.[9] Due to this, patients with psychotic illness tend to use stimulants such as coffee or nicotine or other substances with mood-enhancing properties.[3] One needs to be cognizant of the fact that trifluoperazine may also produce some nonspecific withdrawal features such as weakness, dysphoria, sleep disturbance, and irritability on cessation.[1011] However, since trifluoperazine is a dopamine-blocking agent, it is unlikely to stimulate the mesolimbic/mesocortical dopaminergic reward circuit, which occurs with other dependence-producing substances.[10]\n\nConsidering the available literature and case characteristics, it seems more likely that trihexyphenidyl was the main drug that led to increased and nonprescription use of the medication. Based on the above properties, the WHO gave a consensus statement regarding the use of anticholinergics in psychiatry and concluded that the prophylactic use of these drugs is not recommended.[12] It suggested to withdraw anticholinergic drugs after 3 months, as drug-induced Parkinsonism tends to improve spontaneously over this time despite continued antipsychotic medication.\n\nStrictly following the criteria of dependence of International Classification of Diseases 10 (ICD 10), a diagnosis of dependence may be entertained with demonstration of features of craving, loss of control, tolerance to increasing doses, and preoccupation.[13] However, whether a category of F19, i.e., mental and behavioral disorders due to multiple drug use and use of other psychoactive substances or F55 i.e. abuse of nondependence-producing substances would suit better would be a matter of contention. Although ICD-10 has a category for antidepressants abuse, there is still no place for anticholinergic medications such as trihexyphenidyl. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition has recognized the abuse potential of trihexyphenidyl and has kept it under “Other (or Unknown) Substance Use Disorder” category.[14] The subsequent edition of ICD probably needs to take a look at the placement of trihexyphenidyl misuse in appropriate nosological category.\n\nCONCLUSION\nThe use of anticholinergics in psychiatry needs to be cautious in view of its misuse potential. In some cases, the use of anticholinergic medication is justified. However, the long-term administration of these drugs is unnecessary for many. Hence, a clinician should be vigilant about its misuse in the clinical setting.\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 Kaminer Y Munitz H Wijsenbeek H Trihexyphenidyl (Artane) abuse: Euphoriant and anxiolytic Br J Psychiatry 1982 140 473 4 6125226 \n2 Goggin DA Solomon GF Trihexyphenidyl abuse for euphorigenic effect Am J Psychiatry 1979 136 459 60 426119 \n3 Dose M Tempel HD Abuse potential of anticholinergics Pharmacopsychiatry 2000 33 Suppl 1 43 6 11072764 \n4 McInnis M Petursson H Trihexyphenidyl dependence Acta Psychiatr Scand 1984 69 538 42 6741602 \n5 Buhrich N Weller A Kevans P Misuse of anticholinergic drugs by people with serious mental illness Psychiatr Serv 2000 51 928 9 10875961 \n6 Michael A Murali T Mathai PJ Gopinath PS Trihexyphenidyl dependence-report of two cases Indian J Psychiatry 1984 26 178 9 21965980 \n7 Espi Martinez F Espi Forcen F Shapov A Martinez Moya A Biperiden dependence: Case report and literature review Case Rep Psychiatry 2012 2012 949256 \n8 Fleischhacker WW Barnas C Günther V Meise U Stuppäck C Unterweger B Mood-altering effects of biperiden in healthy volunteers J Affect Disord 1987 12 153 7 2955007 \n9 Soubrie P Neuroleptic-induced anhedonia: Some psychopharmacological implications Behav Brain Sci 1982 5 76 7 \n10 Basu D Marudkar M Khurana H Abuse of neuroleptic drug by psychiatric patients Indian J Med Sci 2000 54 59 62 11271726 \n11 Chakraborty R Chatterjee A Chaudhury S Withdrawal symptoms of trifluoperazine J Neuropsychiatry Clin Neurosci 2008 20 495 6 19196940 \n12 Barnes TR Comment on the WHO consensus statement: Prophylactic use of anticholinergics in patients on long-term neuroleptic treatment Br J Psychiatry 1990 156 413 4 1971769 \n13 World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders Clinical Descriptions and Diagnostic Guidelines 1992 Geneva World Health Organization \n14 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 2013 Washington DC American Psychiatric Publishing Incorporated\n\n",
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"keywords": "Delusional disorder; dependence; misuse; trihexyphenidyl",
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"abstract": "OBJECTIVE\nPriapism, or prolonged penile erection in the absence of sexual stimulation, may be a medical emergency. Many medications including antianxiety, antidepressants and antipsychotics have been implicated. This paper presents a case of priapism associated with topiramate use.\n\n\nMETHODS\nThis is a description of case report where topiramate was prescribed as anticraving medication in a patient with alcohol dependence. Episodic priapism developed soon after topiramate was prescribed. The severity of priapism reduced with reduction of dosage and disappeared with its discontinuation.\n\n\nRESULTS\nReversible priapism (stuttering subtype) is associated with topiramate.\n\n\nCONCLUSIONS\nThis is the first report of priapism associated with topiramate in the scientific literature.",
"affiliations": "Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bengaluru 560029, India. Electronic address: manjunatha.adc@gmail.com.;Centre for Addiction Medicine, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bengaluru 560029, India.",
"authors": "Manjunatha|Narayana|N|;Benegal|Vivek|V|",
"chemical_list": "D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose",
"country": "United States",
"delete": false,
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"issue": "37(6)",
"journal": "General hospital psychiatry",
"keywords": "Alcohol dependence; Dose-dependent; Priapism; Topiramate",
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D000328:Adult; D000437:Alcoholism; D004305:Dose-Response Relationship, Drug; D005632:Fructose; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents; D011317:Priapism; D000077236:Topiramate",
"nlm_unique_id": "7905527",
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"pages": "620.e1-2",
"pmc": null,
"pmid": "26116965",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Stuttering priapism associated with topiramate.",
"title_normalized": "stuttering priapism associated with topiramate"
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},
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},
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] |
{
"abstract": "Brian is a 6-year-old boy who was diagnosed with autism spectrum disorder (ASD) and global developmental delay at age 2. He has no other health conditions of note. Brian lives with his parents and an older brother, who also has ASD, in a rural area 2 hours from the center where he was diagnosed. Brian has a history of intermittent self-injurious behaviors (head-banging, throwing himself onto the floor, etc.) that regularly result in bruising, intense and lengthy tantrums, and aggression toward family and teachers. Brian will occasionally indicate items that he wants, but otherwise has no functional communication skills. Over the past 18 months, Brian's challenging behaviors have waxed and waned. The regional special education program is not equipped to safely manage his behaviors, and there are no in-home or center-based agencies that provide applied behavior analysis (ABA) available. Brian's developmental pediatrician initiated guanfacine (eventually adding a small dose of aripiprazole) and referred the family to psychology for weekly telehealth behavioral parent training to address behavioral concerns using the Research Units in Behavioral Intervention curriculum.1Brian's behavioral problems decreased during the initial weeks of the COVID-19 crisis, when he no longer had to leave home or attend special education. However, as summer continued, his behaviors worsened substantially (regular bruising and tissue damage, numerous after-hours consultations with his psychologist and developmental pediatrician, and one trip to the emergency department). The intensity of Brian's behaviors (maintained primarily by access to tangible items and escape from demands) made progress with behavioral supports slow and discouraging for his parents. Other psychosocial stressors coalesced for the family as well, including employment loss, limited social support because of social distancing requirements, and illness of one of his parents. The developmental pediatrician continued to modify the medication regimen over the summer, transitioning Brian from guanfacine to clonidine and increasing his aripiprazole incrementally (with clear increased benefit); hydroxyzine was also used as needed during the episodes of highest intensity.Despite the availability of best-practice guidelines for children with Brian's presenting concerns,2 a confluence of barriers (geographic, economic, ABA work force, global pandemic, etc.) present serious questions for his family and care team related to the next steps in Brian's care. Should he attend in-person school in the fall, knowing that the available program may have limited educational benefit and increase his risk of COVID-19 exposure (not to mention self-injury)? Would the potential benefits of cross-country travel to an intensive behavioral treatment program outweigh the associated psychosocial and economic stressors? How else can the virtual care team support this family?\n\n\n\n1. Bearss K, Johnson C, Smith T, et al. Effect of parent training vs parent education on behavioral problems in children with autism spectrum disorder: a randomized clinical trial. JAMA. 2015;313: 1524-1533.2. Hyman SL, Levy SE, Myers SM, et al. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics. 2020;145:e20193447.",
"affiliations": "Division of Developmental and Behavioral Health, Children's Mercy Kansas City, Kansas City, MO.;Texas Children's Hospital, Meyer Center for Developmental Pediatrics and Autism Center, Houston, TX.;Developmental Pediatrics, Children's Hospital Colorado, Aurora, CO.;Division of Developmental and Behavioral Health, Children's Mercy Kansas City, Kansas City, MO.",
"authors": "Nadler|Cy|C|;Godwin|Dinah L|DL|;Dempsey|Jack|J|;Nyp|Sarah S|SS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/DBP.0000000000000894",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-206X",
"issue": "42(1)",
"journal": "Journal of developmental and behavioral pediatrics : JDBP",
"keywords": null,
"medline_ta": "J Dev Behav Pediatr",
"mesh_terms": "D001321:Autistic Disorder; D000086382:COVID-19; D002648:Child; D006297:Health Services Accessibility; D006801:Humans; D008297:Male; D000085762:Physical Distancing; D019956:Stereotypic Movement Disorder",
"nlm_unique_id": "8006933",
"other_id": null,
"pages": "73-75",
"pmc": null,
"pmid": "33229969",
"pubdate": "2021-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Autism and Access to Care During the COVID-19 Crisis.",
"title_normalized": "autism and access to care during the covid 19 crisis"
} | [
{
"companynumb": "US-OTSUKA-2020_030966",
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"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
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}
],
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"reaction": [
{
"reactionmeddrapt": "No adverse event",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Nadler C, Godwin D.L,Dempsey J, Nyp S.S.. Autism and Access to Care During the COVID-19 Crisis. Journal of developmental and behavioral pediatrics : JDBP. 2020",
"literaturereference_normalized": "autism and access to care during the covid 19 crisis",
"qualification": "3",
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},
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},
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},
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"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
}
] |
{
"abstract": "To explore the impact of digoxin on hemodynamic parameters in patients with sepsis and tachycardia admitted to the intensive care unit.\n\n\n\nRetrospective review of adult patients admitted to the medical and mixed ICU at Mayo Clinic Rochester, Minnesota from March 2008 to February 2018, initiated on digoxin within 24 h of ICU stay. Hemodynamic parameters were reviewed before digoxin administration and at 6, 12 and 24 h after. Adverse events including new onset conduction abnormalities or arrhythmias during the first 48 h after digoxin administration were reviewed by a critical care cardiologist.\n\n\n\nStudy included 180 patients. We observed significant decrease in heart rate from 124 (115-138) beats/min 1 h before digoxin to 101 (87-117) 6 h after digoxin and 94 (84-112) 12 h after (p < .01). Median systolic blood pressure increased from 100 (91-112) mm Hg 1 h before to 110 (100-122) (p < .01) and 111 (103-124) at 6 and 12 h respectively after digoxin.\n\n\n\nEarly digoxin administration in patients with sepsis and tachycardia is uncommon but associated with improvements of hemodynamic parameters. These preliminary results will help formulate future hypotheses for focused trials on utility, efficacy and safety of digoxin in sepsis.",
"affiliations": "Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, United States of America. Electronic address: Herasevich.Svetlana@mayo.edu.;Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of America.;Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States of America.;Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States of America.;Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, United States of America.;Department of Emergency Medicine, Division of Pulmonary Critical Care Medicine, Henry Ford Hospital, Detroit, MI, United States of America.",
"authors": "Herasevich|Svetlana|S|;Bennett|Courtney E|CE|;Schwegman|Alex R|AR|;Subat|Yosuf W|YW|;Gajic|Ognjen|O|;Jayaprakash|Namita|N|",
"chemical_list": "D002316:Cardiotonic Agents; D004077:Digoxin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcrc.2019.08.026",
"fulltext": null,
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"medline_ta": "J Crit Care",
"mesh_terms": "D000368:Aged; D001794:Blood Pressure; D002316:Cardiotonic Agents; D003422:Critical Care; D004077:Digoxin; D005260:Female; D006339:Heart Rate; D006439:Hemodynamics; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018805:Sepsis; D013610:Tachycardia",
"nlm_unique_id": "8610642",
"other_id": null,
"pages": "175-179",
"pmc": null,
"pmid": "31476653",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hemodynamic profiles following digoxin use in patients with sepsis in the ICU.",
"title_normalized": "hemodynamic profiles following digoxin use in patients with sepsis in the icu"
} | [
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],
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"reactionmeddrapt": "Atrial fibrillation",
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{
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}
],
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},
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},
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{
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"qualification": "1",
"reportercountry": "US"
},
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"receiptdate": "20191011",
"receivedate": "20191011",
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"receivertype": "6"
},
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"sendertype": "2"
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},
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"medicinalproduct": "DIGOXIN."
}
],
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "HERASEVICH S, BENNETT CE, SCHWEGMAN AR, SUBAT YW, GAJIC O, JAYAPRAKASH N ET AL.. HEMODYNAMIC PROFILES FOLLOWING DIGOXIN USE IN PATIENTS WITH SEPSIS IN THE ICU. JOURNAL OF CRITICAL CARE. 2019?54:175-9",
"literaturereference_normalized": "hemodynamic profiles following digoxin use in patients with sepsis in the icu",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20191015",
"receivedate": "20191015",
"receiver": {
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"receivertype": "6"
},
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"sendertype": "2"
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}
] |
{
"abstract": "Acute subdural hematoma is a devastating neurological injury with significant morbidity and mortality. In patients with large subdural hematoma resulting in compression of the underlying brain and lateral brain shift, severe neurological deficits and coma can occur. Emergent neurosurgical decompression is a life-saving intervention which improves mortality and neurological function. Persistent coma despite subdural hematoma evacuation is often the result of persistent midline shift, cerebral infarctions related to initial elevated intracranial pressure and herniation, nonconvulsive seizures, and other metabolic and infectious causes; however, a subset of patients remains comatose without a discernable etiology. In this report, we describe an elderly patient who remained comatose without a known cause for several weeks after subdural hematoma evacuation and was found to have delayed cerebral hyperperfusion on brain imaging. After several days, there was marked recovery of consciousness which occurred in a timeframe that matched improvement in brain imaging findings. Cerebral hyperperfusion following subdural hematoma evacuation requires further investigation, and should be considered as a cause of persistent but potentially recoverable coma.",
"affiliations": "Department of Neurology, Brigham and Women's Hospital, Boston, MA; Department of Neurology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA. Electronic address: migdadyiy@gmail.com.;Department of Neurology, Brigham and Women's Hospital, Boston, MA; Department of Neurology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.;Department of Neurology, Brigham and Women's Hospital, Boston, MA; Department of Neurology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.;Department of Neurology, Brigham and Women's Hospital, Boston, MA; Department of Neurology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.;Department of Neurology, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA.",
"authors": "Migdady|Ibrahim|I|;Chen|Patrick|P|;Loza|Alejandra Márquez|AM|;Cashman|Christopher R|CR|;Izzy|Saef|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2021.106165",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "30(12)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Cerebral hypoperfusion; Coma recovery; Craniectomy; Subdural hematoma",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": null,
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "106165",
"pmc": null,
"pmid": "34666233",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cerebral Hyperperfusion and Delayed Coma Recovery after Subdural Hematoma Evacuation.",
"title_normalized": "cerebral hyperperfusion and delayed coma recovery after subdural hematoma evacuation"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-123859",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APIXABAN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "202155",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "Cerebrovascular accident prophylaxis",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "APIXABAN"
}
],
"patientagegroup": null,
"patientonsetage": "75",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cerebral hyperperfusion syndrome",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Subdural haematoma",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Migdady I, Chen P, Loza AM, Cashman CR, Izzy S. Cerebral hyperperfusion and delayed coma recovery after subdural hematoma evacuation. Journal Of Stroke And Cerebrovascular Diseases. 2021;30(12):1-3",
"literaturereference_normalized": "cerebral hyperperfusion and delayed coma recovery after subdural hematoma evacuation",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20211123",
"receivedate": "20211123",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20102601,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "OBJECTIVE\nLong-acting injectable antipsychotics are used to reduce medication nonadherence and relapse in schizophrenia-spectrum disorders. The relative effectiveness of long-acting injectable versions of second-generation and older antipsychotics has not been assessed.\n\n\nOBJECTIVE\nTo compare the effectiveness of the second-generation long-acting injectable antipsychotic paliperidone palmitate with the older long-acting injectable antipsychotic haloperidol decanoate.\n\n\nMETHODS\nMultisite, double-blind, randomized clinical trial conducted from March 2011 to July 2013 at 22 US clinical research sites. Randomized patients (n = 311) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a long-acting injectable antipsychotic.\n\n\nMETHODS\nIntramuscular injections of haloperidol decanoate 25 to 200 mg or paliperidone palmitate 39 to 234 mg every month for as long as 24 months.\n\n\nMETHODS\nEfficacy failure, defined as a psychiatric hospitalization, a need for crisis stabilization, a substantial increase in frequency of outpatient visits, a clinician's decision that oral antipsychotic could not be discontinued within 8 weeks after starting the long-acting injectable antipsychotics, or a clinician's decision to discontinue the assigned long-acting injectable due to inadequate therapeutic benefit. Key secondary outcomes were common adverse effects of antipsychotic medications.\n\n\nRESULTS\nThere was no statistically significant difference in the rate of efficacy failure for paliperidone palmitate compared with haloperidol decanoate (adjusted hazard ratio, 0.98; 95% CI, 0.65-1.47). The number of participants who experienced efficacy failure was 49 (33.8%) in the paliperidone palmitate group and 47 (32.4%) in the haloperidol decanoate group. On average, participants in the paliperidone palmitate group gained weight and those in the haloperidol decanoate group lost weight; after 6 months, the least-squares mean weight change for those taking paliperidone palmitate was increased by 2.17 kg (95% CI, 1.25-3.09) and was decreased for those taking haloperidol decanoate (-0.96 kg; 95% CI, -1.88 to -0.04). Patients taking paliperidone palmitate had significantly higher maximum mean levels of serum prolactin (men, 34.56 µg/L [95% CI, 29.75-39.37] vs 15.41 µg/L [95% CI, 10.73-20.08]; P <.001, and for women, 75.19 [95% CI, 63.03-87.36] vs 26.84 [95% CI, 13.29-40.40]; P<.001). Patients taking haloperidol decanoate had significantly larger increases in global ratings of akathisia (0.73 [95% CI, 0.59-0.87] vs 0.45 [95% CI, 0.31-0.59]; P=.006).\n\n\nCONCLUSIONS\nIn adults with schizophrenia or schizoaffective disorder, use of paliperidone palmitate vs haloperidol decanoate did not result in a statistically significant difference in efficacy failure, but was associated with more weight gain and greater increases in serum prolactin, whereas haloperidol decanoate was associated with more akathisia. However, the CIs do not rule out the possibility of a clinically meaningful advantage with paliperidone palmitate.\n\n\nBACKGROUND\nclinicaltrials.gov Identifier: NCT01136772.",
"affiliations": "Department of Psychiatry and Health Behavior, Georgia Regents University, Augusta.;Department of Psychiatry, UT Southwestern Medical Center, Dallas.;Department of Biostatistics, Gillings School of Public Health, University of North Carolina, Chapel Hill.;Department of Biostatistics, Gillings School of Public Health, University of North Carolina, Chapel Hill.;Department of Psychiatry, Division of Social and Community Psychiatry, Duke University, Durham, North Carolina.;Yale School of Medicine, Yale University, and Northeast Program Evaluation Center, West Haven, Connecticut.;Department of Biostatistics, Gillings School of Public Health, University of North Carolina, Chapel Hill.;Department of Psychiatry, School of Medicine and Dentistry, University of Rochester, Rochester, New York.;Department of Psychiatry and Health Behavior, Georgia Regents University, Augusta.;Department of Biostatistics, Gillings School of Public Health, University of North Carolina, Chapel Hill.;Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York8New York State Psychiatric Institute, New York, New York.",
"authors": "McEvoy|Joseph P|JP|;Byerly|Matthew|M|;Hamer|Robert M|RM|;Dominik|Rosalie|R|;Swartz|Marvin S|MS|;Rosenheck|Robert A|RA|;Ray|Neepa|N|;Lamberti|J Steven|JS|;Buckley|Peter F|PF|;Wilkins|Tania M|TM|;Stroup|T Scott|TS|",
"chemical_list": "D014150:Antipsychotic Agents; D007555:Isoxazoles; D010168:Palmitates; C033563:haloperidol decanoate; D006220:Haloperidol; D000068882:Paliperidone Palmitate",
"country": "United States",
"delete": false,
"doi": "10.1001/jama.2014.4310",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-7484",
"issue": "311(19)",
"journal": "JAMA",
"keywords": null,
"medline_ta": "JAMA",
"mesh_terms": "D000328:Adult; D017109:Akathisia, Drug-Induced; D014150:Antipsychotic Agents; D004311:Double-Blind Method; D005260:Female; D006220:Haloperidol; D006760:Hospitalization; D006801:Humans; D007273:Injections, Intramuscular; D007555:Isoxazoles; D008297:Male; D008875:Middle Aged; D000068882:Paliperidone Palmitate; D010168:Palmitates; D012559:Schizophrenia; D017211:Treatment Failure; D016896:Treatment Outcome; D015430:Weight Gain",
"nlm_unique_id": "7501160",
"other_id": null,
"pages": "1978-87",
"pmc": null,
"pmid": "24846035",
"pubdate": "2014-05-21",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "16172203;24375207;3415422;2720049;19058842;24229745;16198088;15998156;21257294;6121550;19886879;21366475;14645311;17015810;3555385;6347119;19955390;15319799;11777998;18052569",
"title": "Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial.",
"title_normalized": "effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia a randomized clinical trial"
} | [
{
"companynumb": "US-JNJFOC-20140518344",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PALIPERIDONE PALMITATE"
},
"drugadditional": null,
"drugadministrationroute": "030",
"drugauthorizationnumb": "022264",
"drugbatchnumb": "NOT REQUIRED;UNKNOWN;UNKNOWN +MORE",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "39MG, 78 MG, 117 MG, 156 MG,AND 234 MG",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SCHIZOAFFECTIVE DISORDER",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PALIPERIDONE PALMITATE"
},
{
"actiondrug": "1",
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"activesubstancename": "HALOPERIDOL DECANOATE"
},
"drugadditional": null,
"drugadministrationroute": "030",
"drugauthorizationnumb": "018701",
"drugbatchnumb": "UNKNOWN;UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "50 MG/ML OR 100 MG/ML",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SCHIZOAFFECTIVE DISORDER",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "HALOPERIDOL DECANOATE."
}
],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Tardive dyskinesia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Galactorrhoea",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nocturia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Parkinsonism",
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},
{
"reactionmeddrapt": "Insomnia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Incontinence",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Menstruation irregular",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Weight increased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Weight decreased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Constipation",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Treatment noncompliance",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Akathisia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood prolactin increased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Salivary hypersecretion",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Syncope",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypersomnia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "20.1",
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},
{
"reactionmeddrapt": "Somnolence",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Increased appetite",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Homicidal ideation",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Gynaecomastia",
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"abstract": "Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call \"subepithelial surface granulomatosis\" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.",
"affiliations": "Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Pathology, Hakodate Goryokaku Hospital, Hakodate, Japan.;Department of Pathology, Hakodate Goryokaku Hospital, Hakodate, Japan.;Department of Pathology, Hakodate Goryokaku Hospital, Hakodate, Japan.;Department of Surgical Pathology, Sunagawa City Medical Center, Sunagawa, Japan.;Department of Surgical Pathology, Sunagawa City Medical Center, Sunagawa, Japan.;Department of Pathology, Asahikawa Red-Cross Hospital, Asahikawa, Japan.;Department of Pathology, Asahikawa Red-Cross Hospital, Asahikawa, Japan.;Department of Pathology, Otaru City General Hospital, Otaru, Japan.;Department of Pathology, Otaru City General Hospital, Otaru, Japan.;Department of Pathology, Kushiro City General Hospital, Kushiro, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Surgical Pathology, Sapporo Medical University Hospital, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.",
"authors": "Kubo|Terufumi|T|https://orcid.org/0000-0001-9274-2551;Hirohashi|Yoshihiko|Y|https://orcid.org/0000-0002-0608-3914;Keira|Yoshiko|Y|;Akimoto|Mayuko|M|;Ikeda|Tatsuru|T|;Kikuchi|Noriaki|N|;Iwaki|Hiroyuki|H|;Kikuchi|Tomoki|T|;Obata|Masahiko|M|;Morita|Rena|R|;Kasai|Kiyoshi|K|;Segawa|Keiko|K|;Tsukahara|Tomohide|T|https://orcid.org/0000-0002-3678-4359;Kanaseki|Takayuki|T|;Murata|Kenji|K|;Kikuchi|Yasuhiro|Y|;Shinkawa|Tomoyo|T|;Hasegawa|Tadashi|T|;Torigoe|Toshihiko|T|",
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"doi": "10.1111/cas.14773",
"fulltext": "\n==== Front\nCancer Sci\nCancer Sci\n10.1111/(ISSN)1349-7006\nCAS\nCancer Science\n1347-9032\n1349-7006\nJohn Wiley and Sons Inc. Hoboken\n\n33459466\n10.1111/cas.14773\nCAS14773\nReport\nReports\nIdentification of characteristic subepithelial surface granulomatosis in immune‐related adverse event‐associated enterocolitis\nKUBO et al.\nKubo Terufumi https://orcid.org/0000-0001-9274-2551\n1 kuboteru@sapmed.ac.jp\n\nHirohashi Yoshihiko https://orcid.org/0000-0002-0608-3914\n1 hirohash@sapmed.ac.jp\n\nKeira Yoshiko 2\nAkimoto Mayuko 2\nIkeda Tatsuru 2\nKikuchi Noriaki 3\nIwaki Hiroyuki 3\nKikuchi Tomoki 4\nObata Masahiko 4\nMorita Rena 5\nKasai Kiyoshi 5\nSegawa Keiko 6\nTsukahara Tomohide https://orcid.org/0000-0002-3678-4359\n1\nKanaseki Takayuki 1\nMurata Kenji 1\nKikuchi Yasuhiro 1\nShinkawa Tomoyo 1\nHasegawa Tadashi 7\nTorigoe Toshihiko 1\n1 Department of Pathology School of Medicine Sapporo Medical University Sapporo Japan\n2 Department of Pathology Hakodate Goryokaku Hospital Hakodate Japan\n3 Department of Surgical Pathology Sunagawa City Medical Center Sunagawa Japan\n4 Department of Pathology Asahikawa Red‐Cross Hospital Asahikawa Japan\n5 Department of Pathology Otaru City General Hospital Otaru Japan\n6 Department of Pathology Kushiro City General Hospital Kushiro Japan\n7 Department of Surgical Pathology Sapporo Medical University Hospital Sapporo Japan\n* Correspondence\nTerufumi Kubo and Yoshihiko Hirohashi, Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060‐8556, Japan.\nEmails: kuboteru@sapmed.ac.jp (TK) and hirohash@sapmed.ac.jp (YH)\n\n18 1 2021\n3 2021\n112 3 10.1111/cas.v112.3 13201325\n26 10 2020\n03 12 2020\n10 12 2020\n© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nImmune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune‐related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis‐like pattern and a graft vs host disease‐like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call “subepithelial surface granulomatosis” (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.\n\nIn this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with immune checkpoint inhibitors. Interestingly, we found characteristic “subepithelial surface granulomatosis” (SSG) in the colon tissue. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anti‐cancer immune activation.\n\nbiomarker\ncolitis\nimmune checkpoint inhibitors\nimmune‐related adverse event\nsubepithelial surface granulomatosis\nJapan Agency for Medical Research and Development 10.13039/100009619 19cm0106309h0004 source-schema-version-number2.0\ncover-dateMarch 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.9 mode:remove_FC converted:05.03.2021\nKubo T , Hirohashi Y , Keira Y , et al. Identification of characteristic subepithelial surface granulomatosis in immune‐related adverse event‐associated enterocolitis. Cancer Sci. 2021;112 :1320–1325. 10.1111/cas.14773\n\nFunding information\n\nThis work was supported by the Project for Cancer Research and Therapeutic Evolution (P‐CREATE) (Grant number 19cm0106309h0004) from the Japan Agency for Medical Research and Development (AMED) to T. Torigoe.\n==== Body\n1 BACKGROUND\n\nThe increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3\n\nAs described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.\n\n2 METHODS\n\n2.1 Patients and specimens\n\nWith approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.\n\n2.2 IHC staining\n\nTumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.\n\n3 RESULTS\n\n3.1 Patient characteristics\n\nWe analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.\n\nTABLE 1 Clinicopathological features of the 17 patients treated with ICIs\n\n\tAge (years)\tSex\tTumor\tType of ICI (cycles)\tEffect\tSymptom\tEndoscopic finding\tHistology\tSSG\tOther irAE\t\n1\t69\tM\tLung adeno Ca\tPembrolizumab: 200 mg/3 wk (8)\tPR\tDiarrhea\tNonspecific\tGVHD‐like\tPositive\tNo\t\n2\t66\tM\tLung adeno Ca\tNivolumab: 170 mg/2 wk (3)\tPD\tDiarrhea\tNormal\tUC‐like\tNegative\tNo\t\n3\t55\tM\tLung adeno Ca\tNivolumab: 150 mg/2 wk (11)\tPD\tDiarrhea\tNonspecific\tNonspecific\tNegative\tNo\t\n4\t69\tM\tLung adeno Ca\tPembrolizumab: 200 mg/3 wk (16)\tPD\tDiarrhea\tNonspecific\tUC‐like\tNegative\tNo\t\n5\t70\tM\tLung adeno Ca\tPembrolizumab: 200 mg/3 wk (16)\tPR\tDiarrhea\tUC‐like\tUC‐like\tPositive\tUveitis\t\n6\t67\tF\tLung adeno Ca\tPembrolizumab: 200 mg (1)\tPR\tDiarrhea, Melena\tUC‐like\tNonspecific\tNegative\tNo\t\n7\t86\tF\tLung SCC\tNivolumab :155 mg/2 wk (5), 240 mg/2 wk (17)\tSD\tDiarrhea\tNonspecific\tGVHD‐like\tNegative\tNo\t\n8\t58\tF\tLung SCC\tAtezolizumab: 1200 mg/3 wk (10)\tSD\tDiarrhea, melena\tUC‐like\tUC‐like\tPositive\tNo\t\n9\t71\tM\tLung SCC\tPembrolizumab: 200 mg/3 wk (3)\tPR\tNone\tNormal\tNone\tPositive\tNo\t\n10\t69\tF\tLung carcinosarcoma\tPembrolizumab: 200 mg/3 wk (1)\tPD\tMelena\tNonspecific\tUC‐like\tNegative\tNo\t\n11\t66\tM\tUrothelial Ca\tPembrolizumab: 200 mg/3 wk (11)\tCR\tDiarrhea\tUC‐like\tUC‐like\tPositive\tNo\t\n12\t77\tF\tUrothelial Ca\tPembrolizumab: 200 mg/3 wk (10)\tPR\tDiarrhea\tNormal\tGVHD‐like\tPositive\tNo\t\n13\t63\tM\tUrothelial Ca\tPembrolizumab: 200 mg/3 wk (15)\tCR\tMelena\tIschemic\tNonspecific\tNegative\tNo\t\n14\t74\tF\tMelanoma\tNivolumab: 3 mg/kg/2 wk (6)\tCR\tDiarrhea, melena\tUC‐like\tUC‐like\tPositive\tNo\t\n15\t74\tF\tMelanoma\tNivolumab: 3 mg/kg/2 wk (3)\tPD\tDiarrhea\tNonspecific\tGVHD‐like\tPositive\tNo\t\n16\t64\tF\tRenal tumor\tIpilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4)\tCR\tAbdominal pain\tNormal\tGVHD‐like\tPositive\tNo\t\n17\t67\tF\tMucoepidermoid Ca\tNivolumab: 240 mg/3 wk (4)\tPR\tDiarrhea\tNormal\tGVHD‐like\tPositive\tDermatitis\t\nAbbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.\n\nJohn Wiley & Sons, Ltd\n\n3.2 Clinical presentation and endoscopic findings\n\nThe most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.\n\n3.3 Histopathological findings\n\nThere were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).\n\nFIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm\n\nInterestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).\n\nFIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm\n\n4 DISCUSSION\n\nIn this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.\n\nFIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event\n\nOur study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.\n\nIn conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.\n\nDISCLOSURE\n\nThe authors declare that they have no competing interests.\n==== Refs\nREFERENCES\n\n1 Postow MA , Sidlow R , Hellmann MD . Immune‐related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378 :158‐168.29320654\n2 Bellaguarda E , Hanauer S . Checkpoint inhibitor‐induced colitis. Am J Gastroenterol. 2020;115 :202‐210.31922959\n3 Som A , Mandaliya R , Alsaadi D , et al. Immune checkpoint inhibitor‐induced colitis: a comprehensive review. World J Clin Cases. 2019;7 :405‐418.30842952\n4 Gonzalez RS , Salaria SN , Bohannon CD , Huber AR , Feely MM , Shi C . PD‐1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'. Histopathology. 2017;70 :558‐567.28000302\n5 Chen JH , Pezhouh MK , Lauwers GY , Masia R . Histopathologic features of colitis due to immunotherapy with anti‐PD‐1 antibodies. Am J Surg Pathol. 2017;41 :643‐654.28296676\n6 Yanai S , Nakamura S , Kawasaki K , et al. Immune checkpoint inhibitor‐induced diarrhea: clinicopathological study of 11 patients. Dig Endosc. 2020;32 :616‐620.31595568\n7 Barber DL , Sakai S , Kudchadkar RR , et al. Tuberculosis following PD‐1 blockade for cancer immunotherapy. Sci Transl Med. 2019;11 :eaat2702.30651320\n8 Chorti E , Kanaki T , Zimmer L , et al. Drug‐induced sarcoidosis‐like reaction in adjuvant immunotherapy: increased rate and mimicker of metastasis. Eur J Cancer. 2020;131 :18‐26.32248071\n9 Asano M , Nakane A , Minagawa T . Endogenous gamma interferon is essential in granuloma formation induced by glycolipid‐containing mycolic acid in mice. Infect Immun. 1993;61 :2872‐2878.8514390\n10 Patey‐Mariaud de Serre N , Canioni D , Ganousse S , et al. Digestive histopathological presentation of IPEX syndrome. Mod Pathol. 2009;22 :95‐102.18820676\n\n",
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"title": "Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.",
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"abstract": "BACKGROUND\nInflammatory bowel disease can develop in the context of some rheumatic diseases in childhood, including juvenile idiopathic arthritis (JIA). Inflammatory bowel disease (IBD) is frequently associated with other immune-mediated diseases; however, systemic onset JIA (sJIA) has not previously been connected to IBD. Treatment of sJIA has significantly changed in recent years, possibly causing changes in inflammatory patterns. Therefore, data from the German Center for Pediatric and Adolescent Rheumtology from 2010 until 2015 were analyzed by retrospective chart review.\n\n\nRESULTS\nEighty-two patients with confirmed diagosis of sJIA were found. Of these, three were identified with a diagnosis of IBD confirmed by colonoscopy (two cases of Crohn's disease, one case of ulcerative colitis) 0.8 - 4.3 years after diagnosis. All three were treated with IL-1 antagonists (anakinra in two cases, canakinumab in one case) and were well controlled for sJIA symptoms at time of diagnosis of IBD CONCLUSIONS: IBD seems to be a rare, but possible complication of sJIA. Treatment with IL-1 antagonists might be a relevant factor for a switch in the clinical phenotype of the underlying inflammatory process.",
"affiliations": "German Center for Pediatric and Adolescent Rheumatology (GCPAR), Gehfeldstrasse 24, 82467, Garmisch-Partenkirchen, Germany. huegle.boris@rheuma-kinderklinik.de.;German Center for Pediatric and Adolescent Rheumatology (GCPAR), Gehfeldstrasse 24, 82467, Garmisch-Partenkirchen, Germany.;German Center for Pediatric and Adolescent Rheumatology (GCPAR), Gehfeldstrasse 24, 82467, Garmisch-Partenkirchen, Germany.",
"authors": "Hügle|Boris|B|;Speth|Fabian|F|;Haas|Johannes-Peter|JP|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; C541220:canakinumab",
"country": "England",
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"doi": "10.1186/s12969-017-0147-3",
"fulltext": "\n==== Front\nPediatr Rheumatol Online JPediatr Rheumatol Online JPediatric Rheumatology Online Journal1546-0096BioMed Central London 14710.1186/s12969-017-0147-3Short ReportInflammatory bowel disease following anti-interleukin-1-treatment in systemic juvenile idiopathic arthritis Hügle Boris ++49/8821/701-502huegle.boris@rheuma-kinderklinik.de Speth Fabian Haas Johannes-Peter German Center for Pediatric and Adolescent Rheumatology (GCPAR), Gehfeldstrasse 24, 82467 Garmisch-Partenkirchen, Germany 14 3 2017 14 3 2017 2017 15 1628 9 2016 6 3 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nInflammatory bowel disease can develop in the context of some rheumatic diseases in childhood, including juvenile idiopathic arthritis (JIA). Inflammatory bowel disease (IBD) is frequently associated with other immune-mediated diseases; however, systemic onset JIA (sJIA) has not previously been connected to IBD. Treatment of sJIA has significantly changed in recent years, possibly causing changes in inflammatory patterns. Therefore, data from the German Center for Pediatric and Adolescent Rheumtology from 2010 until 2015 were analyzed by retrospective chart review.\n\nFindings\nEighty-two patients with confirmed diagosis of sJIA were found. Of these, three were identified with a diagnosis of IBD confirmed by colonoscopy (two cases of Crohn’s disease, one case of ulcerative colitis) 0.8 – 4.3 years after diagnosis. All three were treated with IL-1 antagonists (anakinra in two cases, canakinumab in one case) and were well controlled for sJIA symptoms at time of diagnosis of IBD\n\nConclusions\nIBD seems to be a rare, but possible complication of sJIA. Treatment with IL-1 antagonists might be a relevant factor for a switch in the clinical phenotype of the underlying inflammatory process.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12969-017-0147-3) contains supplementary material, which is available to authorized users.\n\nKeywords\nSystemic juvenile idiopathic arthritisInflammatory bowel diseaseIL-1 Antagonistsissue-copyright-statement© The Author(s) 2017\n==== Body\nFindings\nSystemic-onset juvenile idiopathic arthritis (sJIA) is an autoinflammatory disease characterized by increased levels of interleukin(IL)-1 and IL-6 [1]. Anakinra and canakinumab are both medications used successfully in sJIA, aiming to neutralize the effects of IL-1 [2, 3].\n\nInflammatory bowel diseases (IBD) are associated with several immune-mediated diseases, with almost a quarter of patients showing first symptoms during childhood or adolescence [4]. While unspecific mild bowel inflammation has been described in sJIA, IBD has not been observed as an extrarticular manifestation [5, 6].\n\nWe present three pediatric cases with confirmed diagnosis of sJIA who developed IBD diagnosed by histology and coloscopy during treatment with IL-1 antagonists.\n\nPatients and Methods\nThe database of the German Center for Pediatric and Adolescent Rheumatology was searched for all sJIA patients (n = 82) with a confirmed diagnosis of IBD from 2010 until 2015. Four patients were identified; one was excluded as histology showed only unspecific round-cell infiltrate. Chart survey was used to extract demographic data, date of diagnosis of sJIA and IBD, clinical and laboratory data and medications.\n\nCase descriptions\nClinical and laboratory data of the cases at time of diagnosis of sJIA and of IBD are described in Tables 1 and 2, respectively. (Additional file 1: Table S1 and Additional file 2: Table S2).Table 1 Demographics of the patients, clinical and laboratory data at time of diagnosis of sJIA, and time and dose of anti-IL-1 medication\n\nPatient\t1\t2\t3\t\nGender\tm\tm\tf\t\nANA/RF/HLA-B27\tneg/neg/neg\tneg/neg/n.d.\tneg/neg/neg\t\nAge at diagnosis\t14.8\t15.8\t6.8\t\nILAR criteria for subtype\tFever, typical rash, splenomegaly, pericardial effusion\tFever, rash, pericardial/pleural effusion, hepatomegaly\tFever, rash, pleural effusion, hepatomegaly\nsplenomegaly\t\nAffected joints\tPolyarthritis\tPolyarthritis\tElbows, hips, wrists\t\nLeukocyte count\t9100/mm3\n\n(4800–10000)\t9100/mm3\n\n(4500–12500)\t16800/mm3\n\n(4800–10000)\t\nPlatelet count\t294000/mm3\n\n(150000–450000)\t208000/mm3\n\n(154000–386000)\t575000/mm3\n\n(150000–450000)\t\nFerritin\t2926 μg/l\n(30–400)\t32722 ng/ml\n(22–322)\t297–1197 μg/l\n(30–400)\t\nC-reactive protein\t7.4 mg/dl\n(0.2–1.0)\t28.54 mg/dl\n(<0.3)\t3.36 mg/dl\n(0.2–1.0)\t\nBone marrow biopsy findings\tNegative\tMAS\t-\t\nStart of IL1-treatment, years after diagnosis\t0 years\t2.2 years\t0.3 years\t\nIL-1 agents, initial dose\tAnakinra\n1.3 mg/kg\tCanakinumab\n1.8 mg/kg\tAnakinra\n1.1 mg/kg\t\nnormal values in parentheses\n\n\nneg negative, n.d. not done\n\n\nTable 2 Colonoscopy findings, clinical and laboratory data at time of diagnosis of IBD of the patients\n\nPatient\t1\t2\t3\t\nTime between diagnoses of sJIA and IBD\t0.9 years\t4.4 years\t4.7 years\t\nTime between start of Anti-IL1 agent and IBD\t0.9 years\t2.2 years\t4.4 years\t\nAnti-IL1 agents, dosage\tAnakinra, 1.3 mg/kg\tCanakinumab, 1.8 mg/kg\tAnakinra, 0.7 mg/kg\t\nOther medications\tNone\tCyclosporin A\tNone\t\nColonoscopy, macroscopic findings\tActive, ulcerous ileitis and colitis, consistent with Crohn’s disease\tActive colitis from sigmoid to coecum, consistent with Crohn’s disease\tColitis in colon descendens, consistent with ulcerative colitis\t\nColonoscopy, microscopic findings\tGranulomatous inflammation\tInflammatory infiltrate\tInflammatory infiltrate\t\nDiarrhea\tPresent\tPresent\tPresent\t\nMacroscopic blood in stool\tAbsent\tAbsent\tPresent\t\nFerritin\t138 ng/ml\n(9–80)\t154 ng/ml\n(30–400)\t10 ng/ml\n(30–400)\t\nCRP\t12.1 mg/dl\n(< 0.8)\t4.67 mg/dl\n(0.02–1.0)\t0.44 mg/dl\n(0.2–1.0)\t\nCalprotectin/stool\tNot available\t877 μg/g\n(<50)\t1264 μg/g\n(<50)\t\nnormal values in parentheses\n\n\n\n\n\nCase I is a Caucasian male. He presented at age 14 years and 10 months with high quotidian fever with associated diffuse exanthema, splenomegaly, mild pericardial effusion and polyarthritis. Infectious workup showed elevated IgG and IgM antibodies against Parvovirus B19. He did not complain about abdominal symptoms and had a normal bowel ultrasound except for splenomegaly. He received methylprednisolone pulse therapy and indomethacin and was started on anakinra, with rapid remission within 3 months.\n\nAfter 11 months on anakinra he developed increasing abdominal pain and diarrhea. Stool cultures were negative. Colonoscopy showed ileitis and discontinuous inflammation in the ascending colon. Histology confirmed granulomatous inflammation. With a diagnosis of Crohn’s disease he was started on azathioprine and prednisolone, while anakinra was tapered. He presented 3 months later with fevers and markedly elevated inflammatory parameters without diarrhea. After excluding systemic inflammation or infection, his colonoscopy was repeated and returned a result of highly active Crohn’s disease. Treatment with infliximab and methotrexate was started, leading to rapid and ongoing remission 8 months later.\n\n\nCase II is a Caucasian male, who presented at age 15 years and 10 months with fevers, arthritis and exanthema and developed polyarthritis, pericardial and pleural effusion within a few weeks. At that time, he had borderline positive IgM antibodies against Coxsackie virus, Adenovirus and Epstein-Barr virus. He was treated with NSAID and steroids, but developed two episodes of macrophage activation syndrome, with recurrence on cyclosporin after the first episode. Three months prior to the second episode, he was diagnosed with Influenza A. Twenty-three months after diagnosis he was started on anakinra after methylprednisolone pulses which led to brief improvement. Three months later he presented with severe signs of systemic arthritis and elevated inflammatory parameters. Treatment with tocilizumab showed no improvement, but canakinumab – in addition to cyclosporine and low dose steroids – led to rapid and lasting remission over the next 2 years.\n\nAfter 24 months on canakinumab he presented with fatigue, arthralgias without arthritis and elevated C-reactive protein, with diarrhea and weight loss. Increasing doses of canakinumab and prednisolone did not lead to improvement. Infectious work-up showed again borderline positive IgM antibodies against Coxsackie, but negative stool cultures. Colonoscopy showed active colitis extending from proximal sigmoid to the cecum with several, partly confluent ulcerations. The iliocecal valve was gaping, and the terminal ileum exhibited erythema and punch defects of the mucosal membrane. Duodenal biopsy showed edematous and coarse villi, with detachment of epithelium and mostly neutrophilic inflammatory infiltrate. Even without granuloma formation, this was interpreted as Crohn’s disease, supported by positive antibodies against Saccharomyces cerevisiae (ASCA). Canakinumab was discontinued, and he was started on budenoside and infliximab, which led to rapid remission, ongoing 18 months after diagnosis of IBD.\n\n\nCase III is a Caucasian male of mixed German and Turkish origin. He presented at age 6 years and 10 months with fevers, arthritis, exanthema, pleural effusion and oligoarthritis. An extensive infectious workup showed no result. He was treated with indomethacin, steroids and methotrexate. He presented 4 months later with arthritis, fevers and elevated inflammatory parameters. Treatment with steroids and etanercept showed no effect after 3 doses, so he was switched to anakinra, leading to prompt improvement of clinical signs and laboratory parameters.\n\nHe entered long lasting remission, but started to develop mild abdominal symptoms after 3 years on anakinra and methotrexate. Methotrexate was discontinued 6 months later, and in the following months he showed increasing abdominal pain and blood in his stools. Stool cultures were negative. He received a colonoscopy 4 years after starting anakinra, which showed severe inflammation of the colon descendens consistent with ulcerative colitis, with histology showing edema of the lamina propria with inflammatory lymphocytic and neutrophilic infiltrate, and also focal inflammation in the crypt walls. He was continued on low dose anakinra (0.5 mg/kg) and started on mesalazin and azathioprine, with ongoing mild gastrointestinal complaints on last follow-up.\n\nDiscussion\nHere we present three patients with confirmed diagnosis of sJIA who developed signs of IBD on treatment with anti-IL1 agents, either anakinra or canakinumab. All cases fulfilled ILAR criteria for sJIA at the time of diagnosis, and none had any clinical signs of IBD at that time. Although the age range in these patients falls well within the described spectrum, the majority of patients with sJIA initially present below the age of 5 years. All patients developed typical manifestations of Crohn’s disease or ulcerative colitis, where monoclonal TNFα antibodies or DMARDS were required to gain disease control (for comparison, see Table 3). The one patient receiving low-dose anakinra in fact continued to have low grade abdominal symptoms, possibly indicating an ongoing pro-inflammatory effect of anti-IL1 medication.Table 3 Similarities to and differences between the presentation of systemic juvenile idiopathic arthritis and inflammatory bowel disease in children\n\n\tJuvenile Idiopathic Arthritis\tInflammatory Bowel Disease\t\nOnset of the disease\tAcute onset with high, quotidian fevers,\tTypically subacute illness with fatigue, anemia, and weight loss. Occasionally more fulminant presentation.\t\nGastrointestinal symptoms\tFrequently abdominal pain, also nausea and anorexia\tLoose stools and/or bloody diarrhea, abdominal pain, tenesmus\t\nMuskuloskeletal symptoms\tInitially, mild oligoarticular arthritis, frequently severe polyarthritis over the course of the disease\tNonerosive, asymmetric arthritis, affecting the large joints, parallel to intestinal involvement\t\nSkin manifestations\tInitial presentation with evanescent, salmon-colored, cutaneous eruption\tErythema nodosum, pyoderma gangrenosum\t\nLaboratory abnormalities\tAnemia, reactive thrombocytosis, markedly elevated erythrocyte sedimentation rate and C-reactive protein. Significantly elevated ferritin. Typically negative antinuclear antibodies and rheumatoid factor.\tAnemia, elevated erythrocyte sedimentation rate and C-reactive protein, depressed albumin level, occult blood in the stool, elevated fecal calprotectin. Ferritin typically low or normal. Typically negative antinuclear antibodies and rheumatoid factor.\t\n\n\n\nFew reports exist of patients with sJIA developing IBD. Twenty-nine patients with various subtypes of JIA, including three with sJIA, have been linked to IBD on treatment with etanercept, and one on infliximab [7–9]. All three patients developed Crohn’s disease between 5 and 12 years after diagnosis of sJIA on treatment with etanercept; all patients went into clinical remission after discontinuation of etanercept and treatment of IBD. A recent survey from the German biologics registry did find IBD in eleven of 3,071 patients with JIA, but none with sJIA [10]. Endoscopic studies on 27 JIA patients with gastrointestinal symptoms also found ulcerative colitis in five patients (19%), but none with sJIA [5]. Phenotypes of rheumatic diseases can evidently change over time, especially in childhood. sJIA changes from IL-1 driven acute febrile sJIA to IL-17 driven chronic active sJIA over time [1]. In endoscopic mucosal samples, IBD similarly exhibits a strong TH1 phenotype in early lesions and switches to a TH17 phenotype, with marked increase in IL-17A, and induction of IL-6 and IL-23; it can occur subsequent to different categories of JIA as well as spondyloarthropathies [11, 12]. IBD, especially Crohn’s disease, is considered an NF-κB activation disorder as part of the spectrum of autoinflammatory diseases, where cross-overs have frequently been observed – a change of sJIA into an IBD phenotype therefore seems at least possible in theory [13]. In fact, a recent study of mucosal biopsies in 33 JIA patients with gastrointestinal symptoms included eight with sJIA, with two patients with mild eosinophilic infiltration in the colon, and one 4 year old patient with active gastrointestinal inflammation [6].\n\nAll three patients were exposed to IL-1 antagonists when developing symptoms of IBD. IL-1 is known to be expressed at high levels in colonic biopsies from patients with IBD, supporting the hypothesis of a pro-inflammatory role. Animal models of colitis both in rabbits and rats improve with blockade of IL-1 [14]. However, recent mouse models show a differentiated role for IL-1α and IL-1β, where IL-1α, produced mainly by colonic epithelial cells, acts in an inflammatory fashion [15]. In comparison, IL-1β, produced mostly by myeloid cells, promotes healing and repair in colonic tissue; IL-1β deficient mice show more severe colitis with failure of repair mechanisms [16]. Anakinra blocks both IL-1α and IL-1β, but in the mouse model described, experimental specific IL-1α antibodies were significantly more efficacious in reducing severity of colitis compared to external IL-1 receptor antagonist (IL-1RA). Canakinumab by design specifically targets IL1-β, with no effect on IL-1α. Disturbance of the IL1-1α/β equilibrium by these medications might possibly create a pro-inflammatory environment in the colon, leading to IBD in selected cases. Patients with active IBD have in fact been shown to have increased levels of IL-1RA [17]. So far, no clinical trials have been reported for IL-1 antagonists in IBD, but one case of IBD worsening with anakinra treatment has been described [18]. One patient with sJIA in a randomized clinical trial for anakinra did also in fact develop Crohn’s disease [19].\n\nGastrointestinal symptoms in JIA are not uncommon, with several series describing results from gastrointestinal investigations [5, 6]. The majority of cases, including those with sJIA, show mild, nonspecific inflammation, frequently with a prominent eosinophilic infiltrate, with more severe inflammation in only a few cases. It is possible that the three cases presented here represent the extreme end of this spectrum. However, all three patients had ongoing, severe abdominal manifestations over several months while sJIA symptoms were well controlled. The three patients had extensive infectious work-up during diagnosis, which showed positive IgM antibodies for various pathogens, whose impact on the disease progression and change in phenotype is unclear.\n\nThis is a case series; therefore, any conclusions about an underlying pathological mechanism would be premature. The impact of medications on the development of IBD is unclear: the interval between IL-1 blocker treatment and IBD manifestations is highly variable, and it is possible that methotrexate withdrawal in case 3 lead to uncovering of a previously subclinical IBD. However, three cases of IBD in a single tertiary center cohort of 82 patients argues against mere coincidence.\n\nIn summary, this is the first report of sJIA patients developing IBD in temporal connection with IL-1 antagonist treatment. It is not clear if these cases are coincident, represent a change in patterns of inflammation of sJIA or are a consequence of treatment. Further efforts should aim at collecting more patients and elucidating the underlying disease processes.\n\nAdditional files\n\nAdditional file 1: Table S1. Supplementary clinical and laboratory data for the patients at time of diagnosis of sJIA. (DOCX 23 kb)\n\n\nAdditional file 2: Table S2. Coloscopy results of the 3 patients, translated and summarized from the German original. (DOCX 23 kb)\n\n\n\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis study was not supported by any outside funding.\n\nAvailability of data and materials\nThe datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nBH designed the study, performed the data collection and the analysis. FS and JPH participated in the analysis and helped draft the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nThe study was approved by the Ethics Committee of the Medical Faculty, Ludwig-Maximilians University Munich, Germany.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Mellins ED Macaubas C Grom AA Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions Nat Rev Rheumatol 2011 7 416 26 10.1038/nrrheum.2011.68 21647204 \n2. Nigrovic PA Mannion M Prince FH Zeft A Rabinovich CE van Rossum MA Cortis E Pardeo M Miettunen PM Janow G Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series Arthritis Rheum 2011 63 545 55 10.1002/art.30128 21280009 \n3. Ruperto N Brunner HI Quartier P Constantin T Wulffraat N Horneff G Brik R McCann L Kasapcopur O Rutkowska-Sak L Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis N Engl J Med 2012 367 2396 406 10.1056/NEJMoa1205099 23252526 \n4. Kappelman MD Galanko JA Porter CQ Sandler RS Association of paediatric inflammatory bowel disease with other immune-mediated diseases Arch Dis Child 2011 96 1042 6 10.1136/archdischild-2011-300633 21903597 \n5. Kokkonen J Arvonen M Vahasalo P Karttunen TJ Intestinal immune activation in juvenile idiopathic arthritis and connective tissue disease Scand J Rheumatol 2007 36 386 9 10.1080/03009740701394005 17963169 \n6. Pichler J, Ong C, Shah N, Sebire N, Kiparrissi F, Borrelli O, Pilkington C, Elawad M. Histopathological features of gastrointestinal mucosal biopsies in children with juvenile idiopathic arthritis. Pediatr Res. 2016.\n7. van Dijken TD Vastert SJ Gerloni VM Pontikaki I Linnemann K Girschick H Armbrust W Minden K Prince FH Kokke FT Development of inflammatory bowel disease in patients with juvenile idiopathic arthritis treated with etanercept J Rheumatol 2011 38 1441 6 10.3899/jrheum.100809 21459936 \n8. Dallocchio A Canioni D Ruemmele F Duquesne A Scoazec JY Bouvier R Paraf F Languepin J Wouters CH Guillot M Occurrence of inflammatory bowel disease during treatment of juvenile idiopathic arthritis with etanercept: a French retrospective study Rheumatology (Oxford) 2010 49 1694 8 10.1093/rheumatology/keq136 20472717 \n9. Ruemmele FM Prieur AM Talbotec C Goulet O Schmitz J Development of Crohn disease during anti-TNF-alpha therapy in a child with juvenile idiopathic arthritis J Pediatr Gastroenterol Nutr 2004 39 203 6 10.1097/00005176-200408000-00016 15269630 \n10. Barthel D Ganser G Kuester RM Onken N Minden K Girschick HJ Hospach A Horneff G Inflammatory bowel disease in juvenile idiopathic arthritis patients treated with biologics J Rheumatol 2015 42 2160 5 10.3899/jrheum.140472 26373564 \n11. Mielants H Veys EM Cuvelier C De Vos M Goemaere S Maertens M Joos R Gut inflammation in children with late onset pauciarticular juvenile chronic arthritis and evolution to adult spondyloarthropathy--a prospective study J Rheumatol 1993 20 1567 72 8164217 \n12. Zorzi F Monteleone I Sarra M Calabrese E Marafini I Cretella M Sedda S Biancone L Pallone F Monteleone G Distinct profiles of effector cytokines mark the different phases of Crohn’s disease PLoS One 2013 8 e54562 10.1371/journal.pone.0054562 23349929 \n13. Masters SL Simon A Aksentijevich I Kastner DL Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*) Annu Rev Immunol 2009 27 621 68 10.1146/annurev.immunol.25.022106.141627 19302049 \n14. Thomas TK Will PC Srivastava A Wilson CL Harbison M Little J Chesonis RS Pignatello M Schmolze D Symington J Evaluation of an interleukin-1 receptor antagonist in the rat acetic acid-induced colitis model Agents Actions 1991 34 187 90 10.1007/BF01993274 1838896 \n15. Bamias G Arseneau KO Cominelli F Cytokines and mucosal immunity Curr Opin Gastroenterol 2014 30 547 52 10.1097/MOG.0000000000000118 25203451 \n16. Bersudsky M Luski L Fishman D White RM Ziv-Sokolovskaya N Dotan S Rider P Kaplanov I Aychek T Dinarello CA Non-redundant properties of IL-1alpha and IL-1beta during acute colon inflammation in mice Gut 2014 63 598 609 10.1136/gutjnl-2012-303329 23793223 \n17. Kuboyama S Increased circulating levels of interleukin-1 receptor antagonist in patients with inflammatory bowel disease Kurume Med J 1998 45 33 7 10.2739/kurumemedj.45.33 9658748 \n18. Carter JD Valeriano J Vasey FB Crohn disease worsened by anakinra administration J Clin Rheumatol 2003 9 276 7 10.1097/01.RHU.0000081265.06408.e4 17041471 \n19. Quartier P Allantaz F Cimaz R Pillet P Messiaen C Bardin C Bossuyt X Boutten A Bienvenu J Duquesne A A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial) Ann Rheum Dis 2011 70 747 54 10.1136/ard.2010.134254 21173013\n\n",
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"title": "Inflammatory bowel disease following anti-interleukin-1-treatment in systemic juvenile idiopathic arthritis.",
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"abstract": "HIV is known for its genetic variability across the globe. The HIV epidemic in India is primarily driven by subtype C, although sporadic circulating and unique recombinant forms are also reported from a few metropolitan cities in which genotyping facilities are available. Here we report a novel CRF01_AE/C recombinant from a multicenter study on the effectiveness of antiretroviral therapy (ART), 12 months after its initiation. Our subject is a 32-year-old heterosexual female, a native of Pune city in western India. Identification and analyses of recombination breakpoints using jpHMM@Gobics and SimPlot bootscanning revealed six recombination breakpoints, indicating insertion of the CRF01_AE genome at three points in the backbone of subtype C. Both subtype C and CRF01_AE are commonly seen in the population at risk of heterosexual HIV transmission, thereby providing an opportunity for cocirculation and recombination. The emergence of a novel recombinant of CRF01_AE/C is indicative of the increasing genetic diversity of the HIV epidemic in India.",
"affiliations": "1 HIV Drug Resistance Laboratory, National AIDS Research Institute , Pune, India .;1 HIV Drug Resistance Laboratory, National AIDS Research Institute , Pune, India .;1 HIV Drug Resistance Laboratory, National AIDS Research Institute , Pune, India .;1 HIV Drug Resistance Laboratory, National AIDS Research Institute , Pune, India .;3 Department of Clinical Sciences, National AIDS Research Institute , Pune, India .;4 Department of Tuberculosis and Chest Diseases, Yashwantrao Chavan Memorial Hospital , Pune, India .;5 National Programme Officer (ART) , National AIDS Control Organization, New Delhi, India .;3 Department of Clinical Sciences, National AIDS Research Institute , Pune, India .",
"authors": "Karade|Santosh|S|;Pandey|Sudhanshu|S|;Gianchandani|Sheetal|S|;Kurle|Swarali N|SN|;Ghate|Manisha|M|;Gaikwad|Nitin S|NS|;Rewari|Bharat B|BB|;Gangakhedkar|Raman R|RR|",
"chemical_list": "D044966:Anti-Retroviral Agents; D012367:RNA, Viral",
"country": "United States",
"delete": false,
"doi": "10.1089/aid.2015.0228",
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"issn_linking": "0889-2229",
"issue": "31(12)",
"journal": "AIDS research and human retroviruses",
"keywords": null,
"medline_ta": "AIDS Res Hum Retroviruses",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D023241:Antiretroviral Therapy, Highly Active; D002947:Cities; D005260:Female; D005838:Genotype; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007194:India; D008969:Molecular Sequence Data; D012367:RNA, Viral; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA",
"nlm_unique_id": "8709376",
"other_id": null,
"pages": "1269-73",
"pmc": null,
"pmid": "26323027",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Near Full-Length Genomic Characterization of a Novel CRF 01_AE/C Recombinant from Western India.",
"title_normalized": "near full length genomic characterization of a novel crf 01 ae c recombinant from western india"
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],
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"literaturereference": "GANGAKHEDKAR R, KARADE S, PANDEY S, GIANCHANDANI S, KURLE S, GHATE M, GAIKWAD N, REWARI B. NEAR FULL-LENGTH GENOMIC CHARACTERIZATION OF A NOVEL CRF 01_AE/C RECOMBINANT FROM WESTERN INDIA. AIDS-RES-HUM-RETROVIRUSES. 2015?31(12):1269-1273.",
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},
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}
] |
{
"abstract": "A 70-year-old man experienced an amoxycillin-induced anaphylactic reaction complicated by acute inferior myocardial infarction with transient ST-segment elevation. There was a spontaneous resolution of ST-segment elevation and the patient was treated for anaphylaxis. Coronary angiography showed severe obstructive coronary atherosclerosis, but not involving the infarct-related artery. Percutaneous coronary intervention of the affected artery was then performed and the patient was discharged three days later. Acute ST-elevation myocardial infarction has been described as one of the severe, still rare cardiovascular complications of anaphylaxis. In the present case, according to the previous reports, the main pathogenetic mechanism involved appears to have been coronary vasospasm probably caused by the release of potent vasoactive mast cell derived mediators in the setting of anaphylaxis.",
"affiliations": null,
"authors": "Del Furia|Francesca|F|;Querceto|Loreno|L|;Testi|Sergio|S|;Santoro|Giovanni Maria|GM|",
"chemical_list": "D000658:Amoxicillin",
"country": "Netherlands",
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"issn_linking": "0167-5273",
"issue": "117(1)",
"journal": "International journal of cardiology",
"keywords": null,
"medline_ta": "Int J Cardiol",
"mesh_terms": "D000368:Aged; D000658:Amoxicillin; D000707:Anaphylaxis; D023921:Coronary Stenosis; D004342:Drug Hypersensitivity; D004562:Electrocardiography; D006801:Humans; D008297:Male; D009203:Myocardial Infarction; D016896:Treatment Outcome",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "e37-9",
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"pmid": "17303266",
"pubdate": "2007-04-12",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Acute ST-segment elevation myocardial infarction complicating amoxycillin-induced anaphylaxis: a case report.",
"title_normalized": "acute st segment elevation myocardial infarction complicating amoxycillin induced anaphylaxis a case report"
} | [
{
"companynumb": "IT-TEVA-717132ACC",
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"literaturereference": "FURIA F. ACUTE ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION COMPLICATING AMOXYCILLIN-INDUCED ANAPHYLAXIS: A CASE REPORT. INTERNATIONAL JOURNAL OF CARDIOLOGY. 2007 JAN 01;E37-E39.",
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},
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},
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] |
{
"abstract": "BACKGROUND\nRelapsed or refractory classical Hodgkin lymphoma could be treated with multiagent salvage chemotherapy followed by autologous haematopoietic stem-cell transplantation. The aim of this study is to establish the safety and activity of dose-dense brentuximab vedotin combined with ifosfamide, carboplatin, and etoposide (BV-ICE) chemotherapy in second-line treatment of classical Hodgkin lymphoma.\n\n\nMETHODS\nWe conducted a single-arm, open-label, phase 1/2 study of dose-dense BV-ICE at the Seattle Cancer Care Alliance, University of Washington (Seattle, WA, USA). Eligibility criteria were age 18 years or older; diagnosis of first relapse, primary refractory classical Hodgkin lymphoma after one previous line of therapy; measurable disease of at least 1 cm in the longest axis, CT of chest, abdomen, and pelvis with PET within the past 28 days; Eastern Cooperative Oncology Group performance status of 0-1; and adequate organ function. A 3 + 3 dose escalation study was done for the phase 1 part of the trial to establish the maximum tolerated dose to be used for the phase 2 study. Brentuximab vedotin was delivered on days 1 and 8 at either 1·2 mg/kg (dose level 1) or 1·5 mg/kg (dose level 2) intravenously (capped at 150 mg) with standard dosing of ICE on days 1-3 (ifosfamide 5 g/m2 plus mesna 5 g/m2 intravenously over 24 h on day 2, carboplatin area under the curve 5 on day 2 in one intravenous injection, and etoposide 100 mg/m2 on days 1-3 in one intravenous injection per day) for two 21-day cycles. The primary endpoint was to establish the recommended phase 2 dose (phase 1 part) and complete response rate after two cycles, with a prespecified target of 78% (phase 2 part). Safety analysis was done in all enrolled participants and the primary activity analysis was done in all patients with evaluable response data. This study is registered with ClinicalTrials.gov (NCT02227199); enrolment and study treatment are complete.\n\n\nRESULTS\nBetween Oct 16, 2014, and Feb 10, 2020, we enrolled 45 patients with a median age of 31 years (IQR 28-45). The recommended phase 2 dose of brentuximab vedotin was established to be 1·5 mg/kg. After a median follow-up of 3·1 years (IQR 1·7-4·1), 32 (74%; 95% CI 58·8-86·5) of 43 evaluable patients had complete responses after two cycles of treatment. Grade 3-4 haematological toxic effects were common, including neutropenia (33 [73%]), anaemia (six [13%]), and thrombocytopenia (36 [80%]). The most common grade 3-4 non-haematological toxic effects were febrile neutropenia (four [9%]), sepsis (six [13%]), increased alanine aminotransferase (five [11%]), hyperglycaemia (three [7%]), pulmonary embolism (two [4%]), and increased aspartate aminotransferase (two [4%]). There was one (2%) on-treatment death due to multisystem organ failure that was considered treatment related. Serious adverse events occurred in 13 (29%) patients.\n\n\nCONCLUSIONS\nOur data suggest that dose-dense BV-ICE is a rapidly administered and active salvage regimen for patients with relapsed or refractory classical Hodgkin lymphoma despite a complete response in this trial lower than the prespecified phase 2 target. Although cross-trial comparisons should be made with caution, activity results seem to be similar to previously presented brentuximab vedotin chemotherapy salvage combinations delivered over much longer durations and can be considered in young (<60 years), transplantation-eligible patients for second-line therapy.\n\n\nBACKGROUND\nSeagen, Lymphoma Research Foundation, National Institutes of Health/National Cancer Institute, and generous philanthropic donations to the University of Washington from numerous individuals and families in support of lymphoma research.",
"affiliations": "Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.;Seattle Cancer Care Alliance, Seattle, WA, USA.;Seattle Cancer Care Alliance, Seattle, WA, USA.;Seattle Cancer Care Alliance, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA.;Department of Radiology, University of Washington, Seattle, WA, USA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Electronic address: agopal@uw.edu.",
"authors": "Lynch|Ryan C|RC|;Cassaday|Ryan D|RD|;Smith|Stephen D|SD|;Fromm|Jonathan R|JR|;Cowan|Andrew J|AJ|;Warren|Edus H|EH|;Shadman|Mazyar S|MS|;Shustov|Andrei|A|;Till|Brian G|BG|;Ujjani|Chaitra S|CS|;Libby|Edward N|EN|;Philip|Mary|M|;Coye|Hilary|H|;Martino|Christen N|CN|;Bhark|Sandra L|SL|;Morris|Karolyn|K|;Rasmussen|Heather|H|;Behnia|Sanaz|S|;Voutsinas|Jenna|J|;Gopal|Ajay K|AK|",
"chemical_list": "D005047:Etoposide; D000079963:Brentuximab Vedotin; D016190:Carboplatin; D007069:Ifosfamide",
"country": "England",
"delete": false,
"doi": "10.1016/S2352-3026(21)00170-8",
"fulltext": null,
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"issn_linking": "2352-3026",
"issue": "8(8)",
"journal": "The Lancet. Haematology",
"keywords": null,
"medline_ta": "Lancet Haematol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000079963:Brentuximab Vedotin; D016190:Carboplatin; D019008:Drug Resistance, Neoplasm; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D006689:Hodgkin Disease; D006801:Humans; D007069:Ifosfamide; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e562-e571",
"pmc": null,
"pmid": "34329577",
"pubdate": "2021-08",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "25683846;25267740;16954517;25901426;22184409;17426059;24970842;25533035;10577849;30657848;25098425;28291393;32048731;29224502;23182987;29229594;28992848;17242396;16329112;29449275;20660832;30266774;22454421;27332902;29703778;20220182",
"title": "Dose-dense brentuximab vedotin plus ifosfamide, carboplatin, and etoposide for second-line treatment of relapsed or refractory classical Hodgkin lymphoma: a single centre, phase 1/2 study.",
"title_normalized": "dose dense brentuximab vedotin plus ifosfamide carboplatin and etoposide for second line treatment of relapsed or refractory classical hodgkin lymphoma a single centre phase 1 2 study"
} | [
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],
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Sepsis",
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"reactionoutcome": "6"
}
],
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"literaturereference_normalized": "dose dense brentuximab vedotin plus ifosfamide carboplatin and etoposide for second line treatment of relapsed or refractory classical hodgkin lymphoma a single centre phase 1 2 study",
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"abstract": "BACKGROUND\nCongenital infection with human cytomegalovirus is a major cause of morbidity and mortality. A randomized controlled trial showed that high-dosage valacyclovir prevents cytomegalovirus disease in transplant recipients. Fetuses showing ultrasound features of infection are at high risk of being symptomatic at or before birth. In a pilot study, oral administration of high-dosage valacyclovir to mothers significantly decreased viral load and produced therapeutic concentrations in the blood of infected fetuses. A randomized controlled trial comparing prenatal treatment with valacyclovir against placebo in infected fetuses failed to recruit because women declined randomization. Randomized controlled trials in fetal medicine have often proven unacceptable by women who decline termination of pregnancy and are not prepared to resign themselves to the odds of the natural history of the disease.\n\n\nOBJECTIVE\nWe evaluated the efficacy of oral valacyclovir, 8 g daily, for pregnant women carrying a symptomatic cytomegalovirus-infected fetus, targeting a high-risk group for developing both neurosensory and neurological impairment.\n\n\nMETHODS\nWe designed a multicenter, open-label, phase II study with 1 arm, using one of Simon's optimal 2-stage designs. Symptomatic fetuses were defined by the presence of measurable extracerebral or mild cerebral ultrasound symptoms. They were treated in utero from prenatal diagnosis at a median of 25.9 weeks' gestation until delivery or termination of pregnancy. Fetuses with severe brain anomalies on ultrasound were not included as were cases completely asymptomatic at presentation, because treatment was unlikely to modify either outcome. The primary endpoint was the proportion of asymptomatic neonates born to treated mothers.\n\n\nRESULTS\nAt the interim analysis, 8 of 11 women delivered an asymptomatic neonate (required: ≥7). In step 2, 32 additional cases were included for a total of 43; the final number of asymptomatic neonates was 34, more than the 31 required to indicate efficacy according to the Simon 2-stage design. They remained asymptomatic at 12 months. High-dosage valacyclovir given for a median of 89 days to pregnant women carrying a moderately infected fetus was efficient at giving birth to asymptomatic neonates. Fetal blood viral loads decreased and platelet counts increased, both significantly (P = .01 and P < .001, respectively), between treatment initiation and birth after treatment completion, regardless of duration of fetal infection. Compared with a historical cohort obtained by a metaanalysis of the literature, the use of valacyclovir (8 g daily) significantly increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment. Although the pill burden was high (16 pills a day) adherence to treatment was >90%. Finally, valacyclovir at this high dosage was extremely well tolerated.\n\n\nCONCLUSIONS\nOur results indicate that high-dosage valacyclovir given in pregnancy is effective for improving the outcome of moderately symptomatic infected fetuses. Although this study is not a randomized controlled trial, this is the first study reporting the efficacy of an antiviral drug to treat cytomegalovirus-infected fetuses. Moreover, this first study will allow new trials to be conducted, using valacyclovir as a baseline safe and effective treatment in pregnancy, to be compared to the new emerging and more potent anticytomegalovirus drugs that have not currently been tested in pregnancy.",
"affiliations": "Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Laboratoire de Microbiologie Clinique, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France; Centre National de Réfèrence Cytomegalovirus-Laboratoire Associé, Paris, France.;Assistance publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Unité de Recherche Clinique et Département de Santé Publique, Boulogne, France; Université Versailles Saint Quentin, Unité Mixte de Recherche-S 1168, Université Versailles St-Quentin-en-Yvelines, Montigny, France.;Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Unité de Recherche Clinique, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France.;Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Maternité, Unité de Médecine Fœtale, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France.;Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Réanimation Néonatale, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France.;Hôpital Intercommunal de Poissy-Saint Germain, Maternité, Poissy, France.;Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Maternité, Unité de Médecine Fœtale, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France.;Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Laboratoire de Microbiologie Clinique, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France; Centre National de Réfèrence Cytomegalovirus-Laboratoire Associé, Paris, France.;Assistance publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Unité de Recherche Clinique et Département de Santé Publique, Boulogne, France; Université Versailles Saint Quentin, Unité Mixte de Recherche-S 1168, Université Versailles St-Quentin-en-Yvelines, Montigny, France.;Hôpital Universitaire de Caen, Maternité, Caen, France.;Hôpital Universitaire de Nantes, Département d'Obstétrique et de Médecine Fœtale, Nantes, France; UMR 1280 Physiologie des Adaptations Nutritionnelles, Institut National de Recherche Agronomique, Université de Nantes, France.;Hôpital Foch, Service de Gynécologie-Obstétrique, Suresnes, France.;Hôpital Américain de Paris, Unité de Médecine prénatale, Neuilly Sur Seine, France.;Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Maternité, Unité de Médecine Fœtale, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France. Electronic address: Ville.yves@gmail.com.",
"authors": "Leruez-Ville|Marianne|M|;Ghout|Idir|I|;Bussières|Laurence|L|;Stirnemann|Julien|J|;Magny|Jean-François|JF|;Couderc|Sophie|S|;Salomon|Laurent J|LJ|;Guilleminot|Tiffany|T|;Aegerter|Philippe|P|;Benoist|Guillaume|G|;Winer|Norbert|N|;Picone|Olivier|O|;Jacquemard|François|F|;Ville|Yves|Y|",
"chemical_list": "D000998:Antiviral Agents; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9378",
"issue": "215(4)",
"journal": "American journal of obstetrics and gynecology",
"keywords": "congenital infection; cytomegalovirus; fetal therapy; fetus; symptomatic; valaciclovir",
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000212:Acyclovir; D000328:Adult; D000998:Antiviral Agents; D003586:Cytomegalovirus Infections; D005260:Female; D005312:Fetal Blood; D005315:Fetal Diseases; D046128:Fetal Therapies; D006801:Humans; D007231:Infant, Newborn; D010976:Platelet Count; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D018566:Pregnancy, High-Risk; D016216:Ultrasonography, Prenatal; D000077483:Valacyclovir; D014633:Valine; D019562:Viral Load",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "462.e1-462.e10",
"pmc": null,
"pmid": "27083761",
"pubdate": "2016-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "In utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter, open-label, phase II study.",
"title_normalized": "in utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter open label phase ii study"
} | [
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{
"abstract": "Clozapine is a uniquely effective antipsychotic indicated for treatment-resistant schizophrenia. However, its use is underutilised and often delayed for years due to potential adverse reactions including myocarditis and cardiomyopathy. The purpose of this study was to conduct a retrospective review of the clinical records of patients initiating clozapine in the Auckland District Health Board (ADHB) region to determine the incidence of clozapine-associated myocarditis and cardiomyopathy and to identify potential risk factors associated with these cardiotoxicities. The incidence of clozapine-associated myocarditis and cardiomyopathy over a two-year period in the ADHB region was 3.8% and 1.3% respectively.",
"affiliations": "Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: bbellissima03@gmail.com.;Auckland Regional Psychiatric Registrar Training Programme, Auckland District Health Board, 2 Park Road, Grafton, Auckland, 1023, New Zealand. Electronic address: alishavara@gmail.com.;Department of Molecular Medicine and Pathology, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: n.helsby@auckland.ac.nz.;Department of Forensic Pathology, Auckland District Health Board, LabPlus, Auckland City Hospital, Gate 4, Grafton Road PO Box 110031, Auckland, New Zealand.;Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: m.tingle@auckland.ac.nz.",
"authors": "Bellissima|Brandi L|BL|;Vara|Alisha|A|;Helsby|Nuala|N|;Garavan|Fintan|F|;Tingle|Malcolm D|MD|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.psychres.2021.113873",
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"issn_linking": "0165-1781",
"issue": "299()",
"journal": "Psychiatry research",
"keywords": "cardiomyopathy; clozapine; incidence; myocarditis; risk factors",
"medline_ta": "Psychiatry Res",
"mesh_terms": "D014150:Antipsychotic Agents; D009202:Cardiomyopathies; D003024:Clozapine; D006801:Humans; D015994:Incidence; D009205:Myocarditis; D009520:New Zealand; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "7911385",
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"pages": "113873",
"pmc": null,
"pmid": "33799127",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence and investigation of potential risk-factors for clozapine-associated myocarditis and cardiomyopathy in a New Zealand cohort.",
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"abstract": "A 58-year-old woman with a 31-year history of Hailey-Hailey (HH) disease that was refractory to treatment with mycophenolate mofetil, cyclosporine, dapsone, sulfasalazine, topical/oral antibiotics, and topical/oral steroids presented for alternative treatment options. Active erythematous, malodorous, eroded, and crusted plaques were present in the axillae, inframammary region, groin, and back (Figure 1). The patient had an undulant course, with acute exacerbations and partial remissions. During a 3-year period, she was prescribed oral methotrexate at a dose of 10 mg to 15 mg per week with daily oral folic acid (1 mg) supplementation, except on the day she took methotrexate. Oral clarithromycin and prednisone were also used intermittently for antibacterial and anti-inflammatory effects.",
"affiliations": "University of Chicago Pritzker School of Medicine, Section of Dermatology, Chicago, IL.;University of Chicago Pritzker School of Medicine, Chicago, IL.;University of Chicago Pritzker School of Medicine, Section of Dermatology, Chicago, IL; vrosic@medicine.bsd.uchicago.edu.",
"authors": "Kaminska|Edidiong Ntuen|EN|;Sansaricq|Freda|F|;Petronic-Rosic|Vesna|V|",
"chemical_list": "D000900:Anti-Bacterial Agents; D003879:Dermatologic Agents; D017291:Clarithromycin; D011241:Prednisone; D008727:Methotrexate",
"country": "United States",
"delete": false,
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"issn_linking": "1540-9740",
"issue": "14(2)",
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"medline_ta": "Skinmed",
"mesh_terms": "D000284:Administration, Oral; D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D003879:Dermatologic Agents; D005260:Female; D006801:Humans; D008727:Methotrexate; D008875:Middle Aged; D061270:Nasal Septal Perforation; D016506:Pemphigus, Benign Familial; D011241:Prednisone",
"nlm_unique_id": "101168327",
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"pages": "139-40",
"pmc": null,
"pmid": "27319962",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Methotrexate-Induced Nasal Septal Perforation.",
"title_normalized": "methotrexate induced nasal septal perforation"
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{
"abstract": "Cystoid macular edema is rarely observed secondary to paclitaxel treatment. A 55-year-old female patient was applied five cures of paclitaxel and carboplatin chemotherapy after being diagnosed with metastatic ovarian cancer. The patient had a normal bilateral vision prior to the chemotherapy treatments. After the fifth cure, the patient complained of bilateral vision loss, which was more severe in the left eye. Ophthalmologic examination revealed that right eye vision was 4/10 blurred without glasses and 7/10 blurred with glasses, left eye vision was 1/10 blurred without glasses and 4/10 blurred with glasses. Pathology was not detected during the biomicroscopic examination. Fundus examination of the patient revealed pigment epithelium irregularity, which was found to be less in the right eye, and it was found a decrease in foveal cavity. For fundus examination, the patient underwent fundus fluorescein angiography (FFA) and optical coherence tomography (OCT). FFA revealed fluorescein leakage and cystoid appearance particularly more apparent in the left eye. Thickening in the macula and cystoid space was observed particularly more in the left eye in the OCT measurement. In conclusion, we presented our case as a rarely observed cystoid macular edema secondary to paclitaxel treatment.",
"affiliations": "N. E. U., Department of Radiation Oncology, Meram Faculty of Medicine, Konya, Turkey. yilmaztezcan@yahoo.com.;N. E. U., Department of Radiation Oncology, Meram Faculty of Medicine, Konya, Turkey.;I. U., Department of Medical Oncology, Istanbul Faculty of Medicine, Istanbul, Turkey.;N. E. U., Department of Radiation Oncology, Meram Faculty of Medicine, Konya, Turkey.",
"authors": "Tezcan|Yilmaz|Y|;Surmeli|Mustafa|M|;Tastekin|Didem|D|;Koc|Mehmet|M|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "Iran",
"delete": false,
"doi": "0151809/AIM.0011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1029-2977",
"issue": "18(9)",
"journal": "Archives of Iranian medicine",
"keywords": null,
"medline_ta": "Arch Iran Med",
"mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008269:Macular Edema; D008875:Middle Aged; D017239:Paclitaxel; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "100889644",
"other_id": null,
"pages": "606-7",
"pmc": null,
"pmid": "26317603",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral Cystoid Macular Edema Secondary to Paclitaxel Treatment.",
"title_normalized": "bilateral cystoid macular edema secondary to paclitaxel treatment"
} | [
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"literaturereference": "TEZCAN Y, SURMELI M, TASTEKIN D, KOC M.. BILATERAL CYSTOID MACULAR EDEMA SECONDARY TO PACLITAXEL TREATMENT.. ARCH IRAN MED.. 2015?18 (9):606-607. DOI:0151809/AIM.0011.",
"literaturereference_normalized": "bilateral cystoid macular edema secondary to paclitaxel treatment",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20151110",
"receivedate": "20151110",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11720319,
"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"
}
] |
{
"abstract": "We report a case of darunavir-induced cholestatic hepatitis in a human immunodeficiency virus (HIV)-infected patient in the third year of his combined antiretroviral therapy. During the patient's monthly follow-up with regard to his HIV infection, elevated transaminase levels were detected. The patient was subsequently hospitalised at the AIDS and gastroenterology departments. All tested viral hepatitis markers were negative. A diagnosis of autoimmune hepatitis was also ruled out. The liver biopsy revealed cholestatic hepatitis. Darunavir withdrawal resulted in a progressive decrease in liver enzyme levels. We highlight the importance of recognising late development of liver injury secondary to the use of darunavir, and the importance of monitoring liver function in patients undergoing prolonged treatment involving darunavir.",
"affiliations": "1 Department of AIDS, Specialized Hospital for Active Treatment of Infectious and Parasitic Diseases \"Prof. Iv. Kirov\" Medical University, Sofia, Bulgaria.;2 Department of Gastroenterology, Tokuda Acibadem Hospital, Sofia, Bulgaria.",
"authors": "Yancheva|Nina|N|0000-0002-0095-263X;Tzonev|Radin|R|",
"chemical_list": "D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D000068898:Raltegravir Potassium; D000069454:Darunavir",
"country": "England",
"delete": false,
"doi": "10.1177/0956462419826723",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "30(6)",
"journal": "International journal of STD & AIDS",
"keywords": "Darunavir; HIV; cholestatic hepatitis",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D000998:Antiviral Agents; D002780:Cholestasis, Intrahepatic; D000069454:Darunavir; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D018451:Homosexuality, Male; D006801:Humans; D008297:Male; D000068898:Raltegravir Potassium; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "620-622",
"pmc": null,
"pmid": "30722751",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of late presentation of darunavir-related cholestatic hepatitis.",
"title_normalized": "a case of late presentation of darunavir related cholestatic hepatitis"
} | [
{
"companynumb": "BG-JNJFOC-20190301569",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
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{
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},
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"drugindication": "HIV INFECTION",
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"medicinalproduct": "ABACAVIR/LAMIVUDINE"
},
{
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"drugindication": "HIV INFECTION",
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"drugstartdate": "2014",
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"medicinalproduct": "RITONAVIR."
},
{
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},
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"drugindication": "HIV INFECTION",
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"medicinalproduct": "DARUNAVIR"
}
],
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"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Drug-induced liver injury",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatitis cholestatic",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201709"
}
},
"primarysource": {
"literaturereference": "YANCHEVA N, TZONEV R. A CASE OF LATE PRESENTATION OF DARUNAVIR-RELATED CHOLESTATIC HEPATITIS. INTERNATIONAL JOURNAL OF STD AND AIDS. 2019?30(6):620-622.",
"literaturereference_normalized": "a case of late presentation of darunavir related cholestatic hepatitis",
"qualification": "3",
"reportercountry": "BG"
},
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"receiptdate": "20190916",
"receivedate": "20190308",
"receiver": {
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},
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"safetyreportversion": 3,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191004"
}
] |
{
"abstract": "Pazopanib is an oral multi-kinase inhibitor approved for the treatment of advanced renal cell carcinoma (RCC). It is an anti-angiogenic agent, which blocks the activation signaling pathways of tyrosine kinases and prevents the activities of primarily vascular endothelial growth factor receptors (VEGFR)-2 and VEGFR-3, which are important in lymphangiogenesis. Herein, we report a patient with advanced RCC who developed asymptomatic left-sided chylothorax under pazopanib therapy. Chylothorax developed in the 16th month and gradually increased until it was diagnosed by thoracentesis in the 22nd month. The development of chylothorax was attributed to pazopanib therapy after ruling out all possible traumatic and nontraumatic etiologies. The 'Adverse Drug Reaction Probability Scale' revealed a total score of 6, which fell into 'probable' category. Chylothorax regressed significantly 5 weeks after the discontinuation of pazopanib therapy.",
"affiliations": "Department of Internal Medicine Department of Pulmonology Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Hacettepe University, Ankara Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Istinye University, Istanbul, Turkey.",
"authors": "Koylu|Bahadir|B|;Tekin|Fatih|F|;Aktas|Burak Yasin|BY|;Kilickap|Saadettin|S|;Koksal|Deniz|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000001172",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": null,
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": null,
"nlm_unique_id": "9100823",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34387587",
"pubdate": "2021-08-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pazopanib-induced chylothorax in a patient with renal cell carcinoma.",
"title_normalized": "pazopanib induced chylothorax in a patient with renal cell carcinoma"
} | [
{
"companynumb": "TR-NOVARTISPH-NVSC2022TR066628",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAZOPANIB"
},
"drugadditional": "1",
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"drugauthorizationnumb": "22465",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": "800 MG, QD",
"drugenddate": "202102",
"drugenddateformat": "610",
"drugindication": "Clear cell renal cell carcinoma",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "201904",
"drugstartdateformat": "610",
"drugstructuredosagenumb": "800",
"drugstructuredosageunit": "003",
"drugtreatmentduration": "22",
"drugtreatmentdurationunit": "802",
"medicinalproduct": "PAZOPANIB"
}
],
"patientagegroup": null,
"patientonsetage": "49",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Chylothorax",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hair colour changes",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Ejection fraction decreased",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20200801"
}
},
"primarysource": {
"literaturereference": "Koylu B, Tekin F, Aktas BY, Kilickap S, Koksal D. Pazopanib-induced chylothorax in a patient with renal cell carcinoma. ANTI-CANCER DRUGS. 2022;33(1):e555-7",
"literaturereference_normalized": "pazopanib induced chylothorax in a patient with renal cell carcinoma",
"qualification": "3",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20220325",
"receivedate": "20220325",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
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"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"
}
] |
{
"abstract": "Human Parvovirus B19 (PVB19), the etiological agent of the fifth disease, is associated with a large spectrum of pathologies, among which is encephalitis. Since it has been detected from the central nervous system in children or in immunocompromised patients, its causative role in serious neurological manifestations is still unclear. Here we report the case of an 18-year-old healthy boy who developed encephalitis complicated by prolonged status epilepticus. The detection of PVB19 DNA in his serum and, subsequently, in his cerebrospinal fluid supports the hypothesis that this virus could potentially play a role in the pathogenesis of neurological complications. In addition, the detection of viral DNA and the presence of specific IgM and IgG antibodies in serum, together with clinical findings such as skin rash, support the presence of a disseminated viral infection. In the presence of neurological disorders, especially when there are no specific signs, but seizures and rash are present, it is important to search for PVB19 both in immunocompromised and immunocompetent patients. Moreover, the introduction of the PVB19 DNA test into diagnostic protocols of neuropathies, especially those undiagnosed, could clarify the etiological agent that otherwise could remain unrecognized.",
"affiliations": "Department of Biomedical and Biotechnological Sciences, University of Catania, Italy; O.U. Central Laboratory, Clinical Virology Unit, A.O.U Policlinico-Vittorio Emanuele, O.P \"Gaspare Rodolico\", Catania, Italy. Electronic address: ileniapalermo@libero.it.;Department of Biomedical and Biotechnological Sciences, University of Catania, Italy; O.U. Central Laboratory, Clinical Virology Unit, A.O.U Policlinico-Vittorio Emanuele, O.P \"Gaspare Rodolico\", Catania, Italy.;Department of Biomedical and Biotechnological Sciences, University of Catania, Italy; O.U. Central Laboratory, Clinical Virology Unit, A.O.U Policlinico-Vittorio Emanuele, O.P \"Gaspare Rodolico\", Catania, Italy.;O.U. Intensive Care, A.O.U Policlinico-Vittorio Emanuele, O.P \"Vittorio Emanuele II\", Catania, Italy.;Department \"G. F. Ingrassia\", Section of Neurosciences, University of Catania, Italy.;Department of Biomedical and Biotechnological Sciences, University of Catania, Italy; O.U. Central Laboratory, Clinical Virology Unit, A.O.U Policlinico-Vittorio Emanuele, O.P \"Gaspare Rodolico\", Catania, Italy.;O.U. Intensive Care, A.O.U Policlinico-Vittorio Emanuele, O.P \"Vittorio Emanuele II\", Catania, Italy.;Department \"G. F. Ingrassia\", Section of Neurosciences, University of Catania, Italy.;Department of Biomedical and Biotechnological Sciences, University of Catania, Italy; O.U. Central Laboratory, Clinical Virology Unit, A.O.U Policlinico-Vittorio Emanuele, O.P \"Gaspare Rodolico\", Catania, Italy.",
"authors": "Palermo|Concetta Ilenia|CI|;Costanzo|Carmela Maria|CM|;Franchina|Concetta|C|;Castiglione|Giacomo|G|;Giuliano|Loretta|L|;Russo|Raffaela|R|;Conti|Alessandro|A|;Sofia|Vito|V|;Scalia|Guido|G|",
"chemical_list": "D004279:DNA, Viral",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6532",
"issue": "80()",
"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "Encephalitis; Immunocompetent host; Parvovirus B19; Polyclonal intravenous immunoglobulins",
"medline_ta": "J Clin Virol",
"mesh_terms": "D000293:Adolescent; D001769:Blood; D002555:Cerebrospinal Fluid; D004279:DNA, Viral; D004660:Encephalitis; D004828:Epilepsies, Partial; D006801:Humans; D008297:Male; D010322:Parvoviridae Infections; D016732:Parvovirus B19, Human; D012680:Sensitivity and Specificity",
"nlm_unique_id": "9815671",
"other_id": null,
"pages": "20-3",
"pmc": null,
"pmid": "27130981",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Focal epilepsy as a long term sequela of Parvovirus B19 encephalitis.",
"title_normalized": "focal epilepsy as a long term sequela of parvovirus b19 encephalitis"
} | [
{
"companynumb": "IT-PFIZER INC-2016468554",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
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"medicinalproduct": "ACYCLOVIR."
},
{
"actiondrug": "5",
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"activesubstancename": "CLONAZEPAM"
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"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "STATUS EPILEPTICUS",
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"medicinalproduct": "CLONAZEPAM."
},
{
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"medicinalproduct": "PARACETAMOL"
},
{
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"activesubstancename": "PHENOBARBITAL"
},
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"medicinalproduct": "PHENOBARBITAL."
},
{
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"activesubstancename": "LEVETIRACETAM"
},
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"drugdosagetext": "250 MG, DAILY",
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"drugindication": "STATUS EPILEPTICUS",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVETIRACETAM."
},
{
"actiondrug": "5",
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"activesubstancename": "LEVETIRACETAM"
},
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"drugindication": "GENERALISED TONIC-CLONIC SEIZURE",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVETIRACETAM."
},
{
"actiondrug": null,
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"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
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"drugauthorizationnumb": null,
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"drugcharacterization": "2",
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"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "EVIDENCE BASED TREATMENT",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CEFTRIAXONE."
}
],
"patientagegroup": null,
"patientonsetage": "18",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PALERMO, CONCETTA ILENIA. FOCAL EPILEPSY AS A LONG TERM SEQUELA OF PARVOVIRUS B19 ENCEPHALITIS. JOURNAL OF CLINICAL VIROLOGY. 2016;80:20-3",
"literaturereference_normalized": "focal epilepsy as a long term sequela of parvovirus b19 encephalitis",
"qualification": "1",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20161017",
"receivedate": "20161010",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12834787,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170207"
},
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"abstract": "Context. Anaplastic thyroid cancer (ATC) is an aggressive tumor with a median survival of 3 to 9 months, a 1-year survival of less than 10% and without definitive therapies. Recently, in BRAF V600E mutated ATCs, new targeted therapy using a combination of a BRAF inhibitor, dabrafenib (Dab), with a mitogen-activated extracellular protein kinase (MEK) inhibitor, trametinib (Tram), has shown significant promise. Case Description. We report a case of aggressive ATC with 5 sequence mutations: BRAF V600E (mutation fraction [MF] 34%), TERT E441del (MF 37%), RET N579K (MF 55%), EZH2 D154E (MF 60%), and CDK4 S259L (MF 48%). The patient had a dramatic response to the Dab/Tram combination with near complete resolution of his lung, bone, hepatic, and splenic lesions soon after starting therapy. Unfortunately, intolerable side effects (grade 2-3) on this regimen required tapering and discontinuation of the treatment. He had a quick resurgence of disease after stopping the combination therapy. The patient died approximately 3 months after discontinuing Dab/Tram. Autopsy revealed an atrophic thyroid gland with microscopic subcapsular focus of well-differentiated papillary thyroid carcinoma. There was extensive lymphatic spread of the tumor throughout bilateral lungs with fibrosis. No other metastatic site was identified. Conclusion. We report a unique case of ATC with 2 new mutations of EZH2 D154E and CDK S529L. This case exemplifies the significant promise Dab/Tram therapy holds, the potential side effects that limit their use, and autopsy findings status post use of this combination therapy.",
"affiliations": "George Washington University Medical Faculty Associates, Washington, DC, USA.;Washington DC VA Medical Center, Washington, DC, USA.;Washington DC VA Medical Center, Washington, DC, USA.;MedStar Georgetown University Medical Center, Washington, DC, USA.;George Washington University Medical Faculty Associates, Washington, DC, USA.;George Washington University Medical Faculty Associates, Washington, DC, USA.",
"authors": "Fazeli|Sasan|S|;Paal|Edina|E|;Maxwell|Jessica H|JH|;Burman|Kenneth D|KD|;Nylen|Eric S|ES|;Khosla|Shikha G|SG|",
"chemical_list": "D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; C561627:dabrafenib",
"country": "United States",
"delete": false,
"doi": "10.1177/2324709619890942",
"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 10.1177/232470961989094210.1177_2324709619890942Case ReportSalutary Response to Targeted Therapy in Anaplastic Thyroid\nCancer Fazeli Sasan MD12Paal Edina MD23Maxwell Jessica H. MD24Burman Kenneth D. MD45Nylen Eric S. MD12Khosla Shikha G. MD, MHA121 George Washington University Medical\nFaculty Associates, Washington, DC, USA2 Washington DC VA Medical Center,\nWashington, DC, USA3 George Washington University,\nWashington, DC, USA4 MedStar Georgetown University Medical\nCenter, Washington, DC, USA5 MedStar Washington Hospital Center,\nWashington, DC, USASasan Fazeli, MD, Department of\nEndocrinology and Metabolism, George Washington University Medical Faculty\nAssociates, 2300 M Street, NW 6th Floor, Washington, DC 20037, USA. Email:\ndrsfazeli@yahoo.com26 11 2019 Jan-Dec 2019 7 23247096198909423 9 2019 17 10 2019 20 10 2019 © 2019 American Federation for Medical\nResearch2019American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which\npermits any use, reproduction and distribution of the work without further\npermission provided the original work is attributed as specified on the SAGE\nand Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Context. Anaplastic thyroid cancer (ATC) is an aggressive tumor\nwith a median survival of 3 to 9 months, a 1-year survival of less than 10% and\nwithout definitive therapies. Recently, in BRAF V600E mutated\nATCs, new targeted therapy using a combination of a BRAF inhibitor, dabrafenib\n(Dab), with a mitogen-activated extracellular protein kinase (MEK) inhibitor,\ntrametinib (Tram), has shown significant promise. Case\nDescription. We report a case of aggressive ATC with 5 sequence\nmutations: BRAF V600E (mutation fraction [MF] 34%),\nTERT E441del (MF 37%), RET N579K (MF 55%),\nEZH2 D154E (MF 60%), and CDK4 S259L (MF\n48%). The patient had a dramatic response to the Dab/Tram combination with near\ncomplete resolution of his lung, bone, hepatic, and splenic lesions soon after\nstarting therapy. Unfortunately, intolerable side effects (grade 2-3) on this\nregimen required tapering and discontinuation of the treatment. He had a quick\nresurgence of disease after stopping the combination therapy. The patient died\napproximately 3 months after discontinuing Dab/Tram. Autopsy revealed an\natrophic thyroid gland with microscopic subcapsular focus of well-differentiated\npapillary thyroid carcinoma. There was extensive lymphatic spread of the tumor\nthroughout bilateral lungs with fibrosis. No other metastatic site was\nidentified. Conclusion. We report a unique case of ATC with 2\nnew mutations of EZH2 D154E and CDK S529L.\nThis case exemplifies the significant promise Dab/Tram therapy holds, the\npotential side effects that limit their use, and autopsy findings status post\nuse of this combination therapy.\n\nanaplastic thyroid cancerBRAF V600EEZH2 mutationCDK4 mutationmitogen-activated extracellular protein kinase inhibitor (MEK inhibitor)BRAF inhibitortargeted therapycover-dateJanuary-December 2019\n==== Body\nIntroduction\nAnaplastic thyroid cancer (ATC) is a rare and aggressive malignancy that accounts for\napproximately 1.3% to 9.8% of all thyroid cancers globally.1 Regional and distant metastases are seen in 90% of cases at the time of diagnosis.2 Response rates to traditional chemotherapy, with or without radiation therapy\nand/or debulking surgery, are abysmal. ATC continues to be a lethal disease with\npreviously reported median survival of 3 to 9 months and a 1-year survival rate of\nless than 10%.3\n\nRecent advances in genomics have improved our understanding of this disease. Studies\nshow that mutations that activate oncogenes and silence tumor suppressor genes\ncontribute to its pathogenesis. Mouse models with BRAF V600E and\np53 mutations develop poorly differentiated thyroid cancers.4 In humans, BRAF V600E mutation is commonly seen in 20% to\n50% of patients with ATC.5 Targeted combination therapy using a BRAF inhibitor, dabrafenib (Dab), with a\nmitogen-activated extracellular protein kinase (MEK) inhibitor, trametinib (Tram),\nhas shown significant promise6 and has recently received an accelerated Food and Drug Administration\napproval.\n\nCase Report\nA 69-year-old healthy, athletic male presented to ENT and Neurology with right-sided\notalgia and headache (ECOG [Eastern Cooperative Oncology Group] grade 0). Over the\nnext month, his symptoms progressed to neck pain, dysphagia, and a new rapidly\nenlarging right anterior neck mass. Thyroid ultrasound showed a 3.5-cm mass possibly\narising from the right thyroid lobe. Computed tomography (CT) scan showed a soft\ntissue mass along the right aspect of the strap muscle, subcutaneous soft tissues\nwith infiltration of skin. The mass was in contact with the right lobe of the\nthyroid gland but was thought to be anatomically separated. It did not arise in the\nright sternocleidomastoid muscle or in the sternoclavicular joint.\n\nAn 18F-FDG-positron emission topography (PET) scan showed intense uptake in the neck\nmass extending to the surrounding musculature (SUVmax [maximum\nstandardized uptake value] = 17.5), multiple neck lymph nodes (SUVmax =\n10.7), right lung opacification (SUVmax = 8.4), mediastinal and hilar\nlymph nodes (SUVmax = 11.9), multiple muscle groups (SUVmax =\n15.0), and right posterior 11th rib (SUVmax = 6.5; Figure 1).\n\nFigure 1. 18F-FDG PET before surgery (before) and 4 months after initiating therapy\n(after): (A) Complete resolution of abnormal neck FDG uptake; (B) Complete\nresolution of 2 of 3 hilar lymph nodes uptake; and (C) Complete resolution\nof lung uptake.\n\nFine needle aspiration biopsy revealed large cohesive sheets of overlapping highly\natypical epithelial cells, signifying poorly differentiated carcinoma of uncertain\norigin. Subsequent skin mapping punch biopsy showed a poorly differentiated\ncarcinoma of uncertain origin infiltrating skeletal muscle, dermis, and subcutis.\nSubsequently, immunostains of both fine needle aspiration and punch biopsy samples\nshowed tumor cells positive for CK7, AE1/AE3, and focally positive for CK5/6 and\nnegative for CK20, thyroid transcription factor-1, thyroglobulin, CEA, chromogranin,\nsynaptophysin, CD56, CDX2, RCC, napsin-A, S-100, and p16. The patient soon developed\nan ulcer over the neck mass. Punch biopsy of this ulcer showed tumor cells with the\nsame morphologic characteristics and Ki-67 20% positive. The working diagnosis at\nthe time was primary adnexal carcinoma versus metastatic carcinoma from lung,\npancreas, liver, kidney, or adrenal gland.\n\nThe patient underwent tumor debulking with a myocutaneous advancement flap for local\ncontrol and symptomatic relief. The involved skin and underlying tumor were\nresected. There was a fascial plane between the tumor and the thyroid gland;\ntherefore, the tumor was resected off the thyroid gland and trachea. Frozen section\nmargins confirmed that tumor invaded into internal jugular vein and the trachea.\nFinal pathology revealed ATC with metastatic carcinoma in 7 of 15 resected lymph\nnodes. Few foci in the neck mass and more obviously in the lymph node metastases\nshowed well-differentiated papillary thyroid carcinoma (PTC). The presence of the\nwell-differentiated foci aided the establishment of the final diagnosis.\nImmunostaining was positive for thyroid transcription factor-1 and thyroglobulin in\nthe well-differentiated tumor component; with focal positivity in the transition\nzone of the tumor and no reactivity in the area with the anaplastic carcinoma. The\nanaplastic tumor retained PAX-8 reactivity. Based on these findings, the punch\nbiopsy sample was consistent with PTC.7-9\n\nHe was diagnosed with metastatic ATC stage IV-C as per the American Thyroid\nAssociation 2012 guidelines.10 Genetic analysis with 125 gene panel (Personal Genome Diagnostics, Baltimore,\nMD; http://www.personalgenome.com/) for microsatellite instability,\nsequence mutation, amplification, and translocation revealed 5 sequence mutations:\nBRAF V600E (mutation fraction [MF] 34%), TERT\nE441del (in-frame deletion; MF 37%), RET N579K (MF\n55%), CDK S259L (MF 48%), and EZH2 D154E (MF 60%).\nProgrammed death ligand receptor-1 immunochemistry was positive in 20% of tumor\ncells (Quest Diagnostics, Chantilly, VA).\n\nPostsurgery, the patient suffered wound dehiscence twice. He became home oxygen\ndependent (ECOG Performance Status, grade 3) and his CT chest showed progression of\nthe disease with bilateral pleural effusions. Given his rapid deterioration, distant\nmetastases, and positive BRAF V600E mutation, he was started on\ncombination of oral Dab 150 mg twice daily, Tram 2 mg daily (Dab/Tram), and\ndexamethasone 8 mg daily on compassionate grounds.6\n\nThe patient had a dramatic response to Dab/Tram combination treatment. At week 8 of\nDab/Tram therapy, he had resolution of pleural effusions and normalization of oxygen\nsaturation at room air with normal performance status (ECOG grade 0). CT scan showed\nsignificant reduction of several lung nodules, near total resolution of bilateral\nbasal lung consolidations, reduction in size of multiple mediastinal, hepatic, and\nsplenic lesions. This was consistent with near complete response (partial response\nby RECIST criteria 1.1). Soon after initiation of therapy, the patient developed\nhigh-grade fever of 105°F for about 30 minutes after taking Dab (Grade 3, by Common\nTerminology Criteria for Adverse Events Version 5.0 [CTCAE]). This was controlled\nwith acetaminophen prophylaxis. He also had an episode of painful (10/10 in\nintensity) oral mucositis (Grade 3 CTCAE), which was treated with magic mouth wash.\nThe mucositis resolved after holding the medication for 3 days and therapy was\nresumed. The valacyclovir prophylaxis was initiated.\n\nThe follow-up PET/CT scan, 16 weeks after initiating therapy, showed complete\nresolution of abnormal neck, lung, and 11th rib uptakes as well as majority of\nmusculature uptake. The hilar lymph node uptake decreased to SUVmax of\n5.3, and right thigh SUVmax decreased to 3.2 (Figure 1).\n\nAt week 27 of initiating Dab/Tram therapy, the patient was pain free, active, and\ngaining weight. A week later, the patient was admitted with continuous high-grade\nfever of 105°F (Grade 4 CTCAE), elevation of liver enzymes to approximately twice\nthe upper limit of normal (Grade 1 CTCAE), and a lowering of platelet count to 99\n000/mm3 (Grade 1 CTCAE). Infectious etiology was ruled out. Dab was\nheld and patient’s pyrexia resolved. The patient subsequently developed an\nerythematous acneiform papulopustular rash with areas of confluent plaques on his\nhead, neck, and upper torso (Grade 2 CTCAE). At week 29, Dab was restarted at a\nlower dose of 150 mg once daily. By week 33, while on the lower dose of Dab, the\npatient had recurrence of high-grade fevers (Grade 3 CTCAE), progression of his rash\n(Grade 3 CTCAE), and developed floaters in his right eye (Grade 1 CTCAE). A week\nlater, both Dab/Tram were stopped by the patient, and he wanted to consider other\ntreatment options. Repeat PET scan at week 37 showed new left upper lung lesions\nwith hilar lymphadenopathy. At week 38, he underwent an endobronchial\nultrasound-guided bronchoscopy for his hilar lung lesion that showed metastatic\ndisease, and a week later, he developed a postobstructive pneumonia. At week 40, he\nwas started on cabozantinib 60 mg per day; however, 4 weeks later, he had\nprogression of his lung nodules, pleural effusion, significant calf and back pain.\nThe pain was likely from metastatic spread of tumor to the spine and possibly as a\nside effect of cabozantinib. The patient was admitted to the hospital at week 46\nwith extensive tumor spread and pulmonary emboli. He died of respiratory failure 48\nweeks after initiating Dab/Tram therapy, 13 weeks after discontinuing Dab/Tram and 8\nweeks after starting cabozantinib.\n\nHis most significant autopsy finding was extensive lymphatic spread of ATC throughout\nhis lungs bilaterally with infiltration of adjacent connective tissue without\nformation of tumor nodules, associated with dense focal acute inflammatory\ninfiltrates and areas of necrosis. A tumor embolus was noted in a small branch of\nthe pulmonary artery that was associated with infarction of the adjacent lung\nparenchyma. There was also significant fibrosis throughout the lungs. The thyroid\nwas atrophic and was difficult to explore due to scarring of the surgical site. The\nentire thyroid gland was examined microscopically. Histology showed presence of a\nmicroscopic focus of well-differentiated PTC in the subcapsular region of the right\nlobe with intraglandular spread, as well as infiltration of the tumor through the\ncapsule into the surrounding connective tissue. Several lymph nodes showed\nmetastatic well-differentiated PTC.\n\nDiscussion\nThe current case illustrates the profound impact mutation-targeted therapy has on the\nclinical course of ATC. Recent advances in our understanding of thyroid cancer, gene\npathways have been vital to utilizing these therapies in its treatment.\n\nOur patient had a rapid and significant reduction in tumor burden while he was able\nto tolerate the combination Dab/Tram therapy. The rapid tumoral response was not\nwithout notable clinical challenges. The patient developed an erythematous acneiform\nmaculopapular rash with a seborrheic distribution most likely due to this drug\ncombination as it improved with a drug holiday. The patient also experienced\nsignificant symptomatic pyrexia with fevers to 105°F, interrupting his treatment.\nUnfortunately, within 1 month of discontinuing the treatment, he showed significant\nresurgence of the disease. His disease did not respond to cabozantinib monotherapy.\nHe expired 13 weeks after stopping Dab/Tram combination therapy. This indicates that\nperhaps there is a small window of opportunity to starting Dab/Tram therapy in\npatients with this rapidly progressive lethal disease without interruption. Further\nstudies need to be done for optimum management of drug intolerability and\nindications for drug holiday to allow use of this combination therapy to its full\npotential.\n\nThere is paucity of literature on the autopsy findings in ATC patients on combination\ntherapy. In our patient, the well-differentiated PTC was seen in the thyroid tissue\nbut only a small amount of ATC was present. This was perhaps due to higher response\nrate of undifferentiated tumor cells to this combination.\n\nAbout 20% to 50% of ATC harbor activating BRAF V600 mutations.6 It has been demonstrated in mouse models that combined inhibition of BRAF and\nMEK kinase enhances antitumor activity compared with single-agent BRAF inhibitors in\nBRAF V600 mutant mice.4 This combination therapy has been successful in treating BRAF\nV600 mutant melanoma and lung cancer.11,12 Importantly, Subbiah et al, in\na phase II, open-label trial, on a cohort of 16 patients with predefined\nBRAF V600E-mutated ATC, showed the BRAF inhibitor Dab and MEK\ninhibitor Tram improved the overall response in 11 of 16 cases (69% response rate,\n95% confidence interval = 41% to 89%), with median follow-up of 47 weeks, and 7\nongoing responses.6\n\nEnhancer of Zeste Homolog 2 (EZH2) has only recently been described in ATC and\nappears to play an important role in tumor growth.13 Borbone et al showed that EZH2 is specifically overexpressed in ATC cell\nlines, and directly controls differentiation of ATC cells by silencing the\nthyroid-specific transcription factor paired-box gene 8.13 They also demonstrated that knockdown of EZH2 in ATC cell lines results in\ncell growth inhibition, loss of anchorage-independent growth, migration, and\ninvasion properties.13 Cyclin-dependent kinase 4 (CDK4) upregulation has been noted in aggressive\nthyroid cancers and their role in mitotic activity of such thyroid tumors is of\ngreat interest.14 CDK4 protein plays a key role in the cell cycle progression across the G1/S\nphase transition.15 A preclinical study of CDK4/6 inhibitor, ribociclib in PTC, and ATC cell\nlines has been shown to inhibit tumor growth with decreased expressions of pRB,\npAKT, and Ki-67, and significantly increased tumor cell apoptosis. In our literature\nsearch on Medline and PubMed, we did not find any cases of ATC with EZH2\nD154E and CDK S259L oncogenic mutations. In the\nCatalogue of Somatic Mutations in Cancer database (COSMIC v89, 2019), none of the\n409 ATC samples that were tested for EZH2 or the 264 samples tested for CDK4\nharbored these mutations (https://cancer.sanger.ac.uk/cosmic/). In the National Institutes of\nHealth ClinVar database for Genomic variations (https://www.ncbi.nlm.nih.gov/clinvar/) EZH2 D154E\nhas not been described and the CDK4 S259L has not been seen in any\nthyroid cancers. The functional consequences of missense mutation EZH2 D154E, and\nthe CDK4 S259L mutation, that were seen in the current case, are unknown and there\nis no approved targeted therapy for these mutations.\n\nIn summary, the combination of proto-oncogene BRAF inhibitor Dab and MEK inhibitor\nTram offers promise in the BRAF V600E-mutated ATC patients. The\nDab/Tram combination displayed a potent and rapid clinical response in our patient\nalthough new challenges in his management are evident. This degree of salutary\nresponse rate has not been previously reported in ATC. This 2-drug combination is\nnow Food and Drug Administration approved for treatment of BRAF\nV600E mutation-positive ATC. Studies using Dab/Tram therapy with\nadditional check point inhibitors in a 3-drug cocktail are currently underway.\nFurther research efforts are needed to better manage the side effect profile of this\ncombination therapy and to understand the role the EZH2 and CDK4 mutations play in\nthe clinical progression and management of this disease.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nInformed Consent: Verbal informed consent was obtained from a legally authorized representative for\nanonymized patient information to be published in this article.\n==== Refs\nReferences\n1 \nVenkatesh YS Ordonez NG Schultz PN Hickey RC Goepfert H Samaan NA. \nAnaplastic carcinoma of the thyroid. A clinicopathologic study of\n121 cases . Cancer .\n1990 ;66 :321 -330 .1695118 \n2 \nMcIver B Hay ID Giuffrida DF , et al\nAnaplastic thyroid\ncarcinoma: a 50-year experience at a single institution .\nSurgery .\n2001 ;130 :1028 -1034 .11742333 \n3 \nUrsino S Fiorica F Stefanelli A , et al\nAnaplastic thyroid cancer: a\ncase report of a long term survival patient and review of literature\ndata . Eur Rev Med Pharmacol Sci .\n2014 ;18 :1368 -1372 .24867515 \n4 \nMcFadden DG Vernon A Santiago PM , et al\np53 constrains progression\nto anaplastic thyroid carcinoma in a BRAF-mutant mouse model of papillary\nthyroid cancer . Proc Natl Acad Sci U S A .\n2014 ;111 :E1600 -E1609 .24711431 \n5 \nGuerra A Di Crescenzo V Garzi A , et al\nGenetic mutations in the\ntreatment of anaplastic thyroid cancer: a systematic review .\nBMC Surg .\n2013 ;13 (suppl\n2 ):S44 .24267151 \n6 \nSubbiah V Kreitman RJ Wainberg ZA , et al\nDabrafenib and trametinib\ntreatment in patients with locally advanced or metastatic BRAF V600-mutant\nanaplastic thyroid cancer . J Clin Oncol .\n2018 ;36 :7 -13 .29072975 \n7 \nBejarano PA Nikiforov YE Swenson ES Biddinger PW. \nThyroid transcription factor-1, thyroglobulin, cytokeratin 7, and\ncytokeratin 20 in thyroid neoplasms . Appl\nImmunohistochem Mol Morphol .\n2000 ;8 :189 -194 .10981870 \n8 \nPan DH Wen DY Luo YH , et al\nThe diagnostic and\nprognostic values of Ki-67/MIB-1 expression in thyroid cancer: a\nmeta-analysis with 6051 cases . Onco Targets\nTher .\n2017 ;10 :3261 -3276 .28740401 \n9 \nBishop JA Sharma R Westra WH. \nPAX8 immunostaining of anaplastic thyroid carcinoma: a reliable\nmeans of discerning thyroid origin for undifferentiated tumors of the head\nand neck . Hum Pathol .\n2011 ;42 :1873 -1877 .21663937 \n10 \nSmallridge RC Ain KB Asa SL , et al\nAmerican Thyroid Association\nguidelines for management of patients with anaplastic thyroid\ncancer . Thyroid .\n2012 ;22 :1104 -1139 .23130564 \n11 \nFlaherty KT Infante JR Daud A , et al\nCombined BRAF and MEK\ninhibition in melanoma with BRAF V600 mutations . N\nEngl J Med .\n2012 ;367 :1694 -1703 .23020132 \n12 \nPlanchard D Smit EF Groen HJM , et al\nDabrafenib plus trametinib\nin patients with previously untreated BRAFV600E-mutant metastatic\nnon-small-cell lung cancer: an open-label, phase 2 trial .\nLancet Oncol .\n2017 ;18 :1307 -1316 .28919011 \n13 \nBorbone E Troncone G Ferraro A , et al\nEnhancer of zeste homolog 2\noverexpression has a role in the development of anaplastic thyroid\ncarcinomas . J Clin Endocrinol Metab .\n2011 ;96 :1029 -1038 .21289264 \n14 \nLee HJ Lee WK Kang CW Ku CR Cho YH Lee EJ. \nA selective cyclin-dependent kinase 4, 6 dual inhibitor,\nRibociclib (LEE011) inhibits cell proliferation and induces apoptosis in\naggressive thyroid cancer . Cancer Lett .\n2018 ;417 :131 -140 .29306020 \n15 \nMusgrove EA Caldon CE Barraclough J Stone A Sutherland RL. \nCyclin D as a therapeutic target in cancer .\nNat Rev Cancer .\n2011 ;11 :558 -572 .21734724\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "7()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "BRAF V600E; BRAF inhibitor; CDK4 mutation; EZH2 mutation; anaplastic thyroid cancer; mitogen-activated extracellular protein kinase inhibitor (MEK inhibitor); targeted therapy",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000368:Aged; D001344:Autopsy; D016203:CDC2 Protein Kinase; D000071221:Enhancer of Zeste Homolog 2 Protein; D017809:Fatal Outcome; D006801:Humans; D007093:Imidazoles; D008297:Male; D058990:Molecular Targeted Therapy; D009154:Mutation; D010091:Oximes; D000072078:Positron Emission Tomography Computed Tomography; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D011728:Pyridones; D011744:Pyrimidinones; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709619890942",
"pmc": null,
"pmid": "31766881",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28740401;23130564;21289264;21663937;11742333;1695118;10981870;29072975;24867515;29306020;24267151;28919011;21734724;23020132;24711431",
"title": "Salutary Response to Targeted Therapy in Anaplastic Thyroid Cancer.",
"title_normalized": "salutary response to targeted therapy in anaplastic thyroid cancer"
} | [
{
"companynumb": "PHHY2018US179336",
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},
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},
{
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},
{
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},
{
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatic enzyme increased",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Weight increased",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stomatitis",
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},
{
"reactionmeddrapt": "Rash erythematous",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Platelet count decreased",
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"reactionoutcome": "6"
}
],
"summary": null
},
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"literaturereference": "FAZELI S, KHOSLA S, PAAL E.E, KRASNOW S.H, MAXWELL J.H, BURMAN K.D ET AL.. SALUTARY RESPONSE TO TARGETED THERAPY IN ANAPLASTIC THYROID CANCER. JOURNAL OF INVESTIGATIVE MEDICINE HIGH IMPACT CASE REPORTS. 2019?7:1-5",
"literaturereference_normalized": "salutary response to targeted therapy in anaplastic thyroid cancer",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
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"receiptdate": "20191206",
"receivedate": "20191206",
"receiver": {
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"receivertype": "6"
},
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"sender": {
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"sendertype": "2"
},
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"transmissiondate": "20200122"
}
] |
{
"abstract": "METHODS\nWe present the case of an 89-year-old patient with impaired consciousness for whom the emergency services were called. She was soporose and showed a pronounced generalized muscle rigidity. Due to a third-party history the incorrect use of a fentanyl patch was found out to be at cause.\n\n\nMETHODS\nThe antidote administration of naloxone led to restoration. The need for repetitive administration confirmed the clinical hypothesis.\n\n\nCONCLUSIONS\nThe application of fentanyl via the skin in the form of transdermal therapeutic systems (TTS) has become more popular over the years. Incorrect administration causes intoxication with the leading symptoms of loss of consciousness and respiratory depression. This case report extends the spectrum of symptoms to include skeletal muscle rigidity otherwise only described in connection with intravenous administration, especially in anaesthetic settings.",
"affiliations": "Zentrale Interdisziplinäre Notaufnahme, Allgemeines Krankenhaus Viersen.;Klinik für Anästhesie und Intensivmedizin, Evangelisches Krankenhaus Oberhausen.",
"authors": "Friebe|Mathias|M|;Coenen|Johanna|J|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1546-4686",
"fulltext": null,
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"issn_linking": "0012-0472",
"issue": "146(18)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": null,
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "1207-1210",
"pmc": null,
"pmid": "34521126",
"pubdate": "2021-09",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Overdose from a patch.",
"title_normalized": "overdose from a patch"
} | [
{
"companynumb": "DE-ARISTO PHARMA-FENT202109201",
"fulfillexpeditecriteria": "1",
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{
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"activesubstance": {
"activesubstancename": "FENTANYL"
},
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"medicinalproduct": "FENTANYL"
}
],
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"reaction": [
{
"reactionmeddrapt": "Altered state of consciousness",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Muscle rigidity",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
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"literaturereference": "Friebe M, Coenen J.. Overdose from a patch. Dtsch Med Wochenschr. 2021;146(18):1207-1210",
"literaturereference_normalized": "overdose from a patch",
"qualification": "3",
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},
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},
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},
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"transmissiondate": "20220303"
}
] |
{
"abstract": "Researchers have yet to determine the optimal care of patients with advanced CKD. Evidence suggests that anemia and CKD-related disordered mineral metabolism (including abnormalities in phosphate and fibroblast growth factor 23 [FGF23]) contribute to adverse outcomes in this population.\n\n\n\nTo investigate whether fixed-dose ferric citrate coordination complex favorably affects multiple biochemical parameters in patients with advanced CKD, we randomly assigned 203 patients with eGFR≤20 ml/min per 1.73 m2 2:1 to receive a fixed dose of ferric citrate coordination complex (two tablets per meal, 210 mg ferric iron per tablet) or usual care for 9 months or until 3 months after starting dialysis. No single biochemical end point was designated as primary; sample size was determined empirically.\n\n\n\nThe two groups had generally similar baseline characteristics, although diabetes and peripheral vascular disease were more common in the usual-care group. Ferric citrate coordination complex significantly increased hemoglobin, transferrin saturation, and serum ferritin, and it significantly reduced serum phosphate and intact FGF23 (P<0.001 for all). Of the 133 patients randomized to ferric citrate coordination complex, 31 (23%) initiated dialysis during the study period, as did 32 of 66 (48%) patients randomized to usual care (P=0.001). Compared with usual care, ferric citrate coordination complex treatment resulted in significantly fewer annualized hospital admissions, fewer days in hospital, and a lower incidence of the composite end point of death, provision of dialysis, or transplantation (P=0.002).\n\n\n\nThe beneficial effects of fixed-dose ferric citrate coordination complex on biochemical parameters, as well as the exploratory results regarding the composite end point and hospitalization, suggest that fixed-dose ferric citrate coordination complex has an excellent safety profile in an unselected population with advanced CKD and merits further study.",
"affiliations": "Reata Pharmaceuticals, Dallas, Texas; geoff@goldenblocks.org.;Denver Nephrology Research Division, Denver, Colorado.;CSC, Inc., Santa Barbara, California.;Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute of Public Health and Medicine, Feinberg School of Medicine, Jesse Brown Veterans Administration Medical Center.;Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Division of Nephrology, Department of Medicine, and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina; and.;Stanford University, Palo Alto, California.",
"authors": "Block|Geoffrey A|GA|;Block|Martha S|MS|;Smits|Gerard|G|;Mehta|Rupal|R|;Isakova|Tamara|T|;Wolf|Myles|M|;Chertow|Glenn M|GM|",
"chemical_list": "C000717427:FGF23 protein, human; D005290:Ferric Compounds; D006454:Hemoglobins; D010710:Phosphates; D014168:Transferrin; D005346:Fibroblast Growth Factors; C025314:ferric citrate; D000089703:Fibroblast Growth Factor-23; D005293:Ferritins",
"country": "United States",
"delete": false,
"doi": "10.1681/ASN.2018101016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-6673",
"issue": "30(8)",
"journal": "Journal of the American Society of Nephrology : JASN",
"keywords": "CKD; FGF23; RCT; anemia; ferric citrate; hyperphosphatemia",
"medline_ta": "J Am Soc Nephrol",
"mesh_terms": "D000368:Aged; D018798:Anemia, Iron-Deficiency; D005260:Female; D005290:Ferric Compounds; D005293:Ferritins; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005919:Glomerular Filtration Rate; D006454:Hemoglobins; D006801:Humans; D054559:Hyperphosphatemia; D007676:Kidney Failure, Chronic; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D010343:Patient Admission; D010710:Phosphates; D010865:Pilot Projects; D006435:Renal Dialysis; D014168:Transferrin",
"nlm_unique_id": "9013836",
"other_id": null,
"pages": "1495-1504",
"pmc": null,
"pmid": "31278194",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "15385656;17108342;17656479;19601992;19880844;20688884;21292817;21389978;21393493;21852581;21985788;22822075;23735819;23763855;24040373;24158986;24262791;24891437;25468387;25804679;26757465;28339831;29167351;29186198;29398136;29459266;29779027;30021759;30380116;9718377",
"title": "A Pilot Randomized Trial of Ferric Citrate Coordination Complex for the Treatment of Advanced CKD.",
"title_normalized": "a pilot randomized trial of ferric citrate coordination complex for the treatment of advanced ckd"
} | [
{
"companynumb": "US-AMGEN-USASP2019158021",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERYTHROPOIETIN"
},
"drugadditional": "3",
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"drugdosageform": "UNKNOWN FORMULATION",
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"drugindication": "CHRONIC KIDNEY DISEASE",
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{
"abstract": "This is a rare case of penile and generalised calciphylaxis. We describe the case of a patient admitted to our hospital for septic shock and necrotic skin findings, end-stage renal disease on peritoneal dialysis. Skin findings turned out to be calciphyactic lesions. The patient was taken to the operating room for penile debridement and started on antibiotics. He was treated with sodium thiosulfate and switched to haemodialysis. Calciphylaxis is a rare disease in which the treatment is basically supportive. Further studies are needed to identify the risk factors, mechanisms of disease and treatment modalities.",
"affiliations": "Department of Internal Medicine, Cooper Medical Center, Camden, New Jersey, USA.",
"authors": "Sarkis|Edmond|E|",
"chemical_list": "D000900:Anti-Bacterial Agents; D013885:Thiosulfates; C017717:sodium thiosulfate",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002115:Calciphylaxis; D003646:Debridement; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D010409:Penile Diseases; D010530:Peritoneal Dialysis; D006435:Renal Dialysis; D012772:Shock, Septic; D013885:Thiosulfates",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25883256",
"pubdate": "2015-04-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21748002;7349051;9740153;18417747;23520041;15777477;10739777;23291368;20634681;3886226;23571078;11422768;22762780;19925764;22748863;20024510",
"title": "Penile and generalised calciphylaxis in peritoneal dialysis.",
"title_normalized": "penile and generalised calciphylaxis in peritoneal dialysis"
} | [
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"abstract": "BACKGROUND\nLarge vessel vasculitis is a rare disorder usually occurring in the context of the autoimmune conditions of giant cell arteritis and Takayasu's arteritis. Case reports have described large vessel vasculitis occurring in individuals with myelodysplastic syndrome, preceding transformation to acute myeloid leukemia.\n\n\nMETHODS\nA 56-year-old Afghanistan-born woman presented with fever, a tender left carotid artery, and raised inflammatory markers. Computed tomography revealed thickening of the wall of her left carotid artery. Her symptoms resolved spontaneously; however, they recurred weeks later on the contralateral side, along with abdominal pain after eating. Further imaging with computed tomography and positron emission tomography demonstrated resolution of her left carotid artery abnormality, but new wall thickening and inflammation in her right carotid artery, abdominal aorta, and superior mesenteric artery. She was diagnosed as having large vessel vasculitis, which resolved with corticosteroids and methotrexate. Five months later, she developed acute myeloid leukemia. She had no known history of myelodysplastic syndrome at the time of diagnosis with vasculitis.\n\n\nCONCLUSIONS\nLarge vessel vasculitis in older individuals presenting with atypical clinical features, such as a migratory pattern of affected vessels, vessel wall tenderness, and marked systemic inflammation, should prompt a search for underlying myelodysplasia. Clinicians should be vigilant for progression to acute myeloid leukemia.",
"affiliations": "Department of Immunopathology, Pathology West, ICPMR, Westmead Hospital, Sydney, 2145, NSW, Australia. cdinusha@gmail.com.;Department of Immunopathology, Pathology West, ICPMR, Westmead Hospital, Sydney, 2145, NSW, Australia.;Department of Vascular Surgery, Westmead Hospital, Sydney, 2145, NSW, Australia.;Department of Haematology, Westmead Hospital, Sydney, 2145, NSW, Australia.;Department of Immunopathology, Pathology West, ICPMR, Westmead Hospital, Sydney, 2145, NSW, Australia.",
"authors": "Chandratilleke|Dinusha|D|http://orcid.org/0000-0001-9833-3003;Anantharajah|Anthea|A|;Vicaretti|Mauro|M|;Benson|Warwick|W|;Berglund|Lucinda J|LJ|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 123910.1186/s13256-017-1239-xCase ReportMigratory large vessel vasculitis preceding acute myeloid leukemia: a case report http://orcid.org/0000-0001-9833-3003Chandratilleke Dinusha cdinusha@gmail.com 12Anantharajah Anthea anthea.anantharajah@hotmail.com 1Vicaretti Mauro mauro.vicaretti@sydney.edu.au 3Benson Warwick warwick.benson@health.nsw.gov.au 4Berglund Lucinda J. lucinda.berglund@health.nsw.gov.au 121 0000 0001 0180 6477grid.413252.3Department of Immunopathology, Pathology West, ICPMR, Westmead Hospital, Sydney, 2145 NSW Australia 2 0000 0004 1936 834Xgrid.1013.3Faculty of Medicine, University of Sydney, Sydney, NSW 2000 Australia 3 0000 0001 0180 6477grid.413252.3Department of Vascular Surgery, Westmead Hospital, Sydney, 2145 NSW Australia 4 0000 0001 0180 6477grid.413252.3Department of Haematology, Westmead Hospital, Sydney, 2145 NSW Australia 16 3 2017 16 3 2017 2017 11 7120 10 2016 12 2 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nLarge vessel vasculitis is a rare disorder usually occurring in the context of the autoimmune conditions of giant cell arteritis and Takayasu’s arteritis. Case reports have described large vessel vasculitis occurring in individuals with myelodysplastic syndrome, preceding transformation to acute myeloid leukemia.\n\nCase presentation\nA 56-year-old Afghanistan-born woman presented with fever, a tender left carotid artery, and raised inflammatory markers. Computed tomography revealed thickening of the wall of her left carotid artery. Her symptoms resolved spontaneously; however, they recurred weeks later on the contralateral side, along with abdominal pain after eating. Further imaging with computed tomography and positron emission tomography demonstrated resolution of her left carotid artery abnormality, but new wall thickening and inflammation in her right carotid artery, abdominal aorta, and superior mesenteric artery. She was diagnosed as having large vessel vasculitis, which resolved with corticosteroids and methotrexate. Five months later, she developed acute myeloid leukemia. She had no known history of myelodysplastic syndrome at the time of diagnosis with vasculitis.\n\nConclusions\nLarge vessel vasculitis in older individuals presenting with atypical clinical features, such as a migratory pattern of affected vessels, vessel wall tenderness, and marked systemic inflammation, should prompt a search for underlying myelodysplasia. Clinicians should be vigilant for progression to acute myeloid leukemia.\n\nKeywords\nLarge vesselVasculitisAcute myeloid leukemiaAMLAutoimmuneMyelodysplasiaMDSMigratoryLucinda Berglundissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nLarge vessel vasculitis is a rare condition characterized by inflammation within the walls of the aorta and its major branches. It can occur in a range of autoimmune disorders, including Takayasu’s arteritis (TA) and giant cell arteritis (GCA), and typically requires treatment with high doses of corticosteroids and other immunosuppressive agents. In the literature, there have been case reports of large vessel vasculitis occurring in individuals with myelodysplastic syndrome (MDS), some of whom have later developed acute myeloid leukemia (AML). We describe a patient with an atypical presentation of large vessel vasculitis, which was migratory in nature and accompanied by marked systemic inflammatory features. Unlike previous case reports, our patient did not have a prior diagnosis of MDS, but subsequently developed AML.\n\nCase presentation\nA 56-year-old Afghanistan-born woman presented to our hospital with a 2-week history of constant left-sided neck pain, associated fevers (38.0 °C), and rigors. Her past medical history included mild asthma and osteoarthritis. A physical examination revealed exquisite tenderness over the anterior triangle of her left neck. Laboratory studies showed a white cell count of 4.1 × 109 cells/L (reference range 3.9 to 11.1), hemoglobin 112 g/L (115 to 165), mean corpuscular volume (MCV) 96 fL (82 to 98), C-reactive protein (CRP) 109 mg/L (≤3), with normal electrolytes and liver function tests. Computed tomography (CT) of her neck (Fig. 1) revealed wall thickening of her left distal common carotid artery with hazing of the adjacent fat. Autoimmune serology, including anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, antibodies to extractable nuclear antigens, double stranded-deoxyribonucleic acid (DNA) antibodies, rheumatoid factor, and antibodies to cyclic citrullinated peptide, were negative. These results were helpful in excluding a systemic small vessel vasculitis. Her serum complement levels were normal, and a left temporal artery biopsy was negative. Her neck pain and fevers resolved spontaneously without corticosteroids or other immunosuppression and she was discharged home on day 6. She presented 17 days later with fever (38.0 °C) and abdominal pain 20 to 30 minutes after eating. A CT of her abdomen (Fig. 2) revealed mild upper abdominal periaortic stranding with mural thickening, similar in appearance to her left common carotid artery from the original CT scan of her neck. During the next 24 to 48 hours, she developed new right-sided neck pain, contralateral to her pain on initial presentation. A CT angiogram revealed improvement in her left common carotid artery thickening, interval development of new right common carotid artery thickening, and hazing around her upper abdominal aorta, coeliac axis, and superior mesenteric arteries. A positron emission tomography (PET) scan (Fig. 3) demonstrated diffuse, intense fluorodeoxyglucose (FDG) uptake of her right common carotid artery, abdominal aorta, and superior mesenteric artery, consistent with a large vessel vasculitis, which had presented with a systemic inflammatory response, carotidynia, and mesenteric angina.Fig. 1 Computed tomography of the neck on initial presentation revealing wall thickening of the left distal common carotid artery with hazing of the adjacent fat (red arrow)\n\n\nFig. 2 Computed tomography of the abdomen on second presentation revealing mild upper abdominal periaortic stranding with mural thickening of the aorta (red arrow), similar in appearance to the left common carotid artery from the original computed tomography of her neck (Fig. 1)\n\n\nFig. 3 Positron emission tomography scan demonstrating diffuse, intense fluorodeoxyglucose uptake of the right common carotid artery (red arrow), abdominal aorta (blue arrow), and superior mesenteric artery (green arrow)\n\n\n\n\nShe was treated with methylprednisolone (500 mg daily for 3 days) administered intravenously with immediate resolution of her abdominal and neck pain and fevers. She was subsequently commenced on methotrexate 15 mg/week administered orally and prednisone 50 mg/day. She remained well over the following 5 months, with continuation of methotrexate, and her prednisone dose was gradually reduced to 15 mg/day.\n\nFive months later, she reported fatigue and persistent cough despite multiple courses of antibiotics. Blood tests revealed neutropenia with >20 % blasts on peripheral blood film. A subsequent bone marrow aspirate (Fig. 4) demonstrated a markedly hypercellular marrow with 69 % blasts, which by flow cytometry were identified as an abnormal population of myeloid cells expressing CD117, CD13, CD33, human leukocyte antigen-antigen D related (HLA-DR), CD123, lacking CD34, with aberrant CD4 expression, consistent with AML. Molecular studies showed a FLT3-internal tandem duplication (ITD) mutation, which characterizes more aggressive disease and frequent relapses [1]. She received induction chemotherapy with cytarabine and idarubicin but a month later a bone marrow aspirate demonstrated residual blasts (9 %) consistent with persistent AML. She received re-induction chemotherapy with cytarabine and idarubicin, and then further re-induction with fludarabine, cytarabine, and idarubicin. Despite initial morphological remission, her AML relapsed 3 months later. She had many infective complications, including febrile neutropenia and Clostridium difficile colitis, but her large vessel vasculitis did not recur. Due to a rapidly rising blast count and refractory disease, she was palliated and died 8 months after her diagnosis of AML.Fig. 4 Bone marrow aspirate demonstrating features of acute myeloid leukemia including myeloblasts (red arrows) >20 %\n\n\n\n\nDiscussion\nWe present a case of large vessel vasculitis with atypical features, including a migratory involvement of affected vessels and marked systemic inflammatory features, with subsequent progression to AML.\n\nLarge vessel vasculitis associated with MDS has rarely been described [2]. In some cases, the diagnoses of MDS and large vessel vasculitis are made simultaneously, and in others, the MDS has been pre-existing. Our patient did not have a previous diagnosis of MDS before the development of vasculitis, and on presentation, had only minimally reduced hemoglobin (112 g/L). Over the following weeks, her peripheral blood neutrophil count fluctuated between normal and mildly reduced (1.4 to 3.4 × 109 cells/L), as did her monocyte count (0.5 to 1.8 × 109 cells/L); however, her platelet count remained normal. With high dose glucocorticoids, her neutrophil count rose to 6.0 × 109 cells/L; however, the absence of a steroid-induced neutrophilia may also suggest a degree of myelodysplasia. The mild monocytosis, although not specific in the context of inflammation, may have been significant, given that her subsequent AML blasts aberrantly expressed CD4, which is normally expressed on monocytes.\n\nLarge vessel vasculitis can occur in autoimmune disorders, including extracranial GCA and TA. Marked systemic inflammation may be a feature of TA, however this disorder classically affects individuals younger than 50 years of age [3, 4]. GCA, more frequently seen in older individuals, typically involves smaller vessels such as the temporal arteries, but can also affect the aorta and its major branches. The few reported cases of MDS-associated large vessel vasculitis presented in a similar manner to our patient: at an age >50 years, with acute inflammation, including tender vessels and a highly raised CRP [2, 5, 6], exceeding the median CRP of 52 mg/L in patients with temporal artery biopsy-proven GCA [7].\n\nIn one review, five of eight patients with MDS-associated large vessel vasculitis developed AML, often refractory, usually within a year of presentation with vasculitis [2]. The timing of large vessel vasculitis preceding AML, and the unusual clinical features of acute inflammation with vessel wall tenderness and highly elevated inflammatory markers, suggest that the vasculitis in these patients may be a paraneoplastic phenomenon. The cytopenias in some forms of MDS may be immune mediated [8], with activated T cells inducing cytokine-mediated apoptosis of myeloid stem cells via tumor necrosis factor (TNF) and interferon gamma [5, 9]. Dysregulated immune mechanisms may thus be involved in the pathogenesis of MDS [10]. The association between MDS and autoimmune phenomena, such as arthritis, vasculitis, and connective tissue diseases, is well recognized in the literature [11, 12]; however MDS-associated vasculitis more commonly affects small caliber vessels [11, 13, 14].\n\nAlthough the vasculitis in our patient responded promptly to glucocorticoids, the subsequent emergence of AML raises the possibility that immunosuppression impaired the cytotoxic anti-tumor response, and thus unmasked the AML. The majority of cases of patients reported with both large vessel vasculitis and MDS, however, received no steroid-sparing agent, yet several still progressed to AML [2]. In light of the poor prognosis when given corticosteroids, it is important to recognize the high risk of progression to AML in these individuals. Consideration may be given to simultaneous treatment for MDS, including azacitidine or even high intensity chemotherapy followed by allogeneic stem cell transplantation in selected patients with good performance status. A recent multicenter study confirmed that treatment with azacitidine in patients with both MDS and a systemic inflammatory or autoimmune disease appeared to have a positive effect on their inflammatory condition [15]; however, whether this treatment would reduce progression to AML in individuals with concurrent large vessel vasculitis is undetermined.\n\nConclusions\nIn summary, we present a 56-year-old woman with a large vessel vasculitis with migratory features, vessel wall tenderness, and marked systemic inflammation, who subsequently developed AML. Large vessel vasculitis with atypical clinical features in older individuals should prompt a search for underlying myelodysplasia, and vigilance for progression to AML.\n\nAbbreviations\nAMLAcute myeloid leukemia\n\nCRPC-reactive protein\n\nCTComputed tomography\n\nDNAdeoxyribonucleic acid\n\nFDGFluorodeoxyglucose\n\nGCAGiant cell arteritis\n\nHLA-DRHuman leukocyte antigen-antigen D related\n\nITDInternal tandem duplication\n\nMCVMean corpuscular volume\n\nMDSMyelodysplastic syndrome\n\nPETPositron emission tomography\n\nTATakayasu’s arteritis\n\nTNFTumor necrosis factor\n\nAcknowledgements\nWe acknowledge Dr Maansi Joshi (Department of Haematology, Westmead Hospital, NSW Australia) for providing the bone marrow aspirate images.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nDC, AA, WB, MV, and LJB were involved in patient care. DC, AA, and LJB wrote the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s next-of-kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Small D. FLT3 mutations: biology and treatment. Hematology Am Soc Hematol Educ Program 2006:178–84. https://www.ncbi.nlm.nih.gov/pubmed/17124058.\n2. Katsuyama T Uchida HA Toma K Maeda Y Hirota D Umebayashi R Sada KE Makino H Large vessel vasculitis with myelodysplastic syndrome Intern Med 2014 53 63 6 10.2169/internalmedicine.53.0949 24390531 \n3. de Souza AW de Carvalho JF Diagnostic and classification criteria of Takayasu arteritis J Autoimmun 2014 48–49 79 83 10.1016/j.jaut.2014.01.012 24461381 \n4. Freitas DS Camargo CZ Mariz HA Arraes AE de Souza AW Takayasu arteritis: assessment of response to medical therapy based on clinical activity criteria and imaging techniques Rheumatol Int 2012 32 703 9 10.1007/s00296-010-1694-9 21152919 \n5. Cohen MJ Shyman A Klein M Ben-Yehuda A Rubinow A Or R Goldschmidt N Large vessel (Takayasu’s) arteritis in a patient with myelodysplastic syndrome: is there a common pathogenesis? Clin Lymphoma Myeloma Leuk 2011 11 60 3 10.3816/CLML.2011.n.008 21454192 \n6. Steurer M Fritsche G Tzankov A Gotwald T Sturm W Konwalinka G Gruber J Large-vessel arteritis and myelodysplastic syndrome: report of two cases Eur J Haematol 2004 73 128 33 10.1111/j.1600-0609.2004.00265.x 15245512 \n7. Kermani TA Schmidt J Crowson CS Ytterberg SR Hunder GG Matteson EL Warrington KJ Utility of erythrocyte sedimentation rate and C-reactive protein for the diagnosis of giant cell arteritis Semin Arthritis Rheum 2012 41 866 71 10.1016/j.semarthrit.2011.10.005 22119103 \n8. Okamoto T Okada M Mori A Saheki K Takatsuka H Wada H Tamura A Fujimori Y Takemoto Y Kanamaru A Kakishita E Correlation between immunological abnormalities and prognosis in myelodysplastic syndrome patients Int J Hematol 1997 66 345 51 10.1016/S0925-5710(97)00042-X 9401280 \n9. Kochenderfer JN Kobayashi S Wieder ED Su C Molldrem JJ Loss of T-lymphocyte clonal dominance in patients with myelodysplastic syndrome responsive to immunosuppression Blood 2002 100 3639 45 10.1182/blood-2002-01-0155 12393644 \n10. Hamblin TJ Immunological abnormalities in myelodysplastic syndromes Semin Hematol 1996 33 150 62 8722685 \n11. Giannouli S Voulgarelis M Zintzaras E Tzioufas AG Moutsopoulos HM Autoimmune phenomena in myelodysplastic syndromes: a 4-yr prospective study Rheumatology (Oxford) 2004 43 626 32 10.1093/rheumatology/keh136 14983106 \n12. Tefferi A Vardiman JW Myelodysplastic syndromes N Engl J Med 2009 361 1872 85 10.1056/NEJMra0902908 19890130 \n13. Castro M Conn DL Su WP Garton JP Rheumatic manifestations in myelodysplastic syndromes J Rheumatol 1991 18 721 7 1865418 \n14. de Hollanda A Beucher A Henrion D Ghali A Lavigne C Levesque H Hamidou M Subra JF Ifrah N Belizna C Systemic and immune manifestations in myelodysplasia: a multicenter retrospective study Arthritis Care Res (Hoboken) 2011 63 1188 94 10.1002/acr.20504 21584947 \n15. Fraison JB Mekinian A Grignano E Kahn JE Arlet JB Decaux O Denis G Buchdahl AL Omouri M Maigne G Efficacy of Azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia Leuk Res 2016 43 13 7 10.1016/j.leukres.2016.02.005 26922775\n\n",
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"patientonsetage": "56",
"patientonsetageunit": "801",
"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute myeloid leukaemia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "5"
},
{
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}
],
"summary": null
},
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},
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},
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"sendertype": "2"
},
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"seriousnessdeath": 1,
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"seriousnesshospitalization": null,
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"transmissiondate": "20170429"
},
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],
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{
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},
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"transmissiondate": "20170830"
},
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"medicinalproduct": "PREDNISONE."
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},
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"medicinalproduct": "METHOTREXATE."
}
],
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"patientonsetage": "56",
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"reaction": [
{
"reactionmeddrapt": "Acute myeloid leukaemia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Unmasking of previously unidentified disease",
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}
],
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},
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"literaturereference_normalized": "migratory large vessel vasculitis preceding acute myeloid leukemia a case report",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20171215",
"receivedate": "20170526",
"receiver": {
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},
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"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180320"
}
] |
{
"abstract": "OBJECTIVE\nOutcome for relapsed acute myeloid leukemia (AML) is poor. Cladribine has activity in AML, and an enhancing effect on other cytostatic drugs thus may help overcome resistance. Here, we present the final analysis of our phase II trial evaluating safety and efficacy of cladribine, cytarabine, and idarubicin (CAI) in relapsed AML.\n\n\nMETHODS\nPatients with relapsed AML after at least 6 months remission received two courses of CAI. After 9 patients, prolonged neutropenia prompted protocol change (omission of idarubicin in 2nd course and dose-reduction of cytarabine). Primary endpoints were remission rate and safety.\n\n\nRESULTS\nTwenty patients received treatment, fourteen one, and six two courses CAI/CA. After first course, complete remission (CR/CRi) was achieved in 60%. Most frequent toxicity was infection. Median OS was 8.8 months in all patients and 21.1 months in those with CR. Nine patients (48%) proceeded to allogeneic stem cell transplantation (allo-SCT), four of those are still alive and in CR, accounting for a 5-year survival rate of 55% of transplanted patients.\n\n\nCONCLUSIONS\nCladribine, cytarabine, and idarubicin in relapsed AML is feasible and induces good response rates. As expected, infections are the most important complication. However, combined with allo-SCT, long-term survival can be achieved in a substantial number of patients.",
"affiliations": "Medizinische Klinik III, Hämatologie/Onkologie/Rheumatologie, Universitätsklinikum Bonn, Bonn, Germany.;Medizinische Klinik III, Hämatologie/Onkologie/Rheumatologie, Universitätsklinikum Bonn, Bonn, Germany.;Medizinische Klinik III, Hämatologie/Onkologie/Rheumatologie, Universitätsklinikum Bonn, Bonn, Germany.;Abteilung für Integrierte Onkologie, Universitätsklinikum Bonn, Bonn, Germany.;Medizinische Klinik III, Hämatologie/Onkologie/Rheumatologie, Universitätsklinikum Bonn, Bonn, Germany.;Medizinische Klinik III, Hämatologie/Onkologie/Rheumatologie, Universitätsklinikum Bonn, Bonn, Germany.;Klinik für Innere Medizin II, Abteilung für Hämatologie und Onkologie, Universitätsklinikum Jena, Jena, Germany.",
"authors": "Mayer|Karin|K|https://orcid.org/0000-0001-7223-9748;Hahn-Ast|Corinna|C|;Schwab|Katjana|K|;Schmidt-Wolf|Ingo G H|IGH|;Brossart|Peter|P|;Glasmacher|Axel|A|;von Lilienfeld-Toal|Marie|M|",
"chemical_list": "D015415:Biomarkers; D003561:Cytarabine; D017338:Cladribine; D015255:Idarubicin",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13395",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "104(6)",
"journal": "European journal of haematology",
"keywords": "allogeneic stem cell transplantation; cladribine; complete remission; infection; neutropenia; relapsed AML; treatment-related mortality",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D017338:Cladribine; D003561:Cytarabine; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015255:Idarubicin; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012008:Recurrence; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "538-545",
"pmc": null,
"pmid": "32049382",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review",
"references": null,
"title": "Long-term follow-up of Cladribine, high-dose Cytarabine, and Idarubicin as salvage treatment for relapsed acute myeloid leukemia and literature review.",
"title_normalized": "long term follow up of cladribine high dose cytarabine and idarubicin as salvage treatment for relapsed acute myeloid leukemia and literature review"
} | [
{
"companynumb": "DE-PFIZER INC-2020076987",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IDARUBICIN HYDROCHLORIDE"
},
"drugadditional": "3",
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"drugauthorizationnumb": "50661",
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"drugdosagetext": "UNK, CYCLIC D1-3",
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"drugindication": "Acute myeloid leukaemia recurrent",
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"medicinalproduct": "IDARUBICIN HYDROCHLORIDE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
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"drugdosagetext": "1000 MG/M2/12H, CYCLIC",
"drugenddate": null,
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"drugindication": "Acute myeloid leukaemia recurrent",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugstructuredosagenumb": "1000",
"drugstructuredosageunit": "009",
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"medicinalproduct": "CYTARABINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLADRIBINE"
},
"drugadditional": "3",
"drugadministrationroute": null,
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": "5MG/M2/12 H, D 1-3, CYCLIC",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Acute myeloid leukaemia recurrent",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "009",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CLADRIBINE"
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
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"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Mayer, K.. Long-term follow-up of Cladribine, high-dose Cytarabine and Idarubicin as salvage treatment for Relapsed acute myeloid Leukemia and Literature Review. European journal of haematology. 2020;104(6):538-545",
"literaturereference_normalized": "long term follow up of cladribine high dose cytarabine and idarubicin as salvage treatment for relapsed acute myeloid leukemia and literature review",
"qualification": "3",
"reportercountry": "DE"
},
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"receiptdate": "20220113",
"receivedate": "20200224",
"receiver": {
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},
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"safetyreportid": 17451809,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 1,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220423"
}
] |
{
"abstract": "The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2- mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2- mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2- mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2- BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status.\n\n\n\nBased on the available efficacy and safety data, the \"new\" alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the \"old\" everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2- mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.",
"affiliations": "IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy. claudio.vernieri@ifom.eu.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.",
"authors": "Vernieri|Claudio|C|;Corti|Francesca|F|;Nichetti|Federico|F|;Ligorio|Francesca|F|;Manglaviti|Sara|S|;Zattarin|Emma|E|;Rea|Carmen G|CG|;Capri|Giuseppe|G|;Bianchi|Giulia V|GV|;de Braud|Filippo|F|",
"chemical_list": "D000730:Androstadienes; D000068338:Everolimus; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; C056516:exemestane",
"country": "England",
"delete": false,
"doi": "10.1186/s13058-020-01271-0",
"fulltext": "\n==== Front\nBreast Cancer Res\nBreast Cancer Res\nBreast Cancer Research : BCR\n1465-5411 1465-542X BioMed Central London \n\n1271\n10.1186/s13058-020-01271-0\nReview\nEverolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications\nVernieri Claudio claudio.vernieri@ifom.euclaudio.vernieri@istitutotumori.mi.it 12 Corti Francesca 2 Nichetti Federico 2 Ligorio Francesca 2 Manglaviti Sara 2 Zattarin Emma 2 Rea Carmen G. 2 Capri Giuseppe 2 Bianchi Giulia V. 2 de Braud Filippo 23 1 grid.7678.e0000 0004 1757 7797IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy \n2 grid.417893.00000 0001 0807 2568Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy \n3 grid.4708.b0000 0004 1757 2822Oncology and Hemato-Oncology Department, University of Milan, 20122 Milan, Italy \n6 4 2020 \n6 4 2020 \n2020 \n22 3319 9 2019 25 3 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThe PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2− mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2− mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2− mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice.\n\nMain body of the abstract\nHere, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2− BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status.\n\nConclusions\nBased on the available efficacy and safety data, the “new” alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the “old” everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2− mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.\n\nKeywords\nAdvanced breast cancerHormone receptor-positive breast cancerEndocrine therapymTORC1PI3KEverolimusAlpelisibPIK3CA mutationsEfficacy comparisonshttp://dx.doi.org/10.13039/501100005010Associazione Italiana per la Ricerca sul CancroMFAG 2019 ID. 22977Vernieri Claudio issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nEndocrine therapy (ET) is the mainstay of treatment for patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC) [1]. However, tumors initially responding to ET, including the most recent ET-Cyclin-Dependent Kinase 4/6 (CDK4/6) inhibitor combinations, almost invariably develop resistance [2–4]. Hence, the identification of targeted therapies that are able to revert or delay endocrine resistance is a clinically relevant issue.\n\nAberrant signaling through the phosphatidylinositol 3-kinase/protein kinase B (AKT)/mechanistic target of rapamycin complex 1 (PI3K/AKT/mTORC1) cascade is clearly implicated in endocrine resistance, thus providing the rationale for combining inhibitors of this pathway with currently available ET [5–7]. Based on the results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus (Eve) has been approved in combination with the aromatase inhibitor (AI) exemestane (Exe) for the treatment of HR+ HER2− mBC progressing on/after one line of non-steroidal aromatase inhibitor (NSAI) treatment [8]. More recently, the PI3Kα-specific inhibitor alpelisib (Alp) plus fulvestrant (Fulv) combination significantly prolonged progression-free survival (PFS) when compared to Fulv alone in patients with PIK3CA-mutated HR+ HER2− mBC, thus leading to FDA registration of Alp in this clinical setting [9]. Based on results of the SOLAR-1 study, Alp is increasingly considered by treating physicians and experts in the field as a candidate to replace Eve in HR+ HER2− mBC treatment [10].\n\nHere, we review data from prospective trials to compare the antitumor efficacy and safety profile of Eve/ET and Alp/ET combinations in women with HR+ HER2− mBC. We also discuss how Alp and Eve could fit in the future treatment scenario of mBC.\n\nMain text\nThe biology of the PI3K/AKT/mTORC1 axis\nThe insulin receptor (IR)/PI3K/AKT/mTORC1 pathway is the most commonly dysregulated pathway in human cancers and plays a crucial role in stimulating tumor cell metabolism, growth, proliferation, and motility [11]. PI3Ks include three classes of kinases with different structural properties and biological functions. Among different PI3Ks, class I PI3Ks, which include class IA (p110α, p110β, and p110δ) and class IB (p110γ) PI3Ks, have been found to be more commonly dysregulated in human cancers [11]. Enhanced activation of the IR/PI3K/AKT/mTORC1 axis can result from (a) increased extracellular concentration of growth factors activating oncogenic receptor tyrosine kinases (RTKs), such as IR or insulin-like growth factor 1 (IGF-1) receptor (IGF1R), on cell plasma membranes [12]; (b) activating mutations or overexpression of RTKs, including members of the HER family for class IA PI3Ks, or G protein-coupled receptors (GPCR) for class IB PI3Ks [13]; and (c) activating mutations or overexpression of downstream kinases, such as PI3K subunits, AKT and mTORC1, or inactivation of the phosphatase and tensin homolog deleted from chromosome 10 (PTEN), tuberous sclerosis complex 1/2 (TSC1/2), or liver kinase B1 (LKB1) tumor suppressor proteins [11].\n\nOnce activated by upstream signals, the PI3K regulatory subunit p85α binds to the phospho-tyrosine residues on receptor protein kinases or adaptor proteins, such as insulin receptor substrate 1 (IRS1), and unleashes the PI3K catalytic subunit p110α (encoded by the PIK3CA gene), which is enabled to phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3) (Fig. 1) [14, 15]. On the other hand, mutated (i.e., constitutively active) PI3K subunits catalyze PIP3 biosynthesis independently of upstream signals; in particular, mutations of the PIK3CA gene are found in approximately 40% of HR+ HER2− BCs and cause constitutive PI3K activation [16, 17]. Once synthesized, PIP3 anchors the serine/threonine AKT kinase to the cell plasma membrane, where it activates mTORC1, either directly or through the inhibition of TSC1/TSC2 [11, 13, 17]. In turn, mTORC1 stimulates cell growth and proliferation by triggering protein translation initiation through phosphorylating eIF4E-binding proteins (4E-BPs) and S6 kinases (S6K1 and S6K2). mTORC1 also inhibits autophagy and stimulates lipogenesis via intermediate lipogenic transcriptional factors and mitochondrial biogenesis (Fig. 1). Overall, mTORC1 activation induces a global metabolic response leading to the stimulation of anabolic processes and macromolecule biosynthesis [18, 19].\nFig. 1 Schematic representation of the PI3K/AKT/mTOR axis and its alterations in breast cancer. Alpelisib selectively inhibits the p110α subunit of PI3K, which is mutated and constitutively activated in approximately 40% of HR+ HER2− BC\n\n\n\nIn parallel with mTORC1 activation, constitutively active PI3K stimulates several biological processes that stimulate tumor cell proliferation, such as the Mitogen Activated Protein Kinase (MAPK) and estrogen receptor α (ERα) pathways [20], as well as the reprogramming of glucose and lipid metabolism via AKT activation and AMPK inhibition (Fig. 1) [15, 21].\n\nTumor suppressor enzymes prevent uncontrolled activation of the PI3K/AKT/mTORC1 cascade at different levels: among them, PTEN counteracts PI3K activity by dephosphorylating PIP3 to PIP2, while LKB1 indirectly inhibits mTORC1 via AMP-activated protein kinase (AMPK)-mediated activation of TSC1/2 [22, 23].\n\nNotably, the PI3K/AKT/mTORC1 pathway is aberrantly activated in approximately 70% of BCs as a result of increased extracellular concentration of growth factors, activating mutations of genes encoding RTKs (e.g., IGFR1 and fibroblast growth factor receptor 1 [FGFR1]) or downstream oncogenes (e.g., PI3KCA or AKT), or, finally, loss-of-function or reduced levels of PTEN, LKB1, or inositol polyphosphate 4-phosphatase type II (INPP4B) tumor suppressor proteins [24, 25]. Among these alterations, PIK3CA mutations are by far the most common ones [16]. Oncogenic PIK3CA mutations include the following: the kinase domain H1047R mutation (exon 20), which results in higher binding affinity of PI3K to the plasma membrane and to PIP2; the helical domain E542K and E545K mutations (exon 9), which enable the direct interaction of PI3K catalytic subunit with IRS1 independently of p85 and IRS1 phosphorylation; and deletions in the C2 domain, which unleash inhibitory contacts with regulatory subunits [13, 14].\n\nAlp selectively binds to and inhibits p110α, while Eve inhibits mTORC1 downstream of PI3K through allosteric binding. When used in in vitro models of HR+ HER2− BC, both PI3K and mTORC1 inhibitors demonstrated synergistic anticancer activity in combination with anti-estrogens. For instance, HR+ BC cells treated with letrozole (Let) plus Eve accumulate in the G1 phase of the cell cycle and undergo proliferation inhibition and apoptosis [26, 27]. Moreover, the mTORC1 inhibitor rapamycin reverts resistance to Fulv or tamoxifen (TAM) in HR+ BC cell lines, both alone and in combination with ET [27]. Finally, inhibitors of p110α and/or p110β showed synthetic lethal effects when combined with different ETs [5, 28, 29]. Mechanistically, these synergistic effects are the result of a crosstalk between the PI3K/AKT/mTORC1 and ER signaling pathways. One of mTORC1 targets, S6K1, is responsible for N-terminal ERα Activation Function 1 (AF1) domain phosphorylation on Serine167, thus leading to its ligand-independent transactivation [20]. Therefore, S6K-induced, ligand-independent activation of ERα can induce HR+ BC resistance to ET, thus providing strong preclinical rationale for combining PI3K/AKT/mTORC1 pathway inhibitors with ET to prevent/revert endocrine resistance.\n\nSince Eve inhibits the PI3K/AKT/mTORC1 cascade downstream of PI3K, its antitumor activity should be independent of PIK3CA mutational status. Conversely, Alp selectively inhibits proliferation of PI3Kα-driven HR+ HER2− BC cells and causes regression of PIK3CA-mutated in vivo tumor models [6, 28]. Therefore, PIK3CA-mutated tumors are the best candidates to respond to Alp [30].\n\nBOLERO-2 and SOLAR-1 trials: a comparison of efficacy and safety data\nThe BOLERO-2 and SOLAR-1 studies are the two randomized trials leading to Eve and Alp registration for HR+ HER2− mBC treatment in combination with standard ET. The main clinical and tumor characteristics of patients enrolled in the BOLERO-2 and SOLAR-1 (only PIK3CA-mutated cohort) trials are summarized in Table 1.\nTable 1 Clinical and tumor characteristics in patients enrolled in the BOLERO-2 and SOLAR-1 trials (cohort of PIK3CA-mutated cancers)\n\nPatient/tumor characteristic\tEverolimus and exemestane group (N = 485)\tPlacebo and exemestane group (N = 239)\tAlpelisib and fulvestrant group (N = 169)\tPlacebo and fulvestrant group (N = 172)\t\nAge (years)\t\n Median\t62\t61\t63\t64\t\n Range\t34–93\t28–90\t25–87\t38–92\t\nECOG Performance Statusa (%)\t\n 0\t60\t59\t66.3\t65.7\t\n 1\t36\t35\t33.1\t33.7\t\n 2\t2\t3\t0\t0\t\n Missing data\tNA\tNA\t0.6\t0.6\t\nVisceral disease (%)\t56\t56\t55\t58.1\t\nMetastatic site (%)\t\n Lung\t29\t33\t33.7\t39.5\t\n Liver\t33\t30\t29\t31.4\t\n Bone\t76\t77\tNA\tNA\t\nNo. of metastatic sites (%)\t\n 0–1\t32\t29\t37.3\t30.2\t\n 2\t31\t34\t34.3\t34.9\t\n ≥ 3\t36\t37\t28.4\t34.3\t\nPrevious chemotherapy (%)\t\n Neoadjuvant or adjuvant only\t44\t40\t59.8\t62.2\t\n Treatment of metastatic disease (with or without neoadjuvant or adjuvant therapy)\t26\t26\t0\t0.6\t\nPrevious CDK 4/6 inhibitorsb (%)\t0\t0\t5.3\t6.4\t\naECOG Performance Status: Eastern Cooperative Oncology Group Performance Status\n\nbCDK 4/6 : Cyclin-Dependent Kinase 4/6\n\n\n\nThe BOLERO-2 was a double-blind, phase III study that investigated the efficacy of the Eve/Exe combination in HR+ HER2− mBC postmenopausal women previously treated with NSAIs [8]. Patients (n = 724) enrolled in the trial were randomized in a 2:1 ratio to receive Eve/Exe or placebo/Exe. The primary endpoint was PFS; secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Median PFS was 11.0 months in the experimental arm versus (vs.) 4.1 months in the control arm (hazard ratio [HR] 0.38; 95% confidence interval [CI] 0.31–0.48; p < 0.0001; Table 2), with an ORR of 12.6% vs. 2.1%, respectively [31]. No significant differences in terms of OS were observed between Eve/Exe and placebo/Exe (median 31.0 months vs. 26.6 months, respectively; HR 0.89; 95% CI 0.73–1.10; p = 0.14) [32]. As for the safety profile, severe (G3/G4) AEs occurred in 33% and 9% of patients receiving the experimental or standard treatment, respectively, with stomatitis (8% vs. < 1%), anemia (6% vs. < 1%), dyspnea (4% vs. 1%), hyperglycemia (6% vs. 1%), fatigue (5% vs. 1%), and pneumonitis (4% vs. 0%) being the most common ones [8, 33] (Table 3). Median duration of Eve treatment was 5.5 months, with the main cause of therapy discontinuation being disease progression (61.9% vs. 88.7% in the Eve and control arms, respectively), followed by AEs (26.3% vs. 5%, respectively). Notably, next-generation sequencing (NGS) analysis performed in archival tumor specimens from a subgroup (n = 302) of patients enrolled in the BOLERO-2 trial showed that Eve provides clinical benefit to patients with both PIK3CA-wild type (wt) (HR 0.37; 95% CI 0.25–0.55) and PIK3CA-mutated (HR 0.51; 95% CI 0.34–0.77) tumors [34].\nTable 2 Efficacy analysis data from the BOLERO-2 trial and the SOLAR-1 study (cohort of PIK3CA-mutated cancer)\n\nClinical endpoint\tEverolimus and exemestane group (N = 482)\tPlacebo and exemestane group (N = 238)\tAlpelisib and fulvestrant group (N = 169)\tPlacebo and fulvestrant group (N = 172)\t\nBest overall response (%)\t\n Complete response CR\t0\t0\t0.6\t1.2\t\n Partial response PR\t12.6\t2.1\t26.0\t11.6\t\n Stable disease SD\t73.4\t62.8\t34.3\t36.6\t\n Neither complete response nor progressive diseasea\t/\t/\t22.5\t14.5\t\n Progressive disease PD\t5.8\t23.4\t9.5\t30.8\t\n Unknown\t8.2\t11.7\t7.1\t5.2\t\nOverall response (%)\t12.6\t2.1\t26.6\t12.8\t\nClinical benefit (%)\t49.9\t22.2\t61.5\t45.3\t\n“/,” not evaluated in this trial\n\naIn this category, the best overall response was evaluated only in patients who had no measurable disease at baseline according to the Response Evaluation Criteria in Solid Tumors, version 1.1\n\nTable 3 Incidence of adverse events in different arms in the BOLERO-2 and SOLAR-1 trials\n\nAdverse event\tEverolimus and exemestane group (N = 482)\tPlacebo and exemestane group (N = 238)\tAlpelisib and fulvestrant group (N = 284)\tPlacebo and fulvestrant group (N = 287)\t\nAny grade\tGrade 3\tGrade 4\tAny grade\tGrade 3\tGrade 4\tAny grade\tGrade 3\tGrade 4\tAny grade\tGrade 3\tGrade 4\t\nHyperglicemia\t16\t6\t< 1\t3\t1\t0\t63.7\t32.7\t3.9\t9.8\t0.3\t0.3\t\nStomatitis\t67\t8\t0\t12\t< 1\t0\t24.6\t2.5\t0\t6.3\t0\t0\t\nRash\t36\t1\t0\t6\t0\t0\t35.6\t9.9\t0\t5.9\t0.3\t0\t\nFatigue\t37\t4\t< 1\t27\t1\t0\t24.3\t3.5\t0\t17.1\t1.0\t0\t\nDiarrhea\t30\t2\t< 1\t16\t1\t0\t57.7\t6.7\t0\t15.7\t0.3\t0\t\nNausea\t27\t< 1\t< 1\t27\t1\t0\t44.7\t2.5\t0\t22.3\t0.3\t0\t\nDecreased appetite\t29\t1\t0\t10\t0\t0\t35.6\t0.7\t0\t10.5\t0.3\t0\t\nVomiting\t14\t< 1\t< 1\t11\t< 1\t0\t27.1\t0.7\t0\t9.8\t0.3\t0\t\nWeight loss\t19\t1\t0\t5\t0\t0\t26.8\t3.9\t0\t2.1\t0\t0\t\nDysgeusia\t21\t< 1\t0\t5\t0\t0\t16.5\t0\t0\t3.5\t0\t0\t\nHeadache\t19\t< 1\t0\t13\t0\t0\t17.6\t0.7\t0\t13.2\t0\t0\t\nAsthenia\t12\t2\t0\t3\t0\t0\t20.4\t1.8\t0\t12.9\t0\t0\t\nPruritus\t11\t< 1\t0\t3\t0\t0\t18\t0.7\t0\t5.6\t0\t0\t\nArthralgia\t16\t1\t0\t16\t0\t0\t11.3\t0.4\t0\t16.4\t1.0\t0\t\nCough\t22\t1\t0\t11\t0\t0\t/\t/\t/\t/\t/\t/\t\nDyspnea\t18\t4\t0\t9\t1\t< 1\t/\t/\t/\t/\t/\t/\t\nPneumonitis\t12\t3\t0\t0\t0\t0\t/\t/\t/\t/\t/\t/\t\nAnemia\t16\t5\t1\t4\t< 1\t< 1\t/\t/\t/\t/\t/\t/\t\nThrombocytopenia\t12\t2\t1\t< 1\t0\t< 1\t/\t/\t/\t/\t/\t/\t\nEpistaxis\t15\t0\t0\t1\t0\t0\t/\t/\t/\t/\t/\t/\t\nPyrexia\t14\t< 1\t0\t6\t< 1\t0\t/\t/\t/\t/\t/\t/\t\nPeripheral edema\t14\t1\t0\t6\t< 1\t0\t/\t/\t/\t/\t/\t/\t\nAST level increaseda\t13\t3\t< 1\t6\t1\t0\t/\t/\t/\t/\t/\t/\t\nALT level increasedb\t11\t3\t< 1\t3\t2\t0\t/\t/\t/\t/\t/\t/\t\nConstipation\t13\t< 1\t0\t11\t< 1\t0\t/\t/\t/\t/\t/\t/\t\nInsomnia\t11\t< 1\t0\t8\t0\t0\t/\t/\t/\t/\t/\t/\t\nBack pain\t11\t0\t0\t8\t1\t0\t/\t/\t/\t/\t/\t/\t\nHyperlipidemia\t14\t1\t0\t2\t0\t0\t/\t/\t/\t/\t/\t/\t\nInfections and infestations\t50\t5\t2\t25\t2\t0\t/\t/\t/\t/\t/\t/\t\nAlopecia\t/\t/\t/\t/\t/\t/\t19.7\t0\t0\t2.4\t0\t0\t\nMucosal inflammation\t/\t/\t/\t/\t/\t/\t18.3\t2.1\t0\t1.0\t0\t0\t\n“/,” adverse event not evaluated in this trial\n\naAspartate aminotransferase\n\nbAlanine aminotransferase\n\n\n\nThe SOLAR-1 study was a double-blind, phase III trial that randomized 571 postmenopausal women (n = 571; 99.83%) or men (n = 1; 0.17%) previously treated with an AI to receive Alp plus Fulv or placebo plus Fulv [9]. The determination of PIK3CA gene mutational status in tumor tissue specimens was mandatory before patient enrollment. Indeed, based on PIK3CA status (mutated vs. wt), patients were assigned to two different cohorts; then, they were randomized in a 1:1 ratio to receive the experimental (Alp/Fulv) or standard (placebo/Fulv) treatment. The primary endpoint of the SOLAR-1 trial was PFS in the cohort of PIK3CA-mutated patients, i.e., those patients with the highest chances to benefit from the experimental treatment based on previous preclinical and clinical studies [30, 35]. Secondary endpoints included OS in the cohort of patients with PIK3CA-mutated tumors, PFS and OS in the PIK3CA-wt cohort, ORR, clinical benefit, and treatment safety in the whole patient population. Notably, less than 7% of patients in all treatment arms had received previous treatment with CDK4/6 inhibitors. After a median follow-up of 20 months, median PFS for patients in the PIK3CA-mutated cohort was 11 months in the experimental arm vs. 5.7 months in the control arm (HR 0.65; 95% CI 0.50–0.85; p < 0.0001 Table 2), with an ORR of 26.6% and 12.8%, respectively. In the cohort of patients with PIK3CA-wt tumors, the experimental treatment was associated with a non-significant difference in terms of median PFS (7.4 vs. 5.6 months, respectively; HR 0.85; 95% CI 0.58–1.25). G3 and G4 AEs occurred in 64.4% and 11.6%, respectively, of Alp/Fulv-treated patients, and in 30.3% and 5.2%, respectively, of placebo/Fulv-treated subjects. The most common G3/G4 AEs in the experimental arm were hyperglycemia (36.6%), rash (9.9%), and diarrhea (6.7%). With a median duration of exposure to Alp of 5.5 months, the most frequent reasons of treatment discontinuation were disease progression (55% vs. 68% in the Alp/Fulv and placebo/Fulv groups, respectively) and the occurrence of AEs (25% vs. 4.2%, respectively), with hyperglycemia and rash being the most common AEs leading to permanent treatment discontinuation (Table 3). Regarding Alp-induced hyperglycemia, patients with fasting plasma glucose levels equal to 140 mg/dl or higher than 140 mg/dl received metformin as per SOLAR-1 protocol. Therefore, metformin administration was started before patients developed grade 3 or 4 hyperglycemia (fasting plasma glucose levels > 250 mg/dl) in most of the cases. Despite this practice, the incidence of severe hyperglycemia in Alp-treated patients was 36.6%, and it reasonable to speculate that it might have been even superior without the precocious administration of metformin [36].\n\nEven if the BOLERO-2 and SOLAR-1 trials enrolled patients with overall similar characteristics at baseline (Table 1), some differences need to be highlighted: (a) the BOLERO-2 trial enrolled patients with ECOG PS of 0–2, while the SOLAR-1 trial only enrolled patients with an ECOG PS of 0–1; (b) patients with previously treated and stable brain metastases were included in the SOLAR-1, but not in the BOLERO-2 trial; (c) enrollment of male patients was allowed in the SOLAR-1, but not in the BOLERO-2 trial; however, only one male patient was finally enrolled in the SOLAR-1 study; (d) patients with type 1 or uncontrolled type 2 diabetes mellitus were excluded from the SOLAR-1 but not from the BOLERO-2 trial; (e) a higher percentage of patients in the SOLAR-1 trial (52.1% in the PIK3CA-mutated cohort) received Alp/Fulv as their first-line treatment for advanced disease when compared to patients treated with Eve/Exe in the BOLERO-2 study (20.6%) [37]; (f) 26% of patients treated with Eve/Exe in the BOLERO-2 trial had received previous chemotherapy for the treatment of advanced disease, whereas these patients were excluded from the SOLAR-1 study; (g) 11.8% of patients with PIK3CA-mutated tumors treated with Alp/Fulv in the SOLAR-1 trial had endocrine-sensitive disease, which was an exclusion criterion in the BOLERO-2 trial; and (h) the type of ET combined with the experimental drug was different in the two studies (Exe and Fulv, respectively).\n\nExcept for the inclusion of patients with brain metastases, the SOLAR-1 trial enrolled a more selected population of HR+ HER2− mBC patients with less pretreated and potentially more endocrine-sensitive disease. This could at least in part explain the longer PFS observed in patients in the control arm of the SOLAR-1 trial (5.7 months) when compared to patients in the control arm of the BOLERO-2 study (4.1 months in the overall population; 2.8 months in a subgroup of patients with PIK3CA-mutated tumors [34]). Despite these differences, the absolute PFS advantage provided by the addition of Eve or Alp to standard ET was similar (6.9 and 5.3 months, respectively, when considering the whole population of patients enrolled in the BOLERO-2 trial and patients with PIK3CA-mutated neoplasms in the SOLAR-1 study; 3.9 and 5.3 months, respectively, when considering only patients with PIK3CA-mutated tumors in both studies). The relative PFS advantage associated with Eve (HR 0.36) was higher than the relative benefit associated with Alp (HR 0.65) when considering all patients enrolled in the BOLERO-2 trial, while it was similar in subgroups of patients with PIK3CA-mutated tumors (0.51 and 0.65, respectively) [34]. The rate of treatment discontinuation was high in both studies (about 25%), but the incidence of G3/G4 AEs was considerably higher in both the treatment (76% vs. 42%, respectively) and control (35.5% vs. 9%, respectively) arm of the SOLAR-1 trial.\n\nOther prospective studies investigating Eve or Alp\nAfter the publication of the BOLERO-2 study, other prospective phase IIIb–IV trials (4EVER [38], BRAWO [39], STEPAUT [40], BALLET [41], EVEREXES [42]) investigated the efficacy and tolerability of Eve/Exe in more heterogeneous patient cohorts when compared to patients enrolled in the BOLERO-2 trial (Table 4) [8]. In particular, the 4EVER, BRAWO, and BALLET studies enrolled patients independently of the number of previous chemotherapy lines for advanced disease, as well as of previous Exe treatment, thus more faithfully recapitulating patients treated in the real-world clinical practice [38, 39, 41]. For instance, 60% and 53.7% of patients in the BALLET and 4EVER studies, respectively, had received previous chemotherapy for advanced disease when compared to 26% of patients in the BOLERO-2 study. Nonetheless, activity and efficacy data from these studies were similar to those from the BOLERO-2 trial, with ORR ranging from 8.2% (BRAWO) to 15.8% (EVEREXES), and mPFS ranging from 5.6 months (4EVER) to 9.5 months (STEPAUT, EVEREXES). The safety profile of Eve/Exe was also consistent with data from the BOLERO-2 study, with the most commonly observed G3/G4 toxicities being stomatitis (range 3.9–10.6%), dyspnea (range 2–4.7%), asthenia/fatigue (range 1.5–3.6%), and hyperglycemia (range 2.9–7%). Treatment discontinuation rates due to AEs ranged from 17.1% (BALLET) to 26% (BRAWO). While the safety profile of Eve/Exe in elderly patients (> 70 years) in the BALLET study was overall similar to that observed in the BOLERO-2 trial, incidence of G3/G4 AEs, dose reductions/interruptions, and treatment discontinuations due to AEs were higher in the elderly vs. non-elderly population [41].\nTable 4 Efficacy and safety data from Eve prospective studies published after the BOLERO-2 trial in HR+, HER2− aBC/mBC\n\nEverolimus\t\nStudy\tStudy design\tPopulation\tN° of pts.\tPrevious CT allowed\tMedian TD (mos)/(R)DIa (mg/d)\tORR\tmPFS (mos)\tmOS (mos)\tAny grade AEs (%) (Eve combination)b\tG3/4 AEs (%) (Eve combination) b\tDiscontinuation ratec\t\n4EVER [38], phase IIIb, open label, single arm\tEve + Exe (10 + 25 mg/d)\tPostmenopausal HR+, HER2− LABC/mBC progressing on or after an NSAI (either adjuvant or for advanced disease)\t299b\tYes, any number of lines for LABC/mBC, prior Exe allowed\tTD/RDI, 4.4/0.98\t8.9% (at 24 weeks)\t5.6\tmOS NR, OS at 48w 66.9%\tOverall 98.7%\n\nStomatitis 49.2%\n\nFatigue 36.1%\n\nDiarrhea 26.4%\n\nNausea 26.1%\n\n\tOverall 58.9%\n\nStomatitis 8.4%\n\nGPHD 6.7%\n\nDyspnea 4.7%\n\nAnemia 4.3%\n\n\t24.7%\t\nBRAWO [39], phase IV, non-interventional\tEve + Exe (5–10 + 25 mg/d)\tHR+, HER2− LABC/mBC progressed after a NSAI Eve + Exe as per clinical practice\t2074\tYes, previous Exe allowed\tTD 10 mg/d, 5.1\n\nTD 5 mg/d, 4.6\n\n\t8.2%\t6.6\tNA\tStomatitis 42.6%\n\nFatigue 19.8%\n\n\tStomatitis 3.9%\n\nFatigue 1.5%\n\n\t26%\t\nSTEPAUT [40], phase IV, non-interventional\tEve + Exe (5–10 + 25 mg/d)\tPostmenopausal HR+, HER2− LABC/mBC progressing on/after prior NSAIs in routine clinical practice\t225\tNS\tTD/DI, NA/NA\tNA\t9.5\tNA\tStomatitis/mucositis 48%\n\nRash/exanthema 22.2%\n\nDyspnea/cough 22.2%\n\n\tStomatitis/mucositis 4.4%\n\nGPHD/weight loss 2.7%\n\nInappetence /nausea 2.2%\n\n\tNA\t\nBALLET [41], phase IIIb, open label, single arm, expanded access trial\tEve + Exe (5–10 + 25 mg/d)\tPostmenopausal HR+, HER2− LABC/mBC progressing on/after prior NSAIs\t2133\tYes, any number of lines for LABC/mBC\tTD/RDI, 3.7/0.98\tNA\tNA\tNA\tOverall 94.7%\n\nStomatitis 52.8%\n\nAsthenia 22.8%\n\nDiarrhea 16.8%\n\nRash 16.5%\n\nInappetence 16%\n\n\tOverall 42.7%\n\nStomatitis 9.4%\n\nAsthenia 3.6%\n\nHyperglycemia 2.9%\n\nDyspnea 2%\n\nNIP 1.9%\n\n\t17.1%\t\nEVEREXES [42], phase IIIb, open label, single arm, Asia and Africa\tEve + Exe (10 + 25 mg/d)\tPostmenopausal HR+, HER2− LABC/mBC progressing on/after prior NSAI (adjuvant or for LABC/mBC)\t232\tYes, no more than 1 prior CT line for LABC/mBC\tTD/DI, NA/9.2\t15.8%\t9.5\tNA\tStomatitis 60.4%\n\nSkin toxicity 27.8%\n\nHyperglycemia 24.7%\n\nFatigue 17.2%\n\nWeight loss 15.4%\n\n\tStomatitis 10.6%\n\nHyperglycemia 7%\n\nFatigue 2.2%\n\nNIP 1.3%\n\nWeight loss 0.9%\n\n\tNA\t\nBOLERO-4 [43], phase II, multicenter, open-label, single-arm\tFirst line: Eve + Let (10 + 2.5 mg/d); at PD second line: Eve + Exe (10 + 25 mg/d)\tPostmenopausal HR+ HER2− LABC/mBC\t202, 50\tNo\tTD/DI, 14.8/8.5 and 2.9/8.3\t45%, 6%\t22, 3.7\tmOS NR, OS at 24 m 78.7%\tEve + Let\n\nOverall 100%\n\nStomatitis 68.8%\n\nLoss of weight 44%\n\nDiarrhea 41%\n\nNausea 37%\n\n\tEve + Let\n\nOverall 58%\n\nAnemia 10% Hypertension 8%\n\nStomatitis 6%\n\nHypertriglyceridemia 6%\n\n\tEve + Let\n\n15.8%\n\n\t\nTAMRAD [44], phase II, open-label, randomized\tEve + TAM (10 + 20 mg/d) vs. TAM (20 mg/d)\tPostmenopausal HR+, HER2−, LABC/mBC progressing on/after prior NSAI (adjuvant or for LABC/mBC)\t54, 57\tYes, any number of lines for LABC/mBC\tTD/DI, 6.2/NA and 4.8/NA\t14%, 13%\t8.6, 4.5\tNR, 32.9\tPain 82%\n\nFatigue 72%\n\nAnemia 69%\n\nStomatitis 56%\n\nLeukopenia 54%\n\n\tStomatitis 11%\n\nPain 9%\n\nInfections 7%\n\nAnorexia 7%\n\nFatigue 6%\n\n\tEve + TAM\n\n22%\n\n\t\nPrE0102 [45], phase II, randomized, double-blind, placebo-controlled\tEve + Fulve (10 mg/d)fvs. Fulve\tPostmenopausal HR+ HER2− LABC/mBC\n\nprogressing on/after prior NSAI (adjuvant or for LABC/mBC)\n\n\t66, 65\tYes, no more than 1 prior CT line for LABC/mBC\tTD/DI, 5.1/NA and 4.6/NA\t18.2%, 12.3%\t10.3, 5.1\t28.3, 31.4\tMucositis 53%\n\nFatigue 42%\n\nRash 38%\n\nAnemia 31%\n\nDiarrhea 23%\n\n\tMucositis 11%\n\nNIP 6%\n\nFatigue 6%\n\n\tEve + Fulv\n\n20%\n\n\t\nMANTA [46], phase II, open-label, randomized\tEve + Fulve (10 mg/d)f, cVIS + Fulve, (50 mg BID)g, iVIS + Fulve (2 days on, 5 days off; 125 mg BID)h, Fulve\tPostmenopausal HR+, LABC/mBC progressing on/after prior NSAI (either adjuvant or for LABC/mBC)\t65, 103, 98, 67\tYes, no more than 1 prior CT line for LABC/mBC\tTD/DI, NA/NA for all arms\t41.2%, 30.4%, 28.6%, 25.0%\t12.3, 7.6, 8.0, 5.4\tNR, 27.1, 24.2, 24.4\tStomatitis 60%\n\nAsthenia 53.3%\n\nRash 50.0%\n\nDiarrhea 31.7%\n\nDecreased appetite 30.0%\n\n\tStomatitis 11.7%\n\nRash 5.0%\n\nAsthenia 3.3%\n\nDiarrhea 1.7%\n\nDecreased appetite 1.7%\n\n\t18.8%\t\nSafra et al. [47], phase II, open-label, single-arm, multicenter trial\tEve + Let (10 + 2.5 mg/d)\tPostmenopausal ER+, HER2− LABC/mBC progressing on/after prior ET (either adjuvant or for LABC/mBC)\t72\tNo\tTD/DI, NA/NA\t23.3%\t8.8\t22.9\tFatigue 61.1%\n\nStomatitis 54.2%\n\nRash 33.4%\n\nCough 33.3%\n\nDecreased appetite 31.9%\n\n\tAnemia 9.7%\n\nStomatitis 8.3%\n\nFatigue 5.6%\n\nDiarrhea 5.6%\n\nHyperglycemia 4.2%\n\n\t12.5%\t\nBOLERO-6 [48], phase II, open-label, randomized\tEve + Exe (10 + 25 mg/d) vs. Eve (10 mg/d) vs. capecitabine (1250 mg/m2 BID)\tPostmenopausal HR+ HER2− LABC/mBC progressing on/after prior NSAI\t104, 103, 102\tYes, no more than 1 prior CT line for LABC/mBC, prior Exe not allowed\tTD/RDI, 6.3/0.92, 4.6/0.98, and 6.1/0.78\tNA\t8.4, 6.8, 9.6\t23.1, 29.3, 25.6\tOverall 100%\n\nStomatitis 49%\n\nFatigue 38%\n\nDiarrhea 35%\n\nAnemia 32%\n\nGGT elevation 15%\n\nAST elevation 15%\n\n\tOverall 70%\n\nAnemia 13%\n\nStomatitis 9%\n\nGGT elevation 9%\n\nFatigue 8%\n\nAST elevation 7%\n\nPneumonitis 7%\n\n\tEve + Exe\n\n8%\n\n\t\nYardley et al. [49], phase II, open label\tEve (10 mg/d) added to the most recent ET on which a patient progressed\tPost/premenopausal HR+, HER2− LABC/mBC refractory to ET (either adjuvant or for LABC/mBC)\t47\tYes no more than 1 prior CT line for LABC/mBC\tTD/DI, 4.1/NA\t6%\t6.6\t21.1\tFatigue 38%\n\nStomatitis 32%\n\nMucosal\n\ninflammation 28%\n\nRash 28%\n\n\tFatigue 4%\n\nStomatitis 6%\n\nMucosal inflammation 4%\n\nRash 4%\n\n\t15%\t\nAEs adverse events, AST aspartate aminotransferase, BID bis in die, CT chemotherapy, cVIS continuous vistusertib, d day, Eve everolimus, Exe exemestane, ET endocrine therapy, Fulv fulvestrant, G grade, GGT gamma glutamyl transferase, GHPD general physical health deterioration, mos months, HER2 human epidermal growth factor receptor 2, HR hormone receptor, iVIS intermittent vistusertib, LABC locally advanced breast cancer, Let letrozole, mBC metastatic breast cancer, mg/d milligrams per day, mPFS median progression-free survival, mOS median overall survival, N° number, NA not available, NE not evaluable, NIP non-infectious pneumonitis, NR not reached, NS not specified, NSAI non-steroideal aromatase inhibitor, ORR overall response rate, PD progressive disease, pts. patients, (R)DI (relative) dose intensity, TAM tamoxifen, TD treatment duration, w weeks\n\naOnly absolute but not relative dose intensity is calculated in mg/d\n\nbReported AEs refer only to the arm including Eve + ET\n\ncStudy treatment discontinuation (referring to the arm containing Eve + ET) due to AEs\n\nd281 patients evaluable for efficacy, 299 patients for safety\n\neFulv 500 mg intramuscular injection on day 1, followed by 500 mg doses on days 15 and 28, and then every 28 days\n\nfRefers to Eve\n\ngRefers to cVIS\n\nhRefers to iVIS\n\n\n\nAltogether, real-world data corroborate the efficacy of Eve in combination with ET for the treatment of HR+ HER2− mBC. Subgroup analyses of these studies indicate that ORR and PFS may be lower in patients treated with a higher number of previous therapy lines, with previous exposure to chemotherapy, or treated with lower Eve treatment intensity [38–40]. Finally, no ORR or PFS differences have been described based on prior treatment with Exe [38]. Of note, the introduction of prophylactic dexamethasone oral solution for the prevention or management of Eve-induced stomatitis has remarkably improved the safety profile of Eve through reducing one of the most common and disturbing toxicities related to the use of this compound [50].\n\nMore recently, the phase II BOLERO-4 study evaluated Eve plus Let as a first-line treatment in 202 postmenopausal women with HR+ HER2 mBC, who received second-line Eve/Exe on progression. First-line Eve/Let was associated with mPFS of 22.0 months (95% CI 18.1–25.1), while mOS was not reached. Of note, mPFS was 3.7 months (95% CI 1.9–7.4 months) with second-line Eve/Exe treatment (50 patients) [43]. While these data indicate that Eve/Let is an effective first-line combination treatment, they also show that Eve continuation after disease progression is a poorly effective therapeutic strategy. Other phase II studies evaluating Eve in combination with Let, Fulv, Exe, or TAM in patients with mBC progressing on/after prior NSAI therapy showed interesting activity and efficacy, in the absence of relevant unforetold toxicities [44–49].\n\nAs for Alp, small prospective trials published before the SOLAR-1 study evaluated the Let/Alp or Fulv/Alp combinations in patients with HR+ HER2− mBC progressing after previous ET. Consistent with SOLAR-1 results, these studies reported an incidence of G3/G4 hyperglycemia and rash in the 10–38.1% and 8–27.8% ranges, respectively, with longer mPFS in patients with PIK3CA-mutated neoplasms (Table 5) [30, 35, 51].\nTable 5 Efficacy and safety data from phase Ib/II trials of alpelisib in HR+, HER2− aBC/mBC\n\nAlpelisib\t\nStudy\tStudy design\tPopulation\tN° of pts.\tPrevious CT allowed\tORR\tmPFS (mos)\tmOS (mos)\tAny grade AEs (%)\tG3/4 AEs (%)\tDiscontinuation ratea\t\nJuric et al. [30], phase Ib, open-label, single-arm\tAlpelisib + Fulvb (300–350–400 mg/d)d\tPostmenopausal PIK3CA-mutated (60%) or PIK3CA-wt (38%) HR+, LABC/mBC progressing on/after prior ET\t87\tNS\tPIK3CA-mutated, 29%; PIK3CA-wt, 0%\tPIK3CA-mutated, 9.1; PIK3CA-wt, 4.7\tNA\tDiarrhea 60%\n\nNausea 53%\n\nHyperglycemia 51%\n\n\tHyperglycemia 22%\n\nMaculopapular rash 13%\n\nRash 8%\n\n\t10%\t\nMayer et al. [35], phase Ib, multicenter, open-label\tAlpelisib + Let (300–350 + 2.5 mg/d)c\tPostmenopausal HR+, HER2− mBC progressing on/after prior ET\t26\tYes\tPIK3CA-mutated, 25%; PIK3CA-wt, 10%\tNA\tNA\tAlpelisib 300 mg/d\n\nDiarrhea 80%\n\nNausea 60%\n\nHyperglicemia 55%\n\nRash 45%\n\nFatigue 45%\n\n\tDiarrhea 10%\n\nHyperglicemia 10%\n\nAST/ALT elevation 5%\n\n\t11%\t\nRugo et al. [51], phase 2, open-label, non-comparative study\tAlpelisib + Fulvbd (300 mg/d)c, Alpelisib + Letd (300 + 2.5 mg/d)\tMen and women with PIK3CA-mutated HR+, HER2− aBC whose disease progressed on/after CDK4/6i + ET\t21, 18\tYes\t20%, 18%\tNA\tNA\tNA\tHyperglycemia 38.1% (Fulv)/27.8% (Let)\n\nRash 4.8% (Fulv)/27.8% (Let)\n\n\t5%, 5%\t\nAEs adverse events, AST aspartate aminotransferase, ALT alanine aminotransferase, CDKi cyclin-dependent kinase inhibitors, CT chemotherapy, d day, ET endocrine therapy, Fulv fulvestrant, G grade, mos months, HR hormone receptor, (L)ABC (locally) advanced breast cancer, mBC metastatic breast cancer, mg/d milligrams per day, mPFS median progression-free survival, mOS median overall survival, N° number, NA not available, NS not specified, ORR overall response rate, pts. patients, wt wild type\n\naStudy treatment discontinuation due to AEs\n\nbFulv 500 mg intramuscular injection on day 1, followed by 500 mg doses on days 15 and 28, and then every 28 days\n\ncRefers to alpelisib\n\ndFulv cohort: patients treated with prior CDKi and aromatase inhibitors; Let cohort: patients treated with prior CDKi and Fulv\n\n\n\nDiscussion\nThe recent registration of the Alp/Fulv combination for the treatment of PIK3CA-mutated HR+ HER2− mBC has been considered a biologically and clinically relevant advancement [10]. Indeed, Alp is the first compound that provided clinically meaningful benefit in a subgroup of HR+ HER2− mBC patients that can be identified on the basis of a specific genetic tumor biomarker.\n\nBased on the comparison of efficacy and safety results of the BOLERO-2 and the SOLAR-1 studies, Eve or Alp in combination with standard ET provide similar PFS benefit when compared to ET alone; however, Alp/Fulv is associated with overall higher incidence of G3/G4 AEs despite the fact that patients in the SOLAR-1 trial had more favorable clinical characteristics, including better ECOG PS, absence of uncontrolled diabetes mellitus at enrollment, and the fact that metformin was administered as per protocol if fasting blood glucose concentration was 140 mg/dl or higher [36]. The toxicity profiles of Eve and Alp, which are partially non-overlapping, indicate that ongoing or future trials aiming to combine these compounds may result in exaggerated incidence of AEs, unless dosages of both drugs are reduced (NCT02077933).\n\nAnother crucial difference between Eve and Alp consists in the fact that patients with both PIK3CA-mutated and PIK3CA-wt tumors benefit from adding Eve to ET, while Alp selectively benefits patients with PIK3CA-mutated tumors, which account for approximately 40% of the HR+ HER2− BCs [16]. From a biological point of view, this is expected because Eve inhibits the PI3K/AKT/mTORC1 axis downstream of PI3K, i.e., independently of PIK3CA mutations or other PI3K/AKT/mTORC1 activating mechanisms. From a clinical point of view, this implies that Alp is not effective in about 60% of all HR+ HER2− mBC patients (i.e., those with PIK3CA-wt disease). On the other hand, Eve and Alp may provide similar relative PFS advantage in patients with PIK3CA-mutated neoplasms [30, 34]; however, this hypothesis derives from a NGS subanalysis of the BOLERO-2 trial and should be confirmed in prospective studies directly comparing Eve and Alp in patients with PIK3CA-mutated HR+ HER2− mBC.\n\nAlthough indirect comparisons between independent trials cannot be used to draw definitive conclusions about different therapeutic approaches, and since no head-to-head trials can be expected soon, the available clinical evidence indicates that the “new” and more expensive Alp might be more toxic than the “old” Eve and has less broad clinical effectiveness (i.e., limited to patients with PIK3CA-mutated disease). For these reasons, the raising enthusiasm around Alp as a potential substitute of Eve in HR+ HER2− mBC treatment is not fully justified. The Eve/Exe combination remains a valid, and in many cases preferable (e.g., PIK3CA-wt neoplasms, or in diabetic or malnourished patients), treatment option for HR+ HER2− mBC patients undergoing disease progression on/after prior AI therapy.\n\nFurther clinical studies are needed to compare the efficacy and safety profile of Eve and Alp in HR+ HER2− mBC patients progressing on/after ET-CDK4/6 inhibitor treatment, which now represents the standard first- or second-line treatment in this clinical setting [2–4, 52–54]. In this clinical setting, the Eve/Exe combination and fulvestrant monotherapy remain two valid treatment options for patients with PIK3CA-wt neoplasms, while patients with PIK3CA-mutated neoplasms could potentially benefit from either fulvestrant/Alp or Eve/Exe. However, in the absence of clinical evidence, it is difficult to make clear clinical recommendations about the most effective second-line therapy in patients with PIK3CA-mutated or PIK3CA-wt tumors progressing on prior ET plus CDK 4/6 inhibitor-containing therapy. In patients with PIK3CA-mutated neoplasms, the sequential use of Eve and Alp in different treatment lines also deserves clinical investigation, at least in patients with PIK3CA-mutated disease; indeed, in the proof-of-concept phase III BELLE-3 trial, the pan-class I PI3K inhibitor buparlisib improved PFS when compared to the placebo in patients undergoing disease progression after prior Eve treatment, with an HR of 0.50 in the subgroup of PIK3CA-mutated neoplasms [55].\n\nConclusions\nWhen compared to the “old” everolimus, the “new” alpelisib may be burdened by higher incidence of severe adverse events, more narrow anticancer activity, and also higher costs after the approval of generic everolimus tablets (https://www.patient.novartisoncology.com/piqray-cost/; fda.gov/drugs/generic-drugs/overview-basics). The everolimus-exemestane combination remains an effective and reasonably well-tolerated second-line therapeutic option after progression to first-line AI plus/minus CDK 4/6 inhibitor treatment in HR+ HER2− mBC patients with PIK3CA-wt disease, as well as in patients with PIK3CA-mutated neoplasms who have contraindications to alpelisib, or those experiencing severe AEs during alpelisib/fulvestrant therapy.\n\nAbbreviations\nAEAdverse event\n\nAIAromatase inhibitor\n\nAlpAlpelisib\n\nAMPKAMP-activated protein kinase\n\nCDK 4/6Cyclin-Dependent Kinase 4/6\n\nCIConfidence interval\n\nEREstrogen receptor\n\nETEndocrine therapy\n\nEveEverolimus\n\nFGFR1Fibroblast growth factor receptor 1\n\nFulvFulvestrant\n\nGPCRG protein-coupled receptor\n\nHER2Human epidermal growth factor receptor 2\n\nHRHazard ratio\n\nHR+Hormone receptor-positive\n\nIGF-1Insulin-like growth factor 1\n\nINPP4BInositol polyphosphate 4-phosphatase type II (INPP4B)\n\nIRInsulin receptor\n\nIRS1Insulin receptor substrate 1\n\nLKB1Liver kinase B1\n\nmBCMetastatic breast cancer\n\nmPFSMedian progression-free survival\n\nmTORC1Mammalian target of rapamycin complex 1\n\nNSAINon-steroidal aromatase inhibitor\n\nORROverall response rate\n\nOSOverall survival\n\nPI3KPhosphoinositide 3-kinase\n\nPIP2Phosphatidylinositol 4,5-bisphosphate\n\nPIP3Phosphatidylinositol 3,4,5-triphosphate\n\nPETNPhosphatase and tensin homolog deleted from chromosome 10\n\nS6KS6 kinase\n\nTSC 1/2Tuberous sclerosis complex 1/2\n\n4E-BP1eIF4E-binding proteins\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank the Associazione Italiana per la Ricerca sul Cancro (AIRC, MFAG#22977: PI: Claudio Vernieri) and the Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori for supporting our research.\n\nAuthors’ contributions\nCV conceived the work. All authors contributed to the data acquisition and analysis. All authors contributed to the manuscript draft. CV was responsible for the critical revision of the final manuscript. The authors read and approved the final manuscript.\n\nFunding\nC.V. is supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, MFAG#22977) and by the Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article (and its supplementary information files).\n\nEthics approval and consent to participate\nThis article does not contain any data from human participants or animals.\n\nConsent for publication\nNot applicable\n\nCompeting interests\nF.d.B. received personal fees from Novartis for expert presentations and as a member of the advisory board. No other disclosures were reported.\n==== Refs\nReferences\n1. 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Hosford SR Dillon LM Bouley SJ Rosati R Yang W Chen VS Demidenko E Morra RP Jr Miller TW Combined inhibition of both p110alpha and p110beta isoforms of phosphatidylinositol 3-kinase is required for sustained therapeutic effect in PTEN-deficient, ER(+) breast cancer Clin Cancer Res 2017 23 11 2795 2805 10.1158/1078-0432.CCR-15-2764 27903677 \n23. Andrade-Vieira R Goguen D Bentley HA Bowen CV Marignani PA Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss Oncotarget 2014 5 24 12738 12752 10.18632/oncotarget.2818 25436981 \n24. Rodon J Tabernero J Improving the armamentarium of PI3K inhibitors with isoform-selective agents: a new light in the darkness Cancer Discov 2017 7 7 666 669 10.1158/2159-8290.CD-17-0500 28684409 \n25. Hopkins BD Pauli C Du X Wang DG Li X Wu D Amadiume SC Goncalves MD Hodakoski C Lundquist MR Suppression of insulin feedback enhances the efficacy of PI3K inhibitors Nature 2018 560 7719 499 503 10.1038/s41586-018-0343-4 30051890 \n26. Boulay A Rudloff J Ye J Zumstein-Mecker S O'Reilly T Evans DB Chen S Lane HA Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer Clin Cancer Res 2005 11 14 5319 5328 10.1158/1078-0432.CCR-04-2402 16033851 \n27. Ghayad SE Bieche I Vendrell JA Keime C Lidereau R Dumontet C Cohen PA mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels Cancer Sci 2008 99 10 1992 2003 19016759 \n28. Bosch A Li Z Bergamaschi A Ellis H Toska E Prat A Tao JJ Spratt DE Viola-Villegas NT Castel P PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer Sci Transl Med 2015 7 283 283ra251 10.1126/scitranslmed.aaa4442 \n29. Chen IC Hsiao LP Huang IW Yu HC Yeh LC Lin CH Wei-Wu Chen T Cheng AL Lu YS Phosphatidylinositol-3 kinase inhibitors, buparlisib and alpelisib, sensitize estrogen receptor-positive breast cancer cells to tamoxifen Sci Rep 2017 7 1 9842 10.1038/s41598-017-10555-z 28852212 \n30. Juric D, Janku F, Rodon J, Burris HA, Mayer IA, Schuler M, Seggewiss-Bernhardt R, Gil-Martin M, Middleton MR, Baselga J, et al. Alpelisib plus fulvestrant in PIK3CA-altered and PIK3CA-wild-type estrogen receptor-positive advanced breast cancer: a phase 1b clinical trial. JAMA Oncol. 2019:5(2):e184475e184475.\n31. Yardley DA Noguchi S Pritchard KI Burris HA 3rd Baselga J Gnant M Hortobagyi GN Campone M Pistilli B Piccart M Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis Adv Ther 2013 30 10 870 884 10.1007/s12325-013-0060-1 24158787 \n32. Piccart M Hortobagyi GN Campone M Pritchard KI Lebrun F Ito Y Noguchi S Perez A Rugo HS Deleu I Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger Ann Oncol 2014 25 12 2357 2362 10.1093/annonc/mdu456 25231953 \n33. Rugo HS Pritchard KI Gnant M Noguchi S Piccart M Hortobagyi G Baselga J Perez A Geberth M Csoszi T Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2 Ann Oncol 2014 25 4 808 815 10.1093/annonc/mdu009 24615500 \n34. Hortobagyi GN Chen D Piccart M Rugo HS Burris HA 3rd Pritchard KI Campone M Noguchi S Perez AT Deleu I Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from BOLERO-2 J Clin Oncol 2016 34 5 419 426 10.1200/JCO.2014.60.1971 26503204 \n35. Mayer IA Abramson VG Formisano L Balko JM Estrada MV Sanders ME Juric D Solit D Berger MF Won HH A phase Ib study of alpelisib (BYL719), a PI3Kalpha-specific inhibitor, with letrozole in ER+/HER2- metastatic breast cancer Clin Cancer Res 2017 23 1 26 34 10.1158/1078-0432.CCR-16-0134 27126994 \n36. Park J Shin SW Alpelisib for PIK3CA-mutated advanced breast cancer N Engl J Med 2019 381 7 686 10.1056/NEJMc1907856 31412191 \n37. Beck JT Hortobagyi GN Campone M Lebrun F Deleu I Rugo HS Pistilli B Masuda N Hart L Melichar B Everolimus plus exemestane as first-line therapy in HR(+), HER2(-) advanced breast cancer in BOLERO-2 Breast Cancer Res Treat 2014 143 3 459 467 10.1007/s10549-013-2814-5 24362951 \n38. Tesch H Stoetzer O Decker T Kurbacher CM Marme F Schneeweiss A Mundhenke C Distelrath A Fasching PA Lux MP Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: results of the single-arm, phase IIIB 4EVER trial Int J Cancer 2019 144 4 877 885 10.1002/ijc.31738 29992557 \n39. Lüftner DS Schuetz F Schneeweiss A Grischke E-M Bloch W Decker T Uleer C Salat C Forster F Schmidt M Mundhenke C Tesch H Jackisch C Fischer T Guderian G Hanson S Fasching P Everolimus + exemestane for HR+ advanced breast cancer in routine clinical practice- final results from the non-interventional trial, BRAWO Cancer Res 2019 79 4 Suppl Abstract nr P6–18-08 \n40. Steger GG, Bartsch R, Pfeiler G, Petru E, Greil R, Helfgott R, Egle D, Ohler L, Lang A, Tinchon C, Haslbauer F, Redl A, Hennebelle M, Miraz B, Winiger-Candolfi I, Gnant M. Efficacy and safety of everolimus plus exemestane in HR+, HER2--advanced breast cancer progressing on/after prior endocrine therapy, in routine clinical practice: 2nd interim analysis from STEPAUT. Cancer Res. 2017;77(4 Suppl):P4–22–20.\n41. Jerusalem G Mariani G Ciruelos EM Martin M Tjan-Heijnen VC Neven P Gavila JG Michelotti A Montemurro F Generali D Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer progressing on prior non-steroidal aromatase inhibitors: primary results of a phase IIIb, open-label, single-arm, expanded-access multicenter trial (BALLET) Ann Oncol 2016 27 9 1719 1725 10.1093/annonc/mdw249 27358383 \n42. Im YH, Uslu R, Lee KS, Nagarkar RV, Sohn J, Altundag AS, Chang YC, Abdel-Razeq H, Im SA, Jeong J, Park HY, Arpornwirat W, Bastick PA, Le TA, Arikan OO, Xue HL, Canatar A, Valenti R, Kim SB. Clinical effectiveness of everolimus and exemestane in advanced breast cancer patients from Asia and Africa: first efficacy andupdated safety results from the phase IIIb EVEREXES Study. Cancer Res. 2016;76(4 Suppl):P4–13–09.\n43. Royce M Bachelot T Villanueva C Ozguroglu M Azevedo SJ Cruz FM Debled M Hegg R Toyama T Falkson C Everolimus plus endocrine therapy for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: a clinical trial JAMA Oncol 2018 4 7 977 984 10.1001/jamaoncol.2018.0060 29566104 \n44. Bachelot T Bourgier C Cropet C Ray-Coquard I Ferrero JM Freyer G Abadie-Lacourtoisie S Eymard JC Debled M Spaeth D Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study J Clin Oncol 2012 30 22 2718 2724 10.1200/JCO.2011.39.0708 22565002 \n45. Kornblum N Zhao F Manola J Klein P Ramaswamy B Brufsky A Stella PJ Burnette B Telli M Makower DF Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102 J Clin Oncol 2018 36 16 1556 1563 10.1200/JCO.2017.76.9331 29664714 \n46. Schmid P, Zaiss M, Harper-Wynne C, Ferreira M, Dubey S, Chan S, Makris A, Nemsadze G, Brunt AM, Kuemmel S, et al. Fulvestrant plus vistusertib vs fulvestrant plus everolimus vs fulvestrant alone for women with hormone receptor-positive metastatic breast cancer: the MANTA phase 2 randomized clinical trial. JAMA Oncol. 2019;5(11):1556–63.\n47. Safra T Kaufman B Kadouri L Efrat Ben-Baruch N Ryvo L Nisenbaum B Evron E Yerushalmi R Everolimus plus letrozole for treatment of patients with HR(+), HER2(-) advanced breast cancer progressing on endocrine therapy: an open-label, phase II trial Clin Breast Cancer 2018 18 2 e197 e203 10.1016/j.clbc.2017.09.004 29097108 \n48. Jerusalem G de Boer RH Hurvitz S Yardley DA Kovalenko E Ejlertsen B Blau S Ozguroglu M Landherr L Ewertz M Everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor-positive, HER2-negative advanced breast cancer: the BOLERO-6 randomized clinical trial JAMA Oncol 2018 4 10 1367 1374 10.1001/jamaoncol.2018.2262 29862411 \n49. Yardley DA, Liggett W, Mainwaring M, Castrellon A, Blakely L, Hemphill B, Anz B 3rd, Young RR, Shastry M, DeBusk LM, et al. A phase II open label study of everolimus in combination with endocrine therapy in resistant hormone receptor-positive HER2-negative advanced breast cancer. Clin Breast Cancer. 2019.\n50. Rugo HS Seneviratne L Beck JT Glaspy JA Peguero JA Pluard TJ Dhillon N Hwang LC Nangia C Mayer IA Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial Lancet Oncol 2017 18 5 654 662 10.1016/S1470-2045(17)30109-2 28314691 \n51. Rugo HS Ruiz Borrego M Chia SKL Juric D Turner NC Drullinsky P Lerebours F Bianchi GV Nienstedt CC Ridolfi A Thuerigen A Ciruelos E Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor-2-negative (HER2-) advanced breast cancer (ABC): first interim BYLieve study results J Clin Oncol 2019 37 15, Suppl 1040 10.1200/JCO.2019.37.15_suppl.1040 \n52. Cristofanilli M Turner NC Bondarenko I Ro J Im SA Masuda N Colleoni M DeMichele A Loi S Verma S Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial Lancet Oncol 2016 17 4 425 439 10.1016/S1470-2045(15)00613-0 26947331 \n53. Slamon DJ Neven P Chia S Fasching PA De Laurentiis M Im SA Petrakova K Bianchi GV Esteva FJ Martin M Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3 J Clin Oncol 2018 36 24 2465 2472 10.1200/JCO.2018.78.9909 29860922 \n54. Sledge GW Jr Toi M Neven P Sohn J Inoue K Pivot X Burdaeva O Okera M Masuda N Kaufman PA MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy J Clin Oncol 2017 35 25 2875 2884 10.1200/JCO.2017.73.7585 28580882 \n55. Di Leo A Johnston S Lee KS Ciruelos E Lonning PE Janni W O'Regan R Mouret-Reynier MA Kalev D Egle D Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial Lancet Oncol 2018 19 1 87 100 10.1016/S1470-2045(17)30688-5 29223745\n\n",
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"keywords": "Advanced breast cancer; Alpelisib; Efficacy comparisons; Endocrine therapy; Everolimus; Hormone receptor-positive breast cancer; PI3K; PIK3CA mutations; mTORC1",
"medline_ta": "Breast Cancer Res",
"mesh_terms": "D000730:Androstadienes; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D002986:Clinical Trials as Topic; D000068338:Everolimus; D005260:Female; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D015337:Multicenter Studies as Topic; D009362:Neoplasm Metastasis; D061214:Patient Safety; D019869:Phosphatidylinositol 3-Kinases; D011446:Prospective Studies; D051057:Proto-Oncogene Proteins c-akt; D016032:Randomized Controlled Trials as Topic; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"pages": "33",
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"pmid": "32252811",
"pubdate": "2020-04-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "28852212;31091374;31412191;30867161;27872127;25231953;29508857;26947331;29992557;24362951;22149876;29223745;29860922;29566104;30051890;16033851;19029956;19366795;29097108;27717303;30602761;28968163;26503204;20005306;19016759;30543347;23000897;29664714;28314691;19925796;28684409;25436981;29862411;20530877;27126994;22565002;30462943;27903677;28802037;22010023;24158787;21278436;31130321;24615500;27959613;31932237;27865536;31465093;25877889;28580882;27358383",
"title": "Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications.",
"title_normalized": "everolimus versus alpelisib in advanced hormone receptor positive her2 negative breast cancer targeting different nodes of the pi3k akt mtorc1 pathway with different clinical implications"
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{
"abstract": "D-penicillamine, used to treat cystinuria, is known to cause impaired collagen deposition and dysfunction in elastic fibers. D-penicillamine also has been associated with glomerular abnormalities, typically membranous glomerulonephritis. We describe a patient with severe bilateral cystic kidney disease that developed after long-term D-penicillamine use for treatment of cystinuria. The cysts in the kidneys were noted during an evaluation for acute kidney injury. The patient had no evidence of cysts on prior renal imaging at a time when his kidney function was normal. Simultaneously, he presented with multiorgan manifestations of D-penicillamine toxicity, including the skin findings of cutix laxa and elastosis perforans serpiginosa. Consequently, D-penicillamine treatment was discontinued, after which the progression of cystic kidney disease gradually ceased, along with the other systemic manifestations of toxicity. To our knowledge, this is the first report of cystic kidney disease associated with and perhaps caused by long-term d-penicillamine therapy. The proposed mechanism of cyst formation is the malfunction of the extracellular matrix of the kidney by d-penicillamine that leads to an impaired repair process after kidney injury.",
"affiliations": "Section of Nephrology, Yale University School of Medicine, New Haven, CT. Electronic address: farrukh.koraishy@yale.edu.",
"authors": "Koraishy|Farrukh M|FM|;Cohen|Robert A|RA|;Israel|Gary M|GM|;Dahl|Neera K|NK|",
"chemical_list": "D002614:Chelating Agents; D010396:Penicillamine",
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "0272-6386",
"issue": "62(4)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Penicillamine; cystic kidney disease",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D002614:Chelating Agents; D003555:Cystinuria; D006801:Humans; D052177:Kidney Diseases, Cystic; D008297:Male; D008875:Middle Aged; D010396:Penicillamine; D013997:Time Factors",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "806-9",
"pmc": null,
"pmid": "23796907",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cystic kidney disease in a patient with systemic toxicity from long-term D-penicillamine use.",
"title_normalized": "cystic kidney disease in a patient with systemic toxicity from long term d penicillamine use"
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{
"abstract": "While Vagus Nerve Stimulation (VNS) is proven to be a safe and effective adjunctive therapy in the general population with medically intractable seizures, little is published about its implantation during pregnancy. Here we illustrate the case of a 21year old primigravid woman with medically refractory seizures who underwent safe and successful VNS implantation and immediate activation of the device in her 32nd week of pregnancy, resulting in dramatically improved seizure control and subsequent delivery of a healthy baby.",
"affiliations": "Department of Neurology, University of Texas Medical Branch, Galveston, TX, United States. Electronic address: nojazebi@utmb.edu.;Department of Neurology, University of Texas Medical Branch, Galveston, TX, United States.;Department of Neurosurgery, University of Texas Medical Branch, Galveston, TX, United States.;Department of Neurosurgery, University of Texas Medical Branch, Galveston, TX, United States.;Department of Neurosurgery, University of Texas Medical Branch, Galveston, TX, United States.;Department of Neurology, University of Texas Medical Branch, Galveston, TX, United States.",
"authors": "Jazebi|N|N|;Moghimi|N|N|;Lall|R|R|;Osadebey|E|E|;Ortega-Barnett|J|J|;Masel|T|T|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2017.03.044",
"fulltext": null,
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"issn_linking": "0967-5868",
"issue": "42()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Epilepsy; Pregnancy; Refractory seizures; Vagus Nerve Stimulation (VNS)",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000069279:Drug Resistant Epilepsy; D005260:Female; D006801:Humans; D058542:Implantable Neurostimulators; D011247:Pregnancy; D016896:Treatment Outcome; D055536:Vagus Nerve Stimulation; D055815:Young Adult",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "114-115",
"pmc": null,
"pmid": "28410885",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Successful implantation and immediate activation of Vagus Nerve Stimulation (VNS) during pregnancy in a patient with intractable epilepsy: A case illustration and review of the literature.",
"title_normalized": "successful implantation and immediate activation of vagus nerve stimulation vns during pregnancy in a patient with intractable epilepsy a case illustration and review of the literature"
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},
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] |
{
"abstract": "Palbociclib is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor that was conditionally approved in the United States (February 2015) and Canada (March 2016) with letrozole as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. A palbociclib expanded-access program (EAP) was initiated as an interim measure to provide drug access before commercial availability of drug.\n\n\n\nEligible women were 18 years or older and postmenopausal with diagnosed metastatic HR-positive, HER2-negative breast cancer and were suitable candidates for letrozole therapy. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or commercial availability of palbociclib. We report combined safety data in both cohorts, and patient-reported outcomes in the Canadian cohort.\n\n\n\nFrom September 2014 to May 2016, a total of 334 patients were enrolled onto the EAP. With rapid regulatory approval and transfer to commercial supply, median duration of palbociclib treatment while on study was 77 days (range, 2-245 days). At least one dose reduction occurred in 24.3% of patients, and 3.6% of patients permanently discontinued palbociclib because of treatment-emergent adverse events. The most common adverse events (> 20%) of any grade included neutropenia (66.5%), fatigue (38%), infection (25.4%), and nausea (22.5%). Grade 3/4 adverse events included neutropenia (54.5%), leukopenia (8.1%), fatigue (4.2%), anemia (3.9%), thrombocytopenia (3.6%), infection (3.3%), and febrile neutropenia (2.1%).\n\n\n\nIn a real-world EAP setting, palbociclib in combination with letrozole was well tolerated, and the safety profile was consistent with other reported clinical trial literature of HR-positive, HER2-negative advanced breast cancer.",
"affiliations": "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD. Electronic address: vstearn1@jhmi.edu.;Magee-Womens Hospital of UPMC, Pittsburgh, PA.;Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada.;Pfizer Inc, New York, NY.;Pfizer Inc, New York, NY.;Pfizer Canada Inc, Kirkland, Quebec, Canada.;Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada.",
"authors": "Stearns|Vered|V|;Brufsky|Adam M|AM|;Verma|Shailendra|S|;Cotter|Matthew J|MJ|;Lu|Dongrui R|DR|;Dequen|Florence|F|;Joy|Anil Abraham|AA|",
"chemical_list": "D014408:Biomarkers, Tumor; D010879:Piperazines; D011725:Pyridines; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000077289:Letrozole; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; C500026:palbociclib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clbc.2018.07.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "18(6)",
"journal": "Clinical breast cancer",
"keywords": "CDK inhibitor; Endocrine therapy; Metastatic disease",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077289:Letrozole; D008207:Lymphatic Metastasis; D010879:Piperazines; D017698:Postmenopause; D011379:Prognosis; D011725:Pyridines; D018719:Receptor, ErbB-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "e1239-e1245",
"pmc": null,
"pmid": "30172722",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Expanded-Access Study of Palbociclib in Combination With Letrozole for Treatment of Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer.",
"title_normalized": "expanded access study of palbociclib in combination with letrozole for treatment of postmenopausal women with hormone receptor positive her2 negative advanced breast cancer"
} | [
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}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20160211"
}
},
"primarysource": {
"literaturereference": "STEARNS, V.. EXPANDED-ACCESS STUDY OF PALBOCICLIB IN COMBINATION WITH LETROZOLE FOR TREATMENT OF POSTMENOPAUSAL WOMEN WITH HORMONE RECEPTOR-POSITIVE, HER2-NEGATIVE ADVANCED BREAST CANCER. CLINICAL BREAST CANCER. 2018?18(6):E1239-E1245",
"literaturereference_normalized": "expanded access study of palbociclib in combination with letrozole for treatment of postmenopausal women with hormone receptor positive her2 negative advanced breast cancer",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "CA",
"receiptdate": "20191002",
"receivedate": "20160304",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 12145722,
"safetyreportversion": 6,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesslifethreatening": null,
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"transmissiondate": "20200122"
}
] |
{
"abstract": "Neuroleptic malignant syndrome (NMS) is a potentially fatal adverse effect of antipsychotics. Atypical presentation of NMS with drugs which are not potential D2 blockers raises question for an alternative hypothesis for NMS. A 30 year old male presented with irritability, assaultive behavior, persecutory delusion and auditory hallucination for three days. Past history of 3 similar episodes. 1st episode preceded by fever and associated with cerebral edema. Subsequent episodes not preceded by fever and patient was treated with Risperidone and Olanzapine. After admission patient was started on Risperidone along with THP when he had fever, tremors, altered sensorium and rigidity at 3 mg dose. After stopping Risperidone fever and rigidity improved with worsening of psychotic symptoms. Following this Olanzapine was started and very gradually uptitrated to 7.5 mg when patient had recurrence of fever and disorientation without tremors and minimal rigidity. Both the instances blood investigations including CPK levels were normal except for thrombocytopenia and leucopenia. Provisional impression of NMS was made in both instances. After stopping Olanzapine fever subsided with improvement of blood counts. Following this patient had catatonic symptoms for which patient received 9 sessions of Electroconvulsive therapy (ECT). In atypical presentations of NMS, hyperthermia and muscle rigidity may be absent, posing diagnostic dilemma. So there is a need for broadening the diagnostic criteria and NMS must be considered with a high index of suspicion.",
"affiliations": "Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, 605006, India. Electronic address: favazvkptaj@gmail.com.;Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, 605006, India.;Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, 605006, India.;Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, 605006, India.",
"authors": "Vellekkatt|Favaz|F|;Kuppili|Pooja Patnaik|PP|;Bharadwaj|Balaji|B|;Menon|Vikas|V|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone; D000077152:Olanzapine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ajp.2019.04.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-2018",
"issue": "43()",
"journal": "Asian journal of psychiatry",
"keywords": "Atypical antipsychotics; Atypical presentation; NMS; Neuroleptic malignant syndrome",
"medline_ta": "Asian J Psychiatr",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D006801:Humans; D008297:Male; D009459:Neuroleptic Malignant Syndrome; D000077152:Olanzapine; D018967:Risperidone",
"nlm_unique_id": "101517820",
"other_id": null,
"pages": "7-8",
"pmc": null,
"pmid": "31071486",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Atypical neuroleptic malignant syndrome - A case report.",
"title_normalized": "atypical neuroleptic malignant syndrome a case report"
} | [
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug withdrawal syndrome",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neuroleptic malignant syndrome",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "VELLEKKATT F, KUPPILI PP, BHARADWAJ B, MENON V. ATYPICAL NEUROLEPTIC MALIGNANT SYNDROME- A CASE REPORT. ASIAN J PSYCHIATR. 2019?43:7-8",
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{
"abstract": "Objective: Metformin-associated lactic acidosis (MALA) is a complication of metformin overdose. Recommendations for observation time after an acute ingestion to monitor for MALA vary. The aim of this study was to characterize the time to development of MALA after an acute metformin overdose.Methods: Utilizing Crystal Reports (Version 11.0), all metformin cases reported to the Illinois Poison Center (IPC) with a National Poison Data System (NPDS) clinical effects code of \"acidosis\" or \"anion gap\" were retrospectively queried over a 14-year period (2001-2014). Demographic data, time to MALA, co-ingestants, therapeutic modality use, and case outcome were extracted. Interrater reliability was assessed using kappa analysis.Results: A total of 88 cases were identified of which 44 met criteria for MALA; 40 were acute, acute on chronic, or unknown ingestions. The remaining four were chronic ingestions which were excluded. The mean age was 41 years (range 19-79 years). Most were female (55.0%) and over half (62.5%) were acute on chronic ingestions. Hypoglycemia was seen in three ingestions of metformin only. Of the 40 MALA cases, 18 developed MALA less than or equal to 6 h after ingestion, 9 between 6-12 h, 3 after 12 h, and 10 patients had an unknown time to MALA. The only death in the cohort had MALA detected beyond the typical 6-h observation period. Of the exposures when time to MALA was known, 40% (12/30) developed MALA greater than 6 h post ingestion.Conclusion: A 6-h observation period after a single acute ingestion of metformin may be inadequate, as a significant portion of exposures developed MALA beyond this time. We recommend a minimum of 12 h of observation following an acute overdose. Further study defining prospectively the time to development of MALA may improve management of this population.",
"affiliations": "Department of Emergency Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Emergency Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Section of Emergency Medicine, University of Chicago, Chicago, IL, USA.;Illinois Poison Center, Chicago, IL, USA.",
"authors": "Theobald|Jillian|J|0000-0002-9906-4148;Schneider|Jamie|J|;Cheema|Navneet|N|;DesLauriers|Carol|C|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2019.1686514",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "58(7)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Metformin; lactate; lactic acidosis; overdose; toxicity",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000140:Acidosis, Lactic; D000328:Adult; D000368:Aged; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007087:Illinois; D008297:Male; D008687:Metformin; D008875:Middle Aged; D011039:Poison Control Centers; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "758-762",
"pmc": null,
"pmid": "31691608",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Time to development of metformin-associated lactic acidosis.",
"title_normalized": "time to development of metformin associated lactic acidosis"
} | [
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"abstract": "Lacosamide is a new-generation antiseizure medication that is approved for use as an adjunctive treatment and monotherapy in focal epilepsy. Its use in generalized epilepsy, however, has not been adequately evaluated in controlled trials. We report a 67-year-old woman who experienced new-onset myoclonic seizures after initiation of lacosamide. We presume that she had an undiagnosed generalized epilepsy syndrome, likely juvenile myoclonic epilepsy. Myoclonic seizures were not reported before introducing lacosamide and completely resolved after lacosamide was discontinued. This suggests that lacosamide may have the potential to worsen myoclonus, similar to what has been reported with another sodium channel agent, lamotrigine, in some individuals with genetic generalized epilepsy (GGE).",
"affiliations": "George Washington University, 2150 Pennsylvania Ave NW, Suite #9-400, Washington, DC 20037, United States.;George Washington University, 2150 Pennsylvania Ave NW, Suite #9-400, Washington, DC 20037, United States.",
"authors": "Birnbaum|Daniel|D|;Koubeissi|Mohamad|M|",
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"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(16)30096-210.1016/j.ebcr.2016.09.006Case ReportUnmasking of myoclonus by lacosamide in generalized epilepsy Birnbaum Daniel DBirnbaum@gwu.edu⁎Koubeissi Mohamad MKoubeissi@mfa.gwu.eduGeorge Washington University, 2150 Pennsylvania Ave NW, Suite #9-400, Washington, DC 20037, United States⁎ Corresponding author. DBirnbaum@gwu.edu16 11 2016 2017 16 11 2016 7 28 30 11 3 2016 25 8 2016 13 9 2016 © 2016 The Author(s)2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Lacosamide is a new-generation antiseizure medication that is approved for use as an adjunctive treatment and monotherapy in focal epilepsy. Its use in generalized epilepsy, however, has not been adequately evaluated in controlled trials. We report a 67-year-old woman who experienced new-onset myoclonic seizures after initiation of lacosamide. We presume that she had an undiagnosed generalized epilepsy syndrome, likely juvenile myoclonic epilepsy. Myoclonic seizures were not reported before introducing lacosamide and completely resolved after lacosamide was discontinued. This suggests that lacosamide may have the potential to worsen myoclonus, similar to what has been reported with another sodium channel agent, lamotrigine, in some individuals with genetic generalized epilepsy (GGE).\n\nKeywords\nJuvenile myoclonic epilepsyGenetic generalized epilepsy (GGE)LacosamideSeizureAggravateMyoclonus\n==== Body\n1 Introduction\nJuvenile myoclonic epilepsy (JME) comprises 2–10% of all epilepsies, and more than 25% of genetic generalized epilepsy (GGE). Estimates of frequency vary in different clinical settings and across regions and countries, which may be due to variations in diagnostic criteria [1]. Appropriate treatment includes valproic acid (VPA), levetiracetam (LEV), topiramate, zonisamide (ZNS), and lamotrigine (LTG) among others [2]. Some antiseizure medications (ASMs) are also known to aggravate JME, including sodium channel agents such as carbamazepine (CBZ), phenytoin (PHT) [3], and oxcarbazepine [4]. Another sodium channel blocker, LTG, is often used successfully in JME, although it can exacerbate myoclonus in some individuals [5].\n\nApproximately 20% of individuals with JME continue to have seizures on VPA, the most efficacious ASM for the syndrome [2]. Although the indication for the majority of new-generation ASMs is in focal epilepsy, there is interest in exploring their application in generalized epilepsy. A case series of three individuals with refractory JME reported benefit from lacosamide (LCM) without adverse reactions [6]. Here, we report a case of de novo myoclonic seizures occurring after introducing LCM, which completely resolved with its discontinuation.\n\n2 Case history\nA 67-year-old right-handed woman has a history of generalized tonic-clonic seizures that started at age 17, when she was sleep-deprived. Her seizures were managed well with phenobarbital (PB) until a decade prior to her presentation, when she had two breakthrough generalized tonic-clonic (GTC) seizures. She was found to have a left-sided subdural hemorrhage and was switched from PB to VPA 1500 mg/day. This was later adjusted to VPA 2000 mg/day and LEV 1000 mg/day was added. Later, VPA was replaced by LCM, given fewer cognitive side effects in the setting of comorbid dementia. Shortly after initiating treatment with LCM, she began experiencing myoclonic jerks 3–4 days per week for 15 min after awakening. According to her husband, these jerks consisted primarily of flexion at the trunk that could cause her to fall. The primary neurologist noted that myoclonic jerks also affected the upper extremities. On the morning prior to admission, she experienced repetitive myoclonic jerks of the entire body for 1 min, which were followed by a generalized seizure, and the myoclonus continued after the generalized seizure. Over the course of approximately fifty years, this was her fifth or sixth generalized seizure. She had a past medical history of advanced dementia, subdural hemorrhage in 2004 that was surgically evacuated, hypertension, and asymptomatic atrial fibrillation. Her family history was positive for epilepsy in her mother and grandmother.\n\nThe patient's physical examination upon admission to the hospital demonstrated confusion. Her general laboratory evaluation was normal. A CT brain taken on admission showed old left cerebellar and pontine lacunar strokes, and a subsequent MRI did not reveal mesial temporal sclerosis. Previous EEG in 2004, by charted information, revealed “bursts of generalized slowing and some sharp and slow waves”, consistent with genetic generalized epilepsy. A later EEG in 2008 was entirely normal. An EEG after discharge in 2014 showed slowing of the posterior background rhythm to 6–7 Hz and generalized, frontal-maximum spike-and-slow waves occurring singly, at a frequency of once every 10–15 min, with phase reversals over F3 and F4 (Fig. 1). In addition, there were some asymmetric sharply-contoured waveforms occurring on the right and left, independently. A follow-up EEG showed only background slowing to 6–8 Hz.Fig. 1 Frontal-maximum, generalized spike-wave discharges (asterisks). Note the phase reversals over F3 and F4, typical of generalized epilepsy.\n\nFig. 1\n\nThe presentation of morning myoclonus followed by GTC seizure, teenage history of seizure after sleep deprivation, family history, and EEG findings were suggestive of generalized epilepsy, likely JME. Thus, LCM was discontinued and ZNS was initiated at 300 mg per day. LEV was increased to 1500 mg per day. A subsequent visit to the hospital, less than a month later, verified that her myoclonus had completely stopped upon discontinuation of LCM. An EEG three months after the admission revealed complete resolution of the interictal epileptiform discharges, with persistence of the background slowing.\n\n3 Discussion\nThe diagnosis of JME in this individual was difficult because continuous video-EEG was not performed to capture ictal episodes. According to the International League Against Epilepsy definition of JME, interictal and ictal EEG may be similar and show rapid, generalized, often irregular spike-waves and polyspike-waves [7]. Other abnormalities that may be present in a random sampling of individuals with JME include frontal (> 8%) and temporal (~ 5%) spike/sharp waves [8]. Our patient's EEG in 2004, 10 years prior to her presentation, was consistent with generalized epilepsy. A subsequent EEG in 2008 was normal, and an EEG after discharge from the hospital demonstrated generalized, frontal maximal, single spike-wave discharges, further supporting generalized epilepsy, associated with myoclonic seizures. Another EEG from 2013 noted frequent sharp waves and occasional higher voltage spikes over the left superior frontal and temporal areas. These focalities and the sharply contoured waves from the 2014 EEG may have represented focal discharges secondary to one of her many comorbidities, including subdural hemorrhage, multiple strokes, and advanced dementia. Alternatively, focal discharges may represent effective inhibitory mechanisms that successfully fragment generalized epileptiform discharges in JME [9]. Ultimately, focal EEG findings can be seen in JME and should not exclude JME as the etiology of an individual's epilepsy [8].\n\nIn the past, uncertainty about a diagnosis of JME in this individual likely revolved around a lack of morning myoclonus. Treatment with LCM unmasked her myoclonus and was followed by a GTC seizure. Given this individual's dementia, it is also possible that earlier in her life she had myoclonus but had forgotten it when later questioned.\n\nTo verify that this was a drug-related adverse event, the Naranjo method was employed. It revealed that this was a “possible” adverse drug reaction. In the future, when myoclonus is encountered with LCM use, in order to establish this as a “probable” or “definite” reaction, clinicians can decrease the dose of LCM prior to discontinuation, consider readministration of LCM after cessation, obtain drug levels, and confirm myoclonus through direct visualization [10].\n\nIn consideration of this myoclonus exacerbation being peculiar to LCM use in IGE and JME, several points can be raised. A review of adverse side effects of LCM does not include myoclonus [11]. Additionally, this individual's myoclonus was unlikely to have been related to high or toxic drug levels. LTG, for example, at toxic levels, can trigger myoclonus even when a seizure history is not present [12]. This individual was using a standard dose of LCM. As there were no other reported side effects, toxicity was unlikely. LCM's pharmacology may have also played a role. Several medications that affect the voltage-gated sodium channel may worsen seizures in generalized epilepsy. In particular, CBZ, OXC, and PHT have been reported to worsen absence and myoclonic seizures in GGE. LTG can worsen myoclonic seizures in some individuals with GGE. This does not occur too commonly to preclude the inclusion of LTG as a first line treatment in JME [2]. Lastly, genetics can modulate the response of subsets of syndromes to medications. For example, individuals with the progressive myoclonic epilepsy, Unverricht-Lundborg disease, appear to be particularly susceptible to worsening of myoclonus when treated with LTG [13]. Similarly, the complex genetics of JME, with multiple chromosomes implicated and possibly with incomplete penetrance [14], may allow subsets of JME to be particularly vulnerable to myoclonus when LCM is utilized. Thus, some individuals may respond optimally to LCM [15], while others may experience adverse effects.\n\n4 Conclusion\nIn summary, this individual's history, physical, and diagnostic information strongly suggest generalized epilepsy, likely JME, with myoclonus that was unmasked by LCM. This case suggests that LCM may have the potential to exacerbate underlying myoclonus, and its exploration as a treatment in generalized epilepsies should take into consideration the possibility of seizure exacerbation.\n==== Refs\nReferences\n1 Camfield C.S. Striano P. Camfield P.R. Epidemiology of juvenile myoclonic epilepsy Epilepsy Behav 28 Suppl. 1 2013 S15 S17 23756473 \n2 Mantoan L. Walker M. Treatment options in juvenile myoclonic epilepsy Curr Treat Options Neurol 13 4 2011 355 370 21494841 \n3 Genton P. Gelisse P. Thomas P. Dravet C. Do carbamazepine and phenytoin aggravate juvenile myoclonic epilepsy? Neurology 55 8 2000 1106 1109 11071486 \n4 Gelisse P. Genton P. Kuate C. Pesenti A. Baldy-Moulinier M. Crespel A. Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies Epilepsia 45 10 2004 1282 1286 15461683 \n5 Auvin S. Treatment of juvenile myoclonic epilepsy CNS Neurosci Ther 14 3 2008 227 233 18684236 \n6 Afra P. Adamolekun B. Lacosamide treatment of juvenile myoclonic epilepsy Seizure 21 3 2012 202 204 22281192 \n7 Proposal for revised classification of epilepsies and epileptic syndromes. Commission on classification and terminology of the international league against epilepsy Epilepsia 30 4 1989 389 399 2502382 \n8 Jayalakshmi S.S. Srinivasa Rao B. Sailaja S. Focal clinical and electroencephalographic features in patients with juvenile myoclonic epilepsy Acta Neurol Scand 122 2 2010 115 123 19845556 \n9 Bonakis A. Koutroumanidis M. Epileptic discharges and phasic sleep phenomena in patients with juvenile myoclonic epilepsy Epilepsia 50 11 2009 2434 2445 19453715 \n10 Naranjo C.A. Busto U. Sellers E.M. Sandor P. Ruiz I. Roberts E.A. A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 30 2 1981 239 245 7249508 \n11 Vimpat: prescribing information [December 16, 2015]. Available from: http://www.vimpat.com/pdf/vimpat_PI.pdf 2015 \n12 Moore P.W. Donovan J.W. Burkhart K.K. Haggerty D. A case series of patients with lamotrigine toxicity at one center from 2003 to 2012 Clin Toxicol (Phila) 51 7 2013 545 549 23869656 \n13 Genton P. Gelisse P. Crespel A. Lack of efficacy and potential aggravation of myoclonus with lamotrigine in Unverricht-Lundborg disease Epilepsia 47 12 2006 2083 2085 17201707 \n14 Panayiotopoulos C. The epilepsies: seizures, syndromes and management 2005 Bladon Medical Publishing Oxfordshire (UK) \n15 Yorns W.R. Jr. Khurana D.S. Carvalho K.S. Hardison H.H. Legido A. Valencia I. Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy J Child Neurol 29 1 2014 23 27 23143718\n\n",
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"abstract": "The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated.\nA pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18-75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam (n = 56), olanzapine (n = 54), or haloperidol (n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118).\nOf 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine (p = 0·03) and haloperidol (p = 0·002). Adverse event rates were similar across the three arms. Dystonia (n = 1) and cardiac arrest (n = 1) were reported in the haloperidol group.\nMidazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects.\nResearch Grants Council, Hong Kong.",
"affiliations": "Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR.;Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR.;Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR.;Accident and Emergency Department, Queen Mary Hospital, Pok Fu Lam, Hong Kong SAR.;Accident and Emergency Department, Tuen Mun Hospital, Tuen Mun, Hong Kong SAR.;Accident and Emergency Department, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong SAR.;Accident and Emergency Medicine Academic Unit, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.;Accident and Emergency Medicine Academic Unit, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.;Accident and Emergency Department, Ruttonjee Hospital, Wan Chai, Hong Kong SAR.;Accident and Emergency Department, United Christian Hospital, Kwun Tong, Hong Kong SAR.;Accident and Emergency Department, United Christian Hospital, Kwun Tong, Hong Kong SAR.;Department of Critical Care, University of Melbourne, Parkville, Australia.;Emergency Department, Austin Hospital, Heidelberg, Victoria, Australia.;Pharmacy Department, Ballarat Health Services, Ballarat, Victoria, Australia.;Emergency Medicine Unit, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR.;Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR.",
"authors": "Chan|Esther W|EW|;Lao|Kim S J|KSJ|;Lam|Lam|L|;Tsui|Sik-Hon|SH|;Lui|Chun-Tat|CT|;Wong|Chi-Pang|CP|;Graham|Colin A|CA|;Cheng|Chi-Hung|CH|;Chung|Tong-Shun|TS|;Lam|Hiu-Fung|HF|;Ting|Soo-Moi|SM|;Knott|Jonathan C|JC|;Taylor|David M|DM|;Kong|David C M|DCM|;Leung|Ling-Pong|LP|;Wong|Ian C K|ICK|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.eclinm.2021.100751",
"fulltext": "\n==== Front\nEClinicalMedicine\nEClinicalMedicine\nEClinicalMedicine\n2589-5370 Elsevier \n\nS2589-5370(21)00031-6\n10.1016/j.eclinm.2021.100751\n100751\nResearch Paper\nIntramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: A multi-centre, double-blind, randomised clinical trial\nChan Esther W. ewchan@hku.hkabc1⁎ Lao Kim S.J. ad1 Lam Lam a Tsui Sik-Hon e Lui Chun-Tat f Wong Chi-Pang g Graham Colin A. hi Cheng Chi-Hung hi Chung Tong-Shun j Lam Hiu-Fung k Ting Soo-Moi k Knott Jonathan C. l Taylor David M. mn Kong David C.M. op Leung Ling-Pong q Wong Ian C.K. wongick@hku.hkabr⁎⁎ a Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR\nb Department of Pharmacy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China\nc Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China\nd Global Medical Affairs, Merck Sharp & Dohme, Xuhui, Shanghai, China\ne Accident and Emergency Department, Queen Mary Hospital, Pok Fu Lam, Hong Kong SAR\nf Accident and Emergency Department, Tuen Mun Hospital, Tuen Mun, Hong Kong SAR\ng Accident and Emergency Department, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong SAR\nh Accident and Emergency Medicine Academic Unit, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR\ni Department of Emergency Medicine, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR\nj Accident and Emergency Department, Ruttonjee Hospital, Wan Chai, Hong Kong SAR\nk Accident and Emergency Department, United Christian Hospital, Kwun Tong, Hong Kong SAR\nl Department of Critical Care, University of Melbourne, Parkville, Australia\nm Emergency Department, Austin Hospital, Heidelberg, Victoria, Australia\nn Department of Medicine, University of Melbourne, Parkville, Victoria, Australia\no Pharmacy Department, Ballarat Health Services, Ballarat, Victoria, Australia\np Centre for Medicine Use and Safety, Monash University, Victoria, Australia\nq Emergency Medicine Unit, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR\nr Research Department of Practice and Policy, UCL School of Pharmacy, London, United Kingdom\n⁎ Corresponding author at: Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR ewchan@hku.hk⁎⁎ Corresponding author at: Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR wongick@hku.hk1 Esther W Chan and Kim SJ Lao contributed equally to this study and are listed as co-first authors.\n\n\n11 2 2021 \n2 2021 \n11 2 2021 \n32 1007516 10 2020 20 1 2021 25 1 2021 © 2021 The Authors2021This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nThe safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated.\n\nMethods\nA pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18–75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam (n = 56), olanzapine (n = 54), or haloperidol (n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118).\n\nFindings\nOf 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine (p = 0·03) and haloperidol (p = 0·002). Adverse event rates were similar across the three arms. Dystonia (n = 1) and cardiac arrest (n = 1) were reported in the haloperidol group.\n\nInterpretation\nMidazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects.\n\nFunding\nResearch Grants Council, Hong Kong.\n==== Body\nResearch in context\nEvidence before this study\nRapid sedation via the intramuscular route is often preferred in patients with acute agitation in emergency settings. Whether intramuscular olanzapine is effective and safe compared to conventional treatment options (including benzodiazepines and first-generation antipsychotics) in emergency settings, where the aetiology of acute agitation is usually undifferentiated and clinical endpoints are urgent, is uncertain.\n\nWe searched PubMed from inception to July 22, 2020, without language restrictions, for randomised trials, systematic reviews, meta-analyses, and observational studies, using the terms “agitation or acute agitation or violence” and “parenteral or intramuscular” and “emergency”. During the study period, we identified four randomised trials (published in 2007, 2011, 2013, and 2016) conducted in psychiatry settings that evaluated the effectiveness and safety of intramuscular olanzapine. We did not find any randomised trials comparing intramuscular olanzapine with other sedatives for the treatment of acute agitation in emergency departments.\n\nAdded value of this study\nWe conducted a randomised, active-controlled trial in six Hong Kong emergency departments comparing time to sedation in patients receiving 5 mg of intramuscular midazolam, olanzapine or haloperidol. All three treatments provided adequate sedation at 60 min and midazolam resulted in faster sedation compared to the others. The proportion of patients observed to be asleep after treatment with midazolam was higher compared with olanzapine and haloperidol. Overall adverse event rates were similar across the three arms while extrapyramidal syndrome (n = 1) and fatal cardiac arrest (n = 1) episodes were reported in the haloperidol arm.\n\nImplications of all the available evidence\nIn patients with undifferentiated agitation admitted to emergency departments, intramuscular midazolam and olanzapine are preferred over haloperidol in view of haloperidol's slower time to sedation and the potential for cardiovascular and extrapyramidal side effects.\n\nAlt-text: Unlabelled box\n\n\n\n1 Introduction\nUndifferentiated acute agitation presenting at the emergency department (ED) often stems from various aetiologies, including underlying mental illness, drug or alcohol intoxication, or a combination of diagnoses [1], [2], [3], [4]. Failed de-escalation strategies or oral medication necessitates parenteral sedation to prevent subsequent harm [5], with intramuscular sedation generally considered prior to intravenous cannulation [2].\n\nA range of medications are currently used for rapid intramuscular sedation to manage acute agitation in the emergency setting, including benzodiazepines (e.g. midazolam [6], [7], [8], [9], [10], [11], [12], [13], lorazepam) [11,14,15], first-generation antipsychotics (e.g. haloperidol [[6], [7], [8],[11], [12], [13],[15], [16], [17], [18], [19], [20]], droperidol) [9,10,16,20], and second-generation antipsychotics (e.g. olanzapine [7,8,18], risperidone [17], ziprasidone) [7,8,10]. Recently, interest in second-generation antipsychotics to manage acute agitation has grown due to the lower incidence of extrapyramidal side effects (EPS) [7,8], over-sedation [8], and need for further rescue medications [10].\n\nIntramuscular olanzapine and other sedatives have not been directly compared using randomised clinical trials in the general ED setting. Studies to date have used observational [21], [22], [23] or open-label study designs [18]. Previous randomised controlled trials have focused on intravenous olanzapine [4,24] or were conducted in psychiatric emergency settings [7,8,18]. The intravenous route provides rapid onset of action but may be inappropriate in some contexts as adequate staff and resources are required to manage potential emergencies. Our survey of emergency physicians in Hong Kong EDs reported a preference for intramuscular sedation over intravenous sedation, whereas the intravenous route was generally preferred in Australasia [25], suggesting regional differences in prescribing culture, and differences in the perceived need for aggressive management. Other studies investigated intramuscular olanzapine in psychiatric settings where patients with agitation were predominantly homogeneous with a history of mental illness [7,8,18] rather than “undifferentiated”, with an undiagnosed cause of agitation. Study results from psychiatric settings are not directly generalisable to inform acute ED practice due to differences in measured outcomes and perceived accept time to adequate sedation in different clinical contexts. To date, evidence of intramuscular olanzapine use in the general ED is scant as all have been observational studies [[21], [22], [23],26]. Therefore, comparing intramuscular olanzapine with haloperidol or midazolam, the two most commonly selected sedating agents in local setting [25], is important in determining a safe and effective choice of an initial agent for acute agitation in the ED setting. This study compares a second-generation antipsychotic (olanzapine) with a conventional antipsychotic (haloperidol) and a benzodiazepine (midazolam) in acute agitation management in the ED.\n\n2 Methods\n2.1 Study design\nThis was a multi-centre, double-blind, randomised, active-controlled pragmatic trial at EDs in six public hospitals under the Hong Kong Hospital Authority (Table S1 and S7). Between April 2014 to March 2019, patient attendances at these 24-h EDs comprised 39% of the Hospital Authority's overall ED visits. The Institutional Review Board or Clinical Research Ethics Committee approval was given at all study sites (Supplementary Table S1). An independent Data Safety and Monitoring Board for the study comprised a Biostatistician (BJC), Clinical Pharmacologist (BMYC), Toxicologist (MLT), Emergency Physician (HFH), Psychiatrist (CWL). This study was registered in ClinicalTrials.gov (NCT02380118).\n\n2.2 Patients\nPatients were enrolled from December 24, 2014 to September 6, 2019. Inclusion criteria were: patients aged 18–75 years; and requiring parenteral drug sedation for acute agitation at the treating physician's discretion. Patients who had received oral or parenteral sedative drug(s) within 12 h, either as usual medications or pre-hospital acute agitation management, were eligible. Exclusion criteria were known hypersensitivity or contraindication to any of the study drugs, immediately reversible aetiology for agitation (e.g. hypotension, hypoxia, hypoglycaemia), known pregnancy, or acute alcohol withdrawal (as it is amendable to benzodiazepines alone) [27]. All eligible patients were initially treated according to the study protocol (Appendix 1).\n\nWritten informed consent was secured from either the patient following recovery, if they had capacity to understand the study and give informed consent, or the patient's authorised representative. Inherent challenges in obtaining informed consent from highly agitated patients attending emergency settings have been acknowledged [3,10,11,22]. Application for patient consent waiver, as used in previous clinical trials internationally [1,3,4,10,11,19], was submitted but not approved. As requested by local ethics committees, patient consent was obtained after intervention or from an authorised representative.\n\n2.3 Randomisation and masking\nEligible patients were assigned to the next sequential study pack pre-assembled by independent pharmacists (not involved in the patient's care during acute agitation episode) from the participating hospital's pharmacy department according to a computer-generated randomisation list. Study packs contained the assigned study drug, data collection tools, an unblinding envelope, and other necessary documents. All study packs and unblinding envelopes were opaque, sealed and tamper-proof. At each site, patients were randomised to “permuted blocks of six”, each containing two packs of haloperidol, olanzapine, and midazolam to ensure each arm had similar allocated numbers. Six randomisation lists were generated independently for each study site.\n\nAs the appearance of each study drug (midazolam/haloperidol: clear liquid ampule; olanzapine: yellow powder vial) could compromise double-blinding, an independent nurse (not involved in the participant's care) prepared and administered all study drugs. Blinding was maintained with all staff involved in patient care, monitoring, data collection, and statistical analysis.\n\n2.4 Procedures\nPatients were randomised to receive an initial 5 mg intramuscular injection of olanzapine, haloperidol, or midazolam with a ratio of 1:1:1, with an optional additional 5 mg dose of the same medication (maximum total dose=10 mg). Study drug selection and doses were based on local Hong Kong clinical practice and survey results [25] on prescribing preferences for acute agitation management, which reported haloperidol and midazolam monotherapy as the sedating agents most frequently selected for undifferentiated agitation in ED. The intramuscular route was the most common choice (63·9%) regardless of drug chosen; median initial and cumulative doses were 5 mg and 10 mg respectively. Although the product monograph recommends a starting dose of 10 mg intramuscular olanzapine, this is seldom prescribed in the local ED setting. Investigators concurred that both the initial (5 mg) and one additional dose (5 mg) would be included in each study pack to allow for flexibility in dosing escalation. To achieve initial or maintain adequate sedation, patients were eligible for alternative sedative drug(s) in addition to the assigned study drug according to clinical response and at the treating physician's discretion.\n\nAgitation/sedation level was measured on a 6-point validated sedation scale: (5=highly aroused, violent; 4=highly aroused, possibly distressed, or fearful; 3=moderately aroused, unreasonable, or hostile; 2=mildly aroused, willing to talk reasonably; 1=minimal agitation; and 0=asleep) [28]. Adequate sedation was defined as a score ≤2. This scale was applied in previous clinical trials that studied sedation in ED [1,3,4,29]. Sedation scores and actual time of measurement were recorded at baseline (immediately before initial dose, t = 0), at first observed adequate sedation, and at 10, 20, 30, 45, and 60 min after the first dose regardless of observed time to sedation. Measurements were recorded by the treating physician, nurses (other than the independent nurse), or research staff. All study participants were given standard sedation care including 1:1 nursing and regular monitoring of sedation level, vital signs, cardiac rhythm, protocol-specified common adverse events, and any other untoward medical occurrence whether or not the occurrence is related to or considered to have a causal relationship with the study drug. Common adverse events related to study drugs were listed in the data collection tool, including airway management (jaw thrust, oral, nasal airway), need for assisted ventilation (bag & mask, intubation), oxygen desaturation <90%, systolic BP<90 mmHg, dystonic reactions, seizures, vomiting or aspiration. If possible, a 12-lead electrocardiogram (ECG) was obtained within 30 min of adequate sedation. However, ECGs are challenging to perform in highly agitated patients and therefore were not always obtained.\n\nOther participant data, including sex, age, and medication history were collected on a standardised Case Report Form. ED presentation details were also collected at triage including perceived possible causes at current presentation such as drug/substance abuse, alcohol intoxication, underlying mental illness, non-compliance to usual medication, and suicidal ideation. Concurrent prescriptions of any antipsychotics, antidepressants, or hypnotics/anxiolytics were also retrieved from the Hospital Authority's computerised medical records system wherever possible.\n\n2.5 Outcomes\nThe primary outcome measure was time to achieve adequate sedation. Three study arms were compared according to: 1) time required to achieve adequate sedation following drug administration; and 2) proportion of patients adequately sedated at 10, 20, 30, 45, and 60 min. Secondary outcome measures included: 1) proportion of patients requiring a second dose of study drug and/or alternative drug(s) to achieve initial adequate sedation; 2) proportion of patients with corrected QT interval (QTc) prolongation on the ECG (defined as QTc interval over 450 ms and 470 ms, respectively, for males and females) [30]; 3) adverse events reported after study drug administration; 4) the proportion of patients with a sedation score of 0 (observed asleep) after study drug administration [28]; and 5) ED length of stay (LOS).\n\n2.6 Statistical analysis\nSample size calculation was based on Isbister et al., where intramuscular droperidol and midazolam were compared head-to-head in an Australian ED [9]. Assuming sedation times were similar to the Australian study and to demonstrate a difference in the mean time to sedation of 20 versus 25 min (standard deviation=12) between the two arms (haloperidol vs. midazolam), 91 patients were required in each arm (2-sided, statistical power 0·8). Thus, we aimed to enrol 282 patients (rounded up from 273 to account for patient loss).\n\nThe modified intention-to-treat principle was applied in the primary analysis. Thirty-six patients received treatment but were excluded due to lack of informed consent. As required by the IRB and stated in the protocol, a primary analysis of patients with informed consent was undertaken according to the allocated study arm, regardless of any unblinding or protocol deviations. The proportion of patients adequately sedated over time were plotted with Kaplan-Meier curves. Time from drug administration to adequate sedation was analysed based on the Kaplan-Meier estimate allowing for interval-censored data. Statistical tests for comparison of every two Kaplan-Meier curves were conducted with asymptotic two-sample log-rank tests. Median time to sedation was calculated for each arm with 95% confidence intervals (CI). Further, the relationship between drug exposure and time to sedation was investigated by fitting Weibull accelerated failure time models adjusted for sex, age, concurrent psychotropic medications, and perceived possible cause of agitation.\n\nDifferences in the median ED LOS from study drug administration to discharge/transfer were tested with the log-rank test. Differences in descriptive data of secondary outcomes were tested using Fisher's exact test/Chi-squared test (categorical variables) and log-rank test (continuous variables). A two-sided p-value <0·05 was considered statistically significant. Interim analysis was conducted at recruitment of 130 patients as detailed in Supplementary-Interim Analysis. Data was analysed using R version 3·4·3 (R Foundation for Statistical Computing, Vienna, Austria) by independent Data Safety and Monitoring Board member BJC and statistician VJF.\n\n2.7 Role of the funding source\nThis study was funded by Research Grants Council, Hong Kong (789813). The study's funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author has full access to all data in the study and has final responsibility for the decision to submit for publication.\n\n3 Results\n3.1 Participants\nDuring the study period 2423 patients were screened, of which 206 received study drugs and 167 provided informed consent (Fig. 1), provided by patients and representatives in 25·1% and 74·9% of cases, respectively. After receiving study drugs, 39 patients were excluded due to failure to consent (n = 36) or found out of age range (n = 3) (Fig. 1). Fifty-six patients were allocated to midazolam arm, 54 to olanzapine, and 57 to haloperidol. The actual sample size was less than planned as the study concluded prematurely due to factors detailed in Supplementary-Early Termination. Patient baseline characteristics were generally balanced, although the haloperidol arm (42%) had a lower proportion of males compared with the midazolam (61%) and olanzapine (70%) arms (Table 1). Use of any antidepressants, hypnotics, and anxiolytics were similar across all arms. Results of interim analysis are listed in Supplementary Table S2–5 and Figure S1.Fig. 1 Flow Diagram of Patient Inclusion (Modified CONSORT Diagram)\n\na, including other exclusion criteria, patients’ preference, profound risk of adverse event, and multiple exclusion reasons; b, the age of these 3 patients was unknown at recruitment, two patients were found to be over 75 years old, one below 18 years old after treatment; c. two patients were unconscious during the length of stay at Emergency Department and not accompanied by any representative; d, one dose of study drug was discarded due to contamination; e, one dose of study drug was given intravenously; f, allocation of two patients was unblinded due to protocol violation (intravenous route; n = 1) and for informing of the procedural sedation for endoscopy after transfer (5 mg given in Emergency Department; n = 1); g, allocation of three patients was unblinded due to adverse event (n = 2) and for informing of further sedation (10 mg given in Emergency Department; n = 1).\n\nFig. 1Table 1 Baseline characteristics of patients.\n\nTable 1\tMidazolam (N = 56)\tOlanzapine (N = 54)\tHaloperidol (N = 57)\t\n\tn\t(%)\tn\t(%)\tn\t(%)\t\nAge (median, IQR)\t44\t(34, 54)\t40\t(30,54)\t42\t(33, 55)\t\nMale\t34\t(61)\t38\t(70)\t24\t(42)\t\nPerceived possible cause\t\t\t\t\t\t\t\nDrug/substance abuse\t16\t(31)\t14\t(27)\t19\t(37)\t\nAlcohol intoxication\t15\t(28)\t12\t(23)\t13\t(25)\t\nUnderlying mental illnesses\t47\t(87)\t45\t(83)\t46\t(84)\t\nNon-compliance to usual medication\t24\t(47)\t22\t(43)\t18\t(35)\t\nSuicidal ideation/attempt\t18\t(34)\t17\t(33)\t18\t(35)\t\nPrior sedative drug\t1a\t(2)\t1b\t(2)\t1c\t(2)\t\nConcurrent psychotropic medications (any antipsychoticsd, antidepressantse, or hypnotics and anxiolyticsf)\t19\t(34)\t17\t(31)\t13\t(23)\t\nBaseline sedation score\t\t\t\t\t\t\t\n3\t13\t(23)\t16\t(30)\t14\t(25)\t\n4\t17\t(30)\t21\t(39)\t17\t(30)\t\n5\t26\t(46)\t16\t(30)\t25\t(44)\t\nIQR, interquartile range; atramadol 50 mg; bhaloperidol 5 mg; chaloperidol 10 mg dantipsychotics were medications under the British National Formulary (BNF) category 4·2·1 and 4·2·2; eantidepressants were defined as medications under the BNF category 4·3; fhypnotics and anxiolytics were defined as medications under the BNF category 4·1.\n\n\n\n3.2 Primary outcomes\nThe median time to sedation estimated by the Kaplan-Meier function was 8·5 (95% CI 8·5–59·5, IQR 8·0), 11·5 (95% CI 7·5–67·0, IQR 30·0), and 23·0 min (95% CI 6·0–53·5, IQR 21·0) for midazolam, olanzapine, and haloperidol, respectively. At 10 min after the initial dose, 52%, 34%, and 21% of patients were adequately sedated in the midazolam, olanzapine, and haloperidol arms, respectively. At 60 min, the proportion of patients sedated increased to 98%, 87%, and 97%, respectively (Table 2). The proportion of patients sedated by time was plotted on Kaplan-Meier curves (Fig. 2). Significant differences were detected in the Kaplan-Meier curves for midazolam compared with olanzapine (p = 0·03) and haloperidol (p = 0·002); however, this was not observed for haloperidol compared with olanzapine (p = 0·78).Table 2 Proportion of patients adequately sedated at each time point.\n\nTable 2\tStudy group\t\n\tMidazolam (N = 56)\tOlanzapine (N = 54)\tHaloperidol (N = 57)\t\n\tn\t(%)\tn\t(%)\tn\t(%)\t\nProportion sedated, min\t\t\t\t\t\t\t\nAt 10\t29·3\t(52)\t18·2\t(34)\t12·0\t(21)\t\nAt 20\t44·0\t(79)\t32·7\t(60)\t23·3\t(41)\t\nAt 30\t51·0\t(91)\t40·0\t(74)\t36·2\t(63)\t\nAt 45\t51·0\t(91)\t43·6\t(81)\t46·5\t(82)\t\nAt 60\t54·8\t(98)\t47·2\t(87)\t55·5\t(97)\t\nInterval-censored data was applied in this analysis.\n\nFig. 2 Proportion of Patients Adequately Sedated by Time in Kaplan-Meier Curve\n\nNo included patient was censored during observation. p-values derived by using asymptotic log-rank two-sample test for comparison of midazolam vs olanzapine, midazolam vs haloperidol, and haloperidol vs olanzapine were 0.03, 0.002 and 0.78, respectively.\n\nFig. 2\n\n3.3 Secondary outcomes\nThe proportion of patients given the second dose of study drug or alternative sedative(s) was similar across all arms (Table 3). Fully-adjusted accelerated factors for olanzapine and haloperidol were compared with midazolam at 1·72 (95% CI 1·16–2·55) and 1·89 (95% CI 1·28–2·80), respectively (Supplementary Table S6), indicating significantly faster sedation for midazolam. The Weibull accelerated failure time model found a minimal effect of sex on time to adequate sedation with an accelerated factor of 0·96 (95% CI 0·49–1·88) for male (compared with female).Table 3 Patients given second dose of study drug or alternative sedatives, with adverse event report, and observed asleep.\n\nTable 3\tStudy group\tP value\t\n\tMidazolam (N = 56)\tOlanzapine (N = 54)\tHaloperidol (N = 57)\t\t\n\tn\t(%)\tn\t(%)\tn\t(%)\t\nAdministered second dose of study drug or alternative sedatives\t18\t(32)\t16\t(30)\t23\t(40)\t0·46\t\nAdministered second dose\t13\t(23)\t15\t(28)\t18\t(32)\t0·61\t\nAdministered alternative sedatives\t9a\t(16)\t6\t(11)\t7b\t(12)\t0·72\t\nMidazolam\t6\t(67)\t2\t(33)\t3\t(43)\t\t\nHaloperidol\t2\t(22)\t4\t(67)\t2\t(29)\t\t\nDiazepam\t3\t(33)\t0\t–\t2\t(29)\t\t\nLorazepam\t1\t(11)\t0\t–\t1\t(14)\t\t\nWith adverse event\t2\t(4)\t3\t(6)\t3\t(5)\t0·91\t\nOxygen desaturation (<90%)\t2\t(4)\t1\t(2)\t1\t(2)\t\t\nDry month\t0\t–\t2\t(4)\t0\t–\t\t\nDystonia\t0\t–\t0\t–\t1\t(2)\t\t\nCardiac arrest\t0\t–\t0\t–\t1\t(2)\t\t\nECG obtained\t(N = 52)\t(N = 52)\t(N = 56)\t\t\nQTc prolongation\t12\t(23)\t9\t(17)\t13\t(23)\t0·59\t\nFell asleep after treatment\t28\t(50)\t10\t(19)\t17\t(30)\t<0·01\t\n*ECG, 12-lead electrocardiogram; QTc, corrected QT interval.\n\nAn adverse event is any untoward medical occurrence in a patient after administration of a medicinal product, which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (for example, an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to study drug.\n\na Three patients were given two alternative sedative drugs.\n\nb One patient was given two alternative sedative drugs.\n\n\n\nOverall, the adverse event rate was similar for midazolam, olanzapine, and haloperidol at 4%, 6%, and 5%, respectively (Table 3). The most common adverse event was oxygen desaturation (midazolam, n = 2; olanzapine, n = 1; haloperidol, n = 1). Two patients in the olanzapine arm reported dry mouth. One patient reported dystonia after one dose of haloperidol (5 mg), which resolved fully with 2 mg intramuscular benztropine. In the single severe adverse event, the patient had a cardiac arrest three hours after two doses of intramuscular haloperidol (10 mg in total; second dose given 33 min after initial dose) and died 8 days later (see Supplementary-Severe Adverse Event).\n\nSimilar proportions of ECG completion and QTc prolongation were observed across the three arms (Table 3). The proportion of patients observed to be asleep after treatment with midazolam was higher compared with olanzapine and haloperidol (p<0·01) (Table 3). LOS data was estimated as 4·52 (95% CI 2·63–8·69), 4·01 (95% CI 2·31–6·42), and 4·02 (95% CI 2·32–6·87) hours for midazolam, olanzapine and haloperidol, respectively. No significant difference in LOS was detected (p = 0·73).\n\n4 Discussion\nIntramuscular midazolam was more effective compared with antipsychotic drugs (olanzapine and haloperidol), as shown by the shorter time to adequate sedation and the higher proportion of patients sedated at any time point. No differences in outcomes were observed between olanzapine and haloperidol. All study drug dosages were effective in managing acute agitation in ED settings within 60 min.\n\nNo significant differences in adverse event rates were found across the three arms. One episode of extrapyramidal syndrome (dystonia) and one severe adverse event (fatal cardiac arrest) were reported in the haloperidol arm. Due to the low number of adverse events, the probability of type II error cannot be ruled out as the study was insufficiently powered to identify such differences. The high risk of extrapyramidal syndrome associated with haloperidol is well recognised and the event was considered to be causally associated with haloperidol [31]. The Data Safety Monitoring Board assessment concluded that the cause of death was associated with potential psychostimulants and unlikely to be solely associated with the study drug.\n\nAdditionally, significant differences were found in the proportion of patients asleep after study drug administration, with the highest percentage in the midazolam arm. Previous studies reported that midazolam posed a higher risk of over-sedation [9], considered as an undesirable clinical outcome [32]. Although no extended ED LOS was detected, patient assessment and referrals to other medical specialties may be delayed, requiring logistical considerations. Although no incident of respiratory depression was observed, midazolam is reported to cause respiratory depression [10] and careful monitoring of vital signs remains important, especially with high or rapidly escalating doses. Although differences in adverse event rate was not observed, intramuscular olanzapine was reported to be associated with a preferred safety profile compared to haloperidol [33]. Our times to sedation by midazolam and haloperidol were consistent with previously reported results. Intramuscular midazolam 2·5/5 mg was reported to achieve sedation within 5·1–18·3 min [6,10,11,13]. The mean time to sedation by intramuscular haloperidol 5 mg was reported to vary from 5 to 3 min [6,11,13]. Data exists concerning time to sedation in EDs by intramuscular olanzapine in randomised clinical trials and the product information suggests that the peak plasma concentration of 5 mg is expected within 15–45 min after administration. Raveendran et al. reported that 87% of violent patients with mental illnesses were sedated within 15 min with 10 mg intramuscular olanzapine in the psychiatry emergency setting [18].\n\nOur recent study conducted in Australian EDs reported that after intravenous olanzapine 10 mg monotherapy (up to 20 mg in total if required), the median time to sedation and the proportion sedated at 60 min were 11 min and 90·8%, respectively [4]. In the current study, after intramuscular olanzapine 5 mg was given (up to 10 mg in total as required), the median time to sedation and the proportion sedated at 60 min were 11·5 min and 87%, respectively. In our previous randomised clinical trial of intravenous olanzapine, we reported that following intravenous midazolam 2·5–5 mg monotherapy, the median time to sedation was 10 min, and proportion of patients sedated by 60 min was 87·0% [1]. In the current study, after intramuscular midazolam 5 mg (up to 10 mg in total if required), the median time to sedation and the proportion sedated at 60 min were 8·5 min and 98%, respectively. These results suggest that the effectiveness of intramuscular olanzapine or midazolam (5 mg or 10 mg) in our predominantly Southern Chinese patient cohort might be comparable to intravenous administration of olanzapine or midazolam at similar doses. However, intramuscular sedation may provide more rapid initiation of emergency sedation, and potentially reduce the risk of injury to patients and staff, particularly during acute behavioural disturbance and in the context of mechanical restraint often being initially required. IV access in these circumstances may be fraught with difficulty and could be dangerous to both patients and staff members, so a less complex alternative route of administration (intramuscular) may provide many potential advantages if it is effective. The initial dose of intramuscular olanzapine (5 mg) may be considered relatively low compared to the manufacturer's recommendation (10 mg). In future studies, effectiveness and safety of higher doses of olanzapine in this clinical scenario could be further investigated.\n\nThe proportion of additional sedatives used in the haloperidol arm was numerically higher than the two other arms despite not reaching statistical significance. Consistently, higher proportions of additional sedative doses were required in patients treated with haloperidol vs. olanzapine as reported in observational studies by Klein et al. (18% vs. 11%)[26] and MacDonald et al. (43% vs. 29%), respectively [23].\n\nOur study has several limitations. Firstly, the study concluded prematurely prior to attaining the full sample size mainly due to study fatigue and several episodes of social unrest in Hong Kong [34]. Early termination factors are detailed in Supplementary-Early Termination. The study period was extended from the initial planned 24 to 58 months. Despite the lower sample size, our study attained sufficient power to identify differences in the primary outcome measure among the three study drugs. Secondly, an imbalance in sex distribution was observed between the study arms, specifically, the haloperidol arm had more females than the other groups. However, the Weibull accelerated failure time model found a minimal effect of sex on time to adequate sedation given the accelerated factor by sex was close to one. Therefore, based on our results, the imbalance in sex distribution across the study arms is unlikely to affect the main results and conclusion. However, the possibility of imbalance in unmeasured baseline characteristics cannot be ruled out. Thirdly, while the sedation scale may introduce measurement bias due to subjectivity, it has been validated and applied in several studies conducted in similar settings [1,3,4]. Fourthly, patients were possibly excluded if physicians had a personal drug choice preference (e.g. antipsychotics preference for patients with known psychotic illness). However, exclusions of screened patients due to physician preference contributed only 1·2% of all excluded patients. Lastly, external validity may be impacted by the exclusion of some patients due to failure to obtain informed consent despite successful consent from 81·1% of those recruited. This discrepancy reflects immense challenges in undertaking pragmatic randomised clinical trials on acute agitation and behavioural emergencies in the ED setting and has been reported by researchers in ED settings elsewhere [22].\n\nOur study indicates that intramuscular midazolam was more effective at 5–10 mg doses compared with olanzapine or haloperidol for acute agitation in ED settings, regardless of aetiology. Intramuscular midazolam's faster sedation time may deem it preferable as an initial sedation agent. Intramuscular midazolam, olanzapine, and haloperidol effectively sedated ED patients with acute agitation within 60 min. Although adverse event rates did not differ significantly, the potential risk of extrapyramidal side effects for haloperidol should be noted. Given the potential risk of adverse events, intramuscular midazolam or olanzapine should be considered over haloperidol for undifferentiated acute agitation in EDs. As this study includes only three of the most commonly prescribed sedatives in a local setting, further investigation to compare other sedatives is warranted.\n\nContributors\nEWC, ICKW, and KSJL had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. EWC, KSJL, ICKW, CAG, JCK, DMT, DCMK, and LPL to developed the study design. EWC, KSJL, ICKW, BJC, JCK, DMT, DCMK, and SHT were responsible for the acquisition, analysis, and interpretation of data. EWC and KSJL drafted the manuscript. ICKW, CAG, JCK, DMT, and DCMK critically revised the manuscript. BJC and VJF contributed to statistical analysis. EWC, KSJL, LL, SHT, CTL, CPW, CAG, CHC, TSC, HFL, and SMT contributed in study site establishment and patient enrolment\n\nFunding\nThis study was funded by Research Grants Council (Early Career Scheme), Hong Kong (789813).\n\nData sharing statement\nDue to institutional review board restrictions associated with the trial, participant data is not available to external sources. Proposals to access the de-identified individual participant data (excluding any trial-specific participant opt-outs) that underlie the results reported in this article for secondary research purposes will be considered 12 months after publication. Proposal should be directed to the corresponding author, with approval by EWC and KSJL. Only proposals that are clearly in the public interest and compatible with the original purpose of the study will be considered. Qualified researchers will need to sign a data access agreement before data would be released.\n\nDeclaration of Competing Interest\nAll authors declare that no other support has been received from any organisation for the submitted work; no other financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted study. Outside the submitted work, EWC has received honorarium from the Hospital Authority, research grants from Narcotics Division of the Security Bureau of HKSAR, National Health and Medical Research Council (NHMRC, Australia), National Natural Science Foundation of China (NSFC), Research Fund Secretariat of the Food and Health Bureau (HMRF, HKSAR), Research Grants Council (RGC, HKSAR), Wellcome Trust; Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Pfizer, RGA and Takeda outside the submitted work.. KSJL reports personal fees from MSD China, outside the submitted work. ICKW received grants from the Research Grants Council (RGC, Hong Kong), Innovative Medicines Initiative (IMI), Shire, Janssen-Cilag, Eli-Lily, Pfizer, Bayer, European Union FP7 program. ICKW is a member of the National Institute for Health and Clinical Excellence (NICE) ADHD Guideline Group, the British Association for Psychopharmacology ADHD guideline group, and advisor to Shire.\n\nAppendix Supplementary materials\nImage, application 1 Image, application 2 \n\nAcknowledgments\nWe thank all patients who participated in this trial. In addition to the authors, we express our appreciation to the following colleagues for their support and participation in this study: Queen Mary Hospital, Hong Kong, Tuen Mun Hospital, Hong Kong, Pamela Youde Nethersole Eastern Hospital, Hong Kong, Prince of Wales Hospital, Hong Kong, Ruttonjee Hospital, Hong Kong, United Christian Hospital, Hong Kong; all pharmacists, physicians and nursing staff in participating sites; research associates and students who participated in this study: X Li, TY Ko, KY Yip, YT Hui, CY Ching, SY Kwok, C Tang, HK Tse, YK Ho, CY Lim, TY Leung, WH Chui, SY Ng, HW Chan, Y Chen, and all summer and exchange students who joined the team to learn about clinical trials. We express our thanks to members of Data Safety and Monitoring Board: BJ Cowling, HF Ho, ML Tse, BMY Cheung, CW Law; Statistician: VJ Fang; Proofreading: L Lam, J Blais, V Geall and KC Yan. Lastly, we are grateful for the support from Ms McShirley Leung who would have been pleased to know about our study findings.\n\nSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.eclinm.2021.100751.\n==== Refs\nReferences\n1 Chan E.W. Taylor D.M. Knott J.C. Phillips G.A. Castle D.J. Kong D.C. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial Ann Emerg Med 61 1 2013 72 81 22981685 \n2 Knott J.C. Isbister G.K. Sedation of agitated patients in the emergency department Emerg Med Australas 20 2 2008 97 100 18377397 \n3 Knott J.C. Taylor D.M. Castle D.J. Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department Ann Emerg Med 47 1 2006 61 67 16387219 \n4 Taylor D.M. Yap C.Y.L. Knott J.C. 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"references": "1554179;26228420;31928765;14512476;18022038;18377397;17954515;11099280;24781751;16387219;15231557;22981685;28160494;9217519;27823873;19281930;25395689;22544013;16282517;26323511;26759570;30745194;17954514;27745766;26635127;29885904;15231461;20523078;21537720;26912127;28237385;23609398;20868907",
"title": "Intramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: A multi-centre, double-blind, randomised clinical trial.",
"title_normalized": "intramuscular midazolam olanzapine or haloperidol for the management of acute agitation a multi centre double blind randomised clinical trial"
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"abstract": "This is a case of acute splenic and bilateral renal infarction in a patient with non-small cell lung carcinoma during chemotherapy with gemcitabine and cisplatin. Till date, bilateral renal infarction following gemcitabine and cisplatin has been reported only once in the past. The case that is being reported has had acute splenic and bilateral renal infarct and has not been reported previously. Splenic and renal infarction should be considered in the differential diagnosis of excruciating abdominal pain and backache in a patient on gemcitabine-based and cisplatin-based chemotherapy.",
"affiliations": "Department of Medical Oncology, Medanta, The Medicity, Gurgaon, Haryana, India. sandeepriya2000@yahoo.com",
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"abstract": "Treatment with a combination of programmed cell death-1 (PD-1) blocker and cytokine-induced killer (CIK) cells has improved outcome in cancer patients but is also associated with various patterns of responses. Pseudoprogression is a unique and uncommon phenomenon with no clear criteria for rapid diagnosis. Although some reports of pseudoprogression during immunotherapy exist, there are few reports of pseudoprogression occurring twice in the same patient. Here, we report the case of 51-year-old female patient with advanced renal cell carcinoma, who received a combination treatment of PD-1 blocker and CIK cells, and where pseudoprogression of lung and brain tumors occurred successively during treatment.",
"affiliations": "Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.",
"authors": "Zhang|Xiaojie|X|;Huang|Hao|H|;Han|Lu|L|;Li|Tiepeng|T|;Wang|Zibing|Z|;Gao|Quanli|Q|",
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"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.640447\nOncology\nCase Report\nAdvanced Renal-Cell Carcinoma Pseudoprogression After Combined Immunotherapy: Case Report and Literature Review\nZhang Xiaojie\n\nHuang Hao\nHan Lu\nLi Tiepeng\nWang Zibing *\n\nGao Quanli *\nDepartment of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China\nEdited by: Qiongzhu Dong, Fudan University, China\n\nReviewed by: Helmut Prosch, Medical University of Vienna, Austria; Jinpu Yu, Tianjin Medical University, China\n\n*Correspondence: Zibing Wang, zlyywzb2118@zzu.edu.cn; Quanli Gao, gaoquanli2015@126.com\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology\n\n28 5 2021\n2021\n11 64044711 12 2020\n26 4 2021\nCopyright © 2021 Zhang, Huang, Han, Li, Wang and Gao\n2021\nZhang, Huang, Han, Li, Wang and Gao\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nTreatment with a combination of programmed cell death-1 (PD-1) blocker and cytokine-induced killer (CIK) cells has improved outcome in cancer patients but is also associated with various patterns of responses. Pseudoprogression is a unique and uncommon phenomenon with no clear criteria for rapid diagnosis. Although some reports of pseudoprogression during immunotherapy exist, there are few reports of pseudoprogression occurring twice in the same patient. Here, we report the case of 51-year-old female patient with advanced renal cell carcinoma, who received a combination treatment of PD-1 blocker and CIK cells, and where pseudoprogression of lung and brain tumors occurred successively during treatment.\n\npseudoprogression\nimmunotherapy\nrenal-cell carcinoma\ncytokine-induced killer (CIK) cells\nPD-1\nScience and Technology Department of Henan Province10.13039/501100011447\n==== Body\nIntroduction\n\nThe incidence of kidney cancer is increasing, with renal cell carcinoma (RCC) now accounting for approximately 85% of adult kidney cancers, about 70% of which are clear cell carcinoma (1). The treatment strategy for advanced RCC is evolving from one using multiple target-kinase inhibitors to one using immunotherapy (2). When successful, immunotherapy treatment significantly prolongs overall survival in advanced RCC (3, 4), but it succeeds in only a minority of patients (4). Many clinical trials using combination immunotherapy for advanced RCC have been conducted (3), but few studies exist using immunotherapy combined with cytokine-induced killer (CIK) cells (4).\n\nGiven the unique mechanism of immunotherapy, many unconventional phenomena can appear. Pseudoprogression is one such treatment response reported in many tumors treated with immunotherapy (5). Recognizing and understanding this phenomenon is crucial since it may lead to discontinuing therapy in patients that are actually responding positively. Although pseudoprogression can be judged in many ways (6–8), it is difficult to quickly distinguish it from real progression. Here, we present a case of RCC metastasized to the lung and brain where significant pseudoprogression appeared twice during treatment with the PD-1 inhibitor nivolumab combined with CIK cells.\n\nCase Presentation\n\nA lump found in the left kidney during physical examination of a 51-year-old woman was diagnosed as kidney cancer, and the woman underwent a radical nephrectomy of the left kidney via laparoscope surgery on 29 November 2016. She had no history of kidney disease nor any family history of cancer. Pathology revealed a nuclear grade 2 clear cell carcinoma (TNM-staging: pT2 pN0 G2 M0) with favorable prognostic features according to MSKCC criteria, and thus the patient underwent a regular comprehensive review after surgery. Right middle femur metastasis occurred in January 2018, and positron emission tomography-CT (PET-CT) showed multiple lung metastases on 5 February 2018. At this time, she experienced low fever, poor appetite, and fatigue. Physical examination of lungs showed clear breath sounds, no weakening and no rales. She began therapy with sunitinib, and zoledronic acid, 4 mg every 4 weeks. During sunitinib treatment, a grade 2 hand-foot skin reaction occurred. After a 2-month treatment, a CT showed that the lung metastasis had increased in size, which was evaluated as progressive disease according to RECIST 1.1.\n\nAfter providing informed consent, the patient received 2 mg/kg nivolumab combined with approximately 5 × 109 CIK cells every 3 weeks starting in April 2018. After two cycles of therapy, the patient experienced increased appetite, but a CT scan performed 2 months after initiation of this therapy revealed enlarged and new pulmonary metastases. We continued to apply nivolumab and CIK cells combination therapy. After 6 months of therapy, a CT showed that the lesions in the lungs had begun to decrease ( Figure 1 ). Subsequent CT scans showed progressive disease reduction until November 2019.\n\nFigure 1 Patient exhibited pseudoprogression of pulmonary lesions after 2 months of treatment with nivolumab plus CIK cell transfer and achieved a partial remission after 4 months.\n\nIn December 2018, the patient experienced intermittent headaches. No fever, nausea or vomiting was present, and no change in blood pressure, appetite and physical status occurred. Enhanced head magnetic resonance imaging (MRI) showed two nodules on the right parietal lobe that were considered metastases. After multidisciplinary consultation, local radiotherapy for head lesions was recommended, but the patient refused. Oral painkillers were used to control headaches and treatment with nivolumab and CIK cells continued. After an additional 5 months (May 2019), symptoms disappeared, and another enhanced MRI found the brain lesions had disappeared ( Figure 2 ).\n\nFigure 2 MRI during treatment with nivolumab and CIK cells. MRI revealed two enhancing metastatic lesions within the brain parenchyma 6 months after the initiation of treatment. The brain lesions disappeared after 6 months of continued treatment.\n\nDuring treatment with nivolumab and CIK cells, no adverse events occurred except for a fever of 38.8 °C at the beginning of therapy. This was managed with physical cooling treatment; no corticosteroids were given.\n\nAt a follow-up in November 2019, CT scans showed right hilar lymph nodes that were significantly enlarged and low fever, fatigue, and poor appetite were present. Treatment with axitinib was started, achieving partial remission (PR). As of the last follow-up on 6 May 2020, the disease continues to stabilize. The timeline of the patient’s disease development, treatment and outcome is shown in Figure 3 .\n\nFigure 3 Timeline of the patient treatment.\n\nDiscussion\n\nImmune checkpoint inhibitors as a new anti-tumor drug have completely changed the treatment mode for kidney cancer. However, the objective response rate is only about 25% and complete remission rate is only about 1% (9). Therefore, a combination treatment strategy is the focus of current research. Research on the combination of targeted chemotherapy drugs and combined immunotherapy is prevalent in the literature. However, few studies on the combination of targeting PD-1 and using CIK cells exist.\n\nCIK cells are a group of heterogeneous immune-active host effector cells created from peripheral blood lymphocytes that are stimulated by interleukin-2 (IL-2), anti-CD3 antibodies, and interleukin-1 (IL-1) in vitro. CIK cells express the dual-functionality of acquiring NK cell function and retaining TCR-mediated cytotoxicity with T cell subsets (10). Blockade of the PD-1 pathway in combination with CIK cells as a treatment program shows better survival advantage and fewer adverse reactions in RCC and lung cancer (4), although the precise mechanisms of this are not clear. One possible mechanism is be that anti-PD-1 therapy increases the number of effector T cells in the tumor microenvironment, and CIK cells, essentially T lymphocytes, have a direct cytotoxic effect against tumor cells (10). Previous studies have shown that CIK cells improve quality of life and progression-free survival rates in patients with cancer (11). In addition, CIK cells alone, or combined with anti-PD-1 therapy, have no significant side effects in clinical applications (12, 13). This may thus provide a new treatment options for some patients who have poor physical fitness scores and cannot tolerate other treatments. However, only a few cases of this treatment have been reported (13), and further research is needed to verify these findings.\n\nPseudoprogression is a special phenomenon that occurs during immunotherapy. It is defined as the presence of a new lesion or an increase in size of an existing lesion, followed by a decrease in the tumor burden. It thus appears to be disease progression until the next imaging assessment. Biopsies have confirmed it is essentially an influx of inflammatory cells, necrosis, or sarcoid-like reactions. The overall incidence of pseudoprogression in solid tumors is low. If pseudoprogression occurs and the patient is clinically stable, according to iRECIST, the patient can continue treatment. However, some patients may consider changing treatment options for fear they have true disease progression. Thus, distinguishing between true progression and pseudoprogression is especially important. iRECIST criteria are currently the definitive guidelines for measuring objective response rates in cancer immunotherapy trials. According to iRECIST, waiting for 4-8 weeks until the next imaging assessment should occur before changing treatment (6). In our case, when lung lesions progressed for the first time and new lesions appeared in the brain, without deterioration in clinical symptoms, we did not change the treatment plan. Subsequent imaging examination confirmed that the change was pseudoprogression. However, patients with true disease progression will have delayed potentially effective treatment. Studies suggest changes in serum interleukin-8 (IL-8) levels and circulating tumor DNA may be useful in the diagnosis of pseudoprogression (7, 8).\n\nOur case demonstrates that pseudoprogression can occur at any time during immunotherapy and that clinicians need to pay special attention to identifying it. Characterizing the relationship between pseudoprogression and long-term survival requires longer term, large sample size observations.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.\n\nEthics Statement\n\nThe study was conducted in accordance with the principles of the Declaration of Helsinki, and the study protocol was approved by the ethics committee of Henan Cancer Hospital. We obtained patient consent before the study. Written informed consent was obtained from the participant for the publication of this case report. Manuscript is approved by all authors for publication.\n\nAuthor Contributions\n\nXZ collected data and wrote the manuscript. ZW and QG appraised and edited the manuscript. HH and LH provided images for publication. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nNational Natural Science Foundation of China (81972690, 81272526) and Science and Technology Department of Henan Province (51010205-206499).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgments\n\nThanks to Chengjuan Zhang for valuable discussion.\n\nAbbreviations\n\nPD-1, programmed cell death-1; RCC, renal cell carcinoma; CIK, cytokine-induced killer; PET-CT, positron emission tomography-CT.\n==== Refs\nReferences\n\n1 Lipworth L Morgans AK Edwards TL Barocas DA Chang SS Herrell SD . Renal Cell Cancer Histological Subtype Distribution Differs by Race and Sex. BJU Int (2016) 117 (2 ):260–5. 10.1111/bju.12950\n2 Rini BI Battle D Figlin RA George DJ Hammers H Hutson T . The Society for Immunotherapy of Cancer Consensus Statement on Immunotherapy for the Treatment of Advanced Renal Cell Carcinoma (RCC). J ImmunoTherapy Cancer (2019) 7 (1 ):354. 10.1186/s40425-019-0813-8\n3 Motzer RJ Escudier B McDermott DF George S Hammers HJ Srinivas S . Nivolumab Versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med (2015) 373 (19 ):1803–13. 10.1056/NEJMoa1510665\n4 Rini BI Plimack ER Stus V Gafanov R Hawkins R Nosov D . Pembrolizumab Plus Axitinib Versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med (2019) 380 (12 ):1116–27. 10.1056/NEJMoa1816714\n5 Zhao L Yang Y Li W Li T Han L Lin H . Pseudoprogression: An Indicator for Cure in Combined Immunotherapy? Immunotherapy (2019) 11 (13 ):1087–93. 10.2217/imt-2019-0034\n6 Sweis RF Zha Y Pass L Heiss B Chongsuwat T Luke JJ . Pseudoprogression Manifesting as Recurrent Ascites With Anti-PD-1 Immunotherapy in Urothelial Bladder Cancer. J Immunother Cancer (2018) 6 (1 ):24. 10.1186/s40425-018-0334-x 29618376\n7 Seymour L Bogaerts J Perrone A Ford R Schwartz LH Mandrekar S . Irecist: Guidelines for Response Criteria for Use in Trials Testing Immunotherapeutics. Lancet Oncol (2017) 18 (3 ):e143–e52. 10.1016/S1470-2045(17)30074-8\n8 Lee JH Long GV Menzies AM Lo S Guminski A Whitbourne K . Association Between Circulating Tumor DNA and Pseudoprogression in Patients With Metastatic Melanoma Treated With Anti-Programmed Cell Death 1 Antibodies. JAMA Oncol (2018) 4 (5 ):717–21. 10.1001/jamaoncol.2017.5332\n9 Sanmamed MF Perez-Gracia JL Schalper KA Fusco JP Gonzalez A Rodriguez-Ruiz ME . Changes in Serum Interleukin-8 (IL-8) Levels Reflect and Predict Response to Anti-PD-1 Treatment in Melanoma and Non-Small-Cell Lung Cancer Patients. Ann Oncol (2017) 28 (8 ):1988–95. 10.1093/annonc/mdx190\n10 Pievani A Borleri G Pende D Moretta L Rambaldi A Golay J . Dual-Functional Capability of CD3+CD56+ CIK Cells, a T-Cell Subset That Acquires NK Function and Retains TCR-Mediated Specific Cytotoxicity. Blood (2011) 118 (12 ):3301–10. 10.1182/blood-2011-02-336321\n11 Hontscha C Borck Y Zhou H Messmer D Schmidt-Wolf IG . Clinical Trials on CIK Cells: First Report of the International Registry on CIK Cells (IRCC). J Cancer Res Clin Oncol (2011) 137 : (2 ):305–10. 10.1007/s00432-010-0887-7\n12 Wang Z Liu Y Li R Shang Y Zhang Y Zhao L . Autologous Cytokine-Induced Killer Cell Transfusion Increases Overall Survival in Advanced Pancreatic Cancer. J Hematol Oncol (2016) 9 :6. 10.1186/s13045-016-0237-6 26842696\n13 Wang Z Liu X Till B Sun M Li X Gao Q . Combination of Cytokine-Induced Killer Cells and Programmed Cell Death-1 Blockade Works Synergistically to Enhance Therapeutic Efficacy in Metastatic Renal Cell Carcinoma and Non-Small Cell Lung Cancer. Front Immunol (2018) 9 :1513. 10.3389/fimmu.2018.01513 30026742\n\n",
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"abstract": "To determine the effect of ibuprofen on posttonsillectomy bleeding when compared with codeine in posttonsillectomy analgesia.\n\n\n\nCase series with chart review.\n\n\n\nTertiary care children's hospital, Philadelphia, Pennsylvania.\n\n\n\nOn July 1, 2012, our institution transitioned from acetaminophen with codeine to ibuprofen for posttonsillectomy analgesia. Pediatric patients (0-18 years old) who underwent surgery from July 1, 2010, to June 30, 2012, were placed in the codeine cohort, and those who underwent surgery from July 1, 2012, to June 30, 2014, were placed in the ibuprofen cohort.\n\n\n\nA total of 6014 patients underwent tonsillectomy between July 1, 2010, and June 30, 2014, and 211 patients presented for posttonsillectomy hemorrhage during the same period. The incidence of readmission for posttonsillectomy hemorrhage was 3.4% and 3.6% (P = .63; odds ratio [OR] = 1.07; 95% confidence interval [95% CI]: 0.811-1.410) for the codeine and ibuprofen groups, respectively, and the incidence of second operation for control of posttonsillectomy bleeding for the codeine and ibuprofen groups was 1.9% and 2.2% (P = .54; OR = 1.117; 95% CI: 0.781-1.600), respectively. Patients aged 11 to 18 years demonstrated a higher incidence of posttonsillectomy bleeding events overall. When age is controlled, multivariate logistic regression demonstrated no statistically significant increase in posttonsillectomy bleeding events among pediatric patients treated with ibuprofen versus patients treated with codeine (readmission: P = .617; OR = 0.932; 95% CI: 0.707-1.228; reoperation: P = .513; OR = 0.887; 95% CI: 0.618-1.272).\n\n\n\nAge is an independent risk factor for posttonsillectomy bleeding. When age is controlled, there is no statistically significant increase in the incidence of posttonsillectomy bleeding events among patients treated with ibuprofen when compared to patients treated with codeine.",
"affiliations": "Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA St Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA juliapf@pcom.edu.;Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA St Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA.;St Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA.",
"authors": "Pfaff|Julia A|JA|;Hsu|Kevin|K|;Chennupati|Sri Kiran|SK|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D003061:Codeine; D007052:Ibuprofen",
"country": "England",
"delete": false,
"doi": "10.1177/0194599816646363",
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"issn_linking": "0194-5998",
"issue": "155(3)",
"journal": "Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery",
"keywords": "NSAID; ibuprofen; posttonsillectomy hemorrhage; tonsillectomy",
"medline_ta": "Otolaryngol Head Neck Surg",
"mesh_terms": "D000233:Adenoidectomy; D000293:Adolescent; D000367:Age Factors; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D002648:Child; D002675:Child, Preschool; D003061:Codeine; D005260:Female; D006801:Humans; D007052:Ibuprofen; D007223:Infant; D008297:Male; D010149:Pain, Postoperative; D010359:Patient Readmission; D019106:Postoperative Hemorrhage; D012307:Risk Factors; D014068:Tonsillectomy",
"nlm_unique_id": "8508176",
"other_id": null,
"pages": "508-13",
"pmc": null,
"pmid": "27188704",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Use of Ibuprofen in Posttonsillectomy Analgesia and Its Effect on Posttonsillectomy Hemorrhage Rate.",
"title_normalized": "the use of ibuprofen in posttonsillectomy analgesia and its effect on posttonsillectomy hemorrhage rate"
} | [
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"reaction": [
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"reactionmeddrapt": "Product use in unapproved indication",
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"literaturereference": "PFAFF JA, HSU K, CHENNUPATI SK. THE USE OF IBUPROFEN IN POSTTONSILLECTOMY ANALGESIA AND ITS EFFECT ON POSTTONSILLECTOMY HEMORRHAGE RATE. OTOLARYNGOLOGY - HEAD AND NECK SURGERY 2016;155 (3):508-13.",
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{
"abstract": "BACKGROUND\nTuberculosis is a major health concern in Mexico, especially among the native population. Tuberculomas are a frequent and severe complication of pediatric tuberculosis, these are observed as tumors in neuroimaging studies but are often not diagnosed adequately.\n\n\nMETHODS\nWe present a case of a 12-year-old native Mexican girl Huichol ethnicity diagnosed with a large posterior fossa tuberculoma found by imaging. This tuberculoma was surgically removed. Histopathologic examination and staining with hematoxylin and eosin, and Ziehl-Neelsen techniques of the surgical specimen were performed. Cerebrospinal fluid was analyzed by using the newly available Xpert® MTB/RIF assay (Cepheid, Sunnyvale CA, USA). Granulomatous inflammation with central caseous necrosis surrounded by edematous brain with reactive gliosis and acid-fast bacilli were revealed on histopathologic analysis. Mycobacterium tuberculosis DNA susceptible to rifampicin was detected in the patient's cerebrospinal fluid and the patient was started on anti-tuberculosis treatment. The girl continued to show severe neurologic damage despite surgery and anti-tuberculosis treatment, and she eventually died of respiratory complications.\n\n\nCONCLUSIONS\nOur case highlights the need for early confirmation of tuberculoma diagnosis by molecular assay so that timely treatment can be initiated to prevent severe brain damage. Furthermore, it emphasizes the need to consider tuberculomas in the differential diagnosis of children with neurologic symptoms living in areas of high tuberculosis incidence and those belonging to native populations in developing countries.",
"affiliations": "Servicio de Hematología y Oncología Pediátrica, Unidad de Infectología, Hospital Civil de Guadalajara, Instituto de Investigación en Cáncer Infantil y de la Adolescencia, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico. grisesme@yahoo.com.mx.",
"authors": "Escobedo-Meléndez|Griselda|G|;Portillo-Gómez|Leopoldo|L|;Andrade-Ramos|Miguel A|MA|;Bocanegra|David|D|;Mercado-Pimentel|Rodrigo|R|;Arredondo|Luis|L|;Torres|Dara|D|;Caniza|Miguela A|MA|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "England",
"delete": false,
"doi": "10.1186/1756-0500-7-919",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 25515023340610.1186/1756-0500-7-919Case ReportPosterior fossa tuberculoma in a Huichol native Mexican child: a case report Escobedo-Meléndez Griselda grisesme@yahoo.com.mx Portillo-Gómez Leopoldo lpgegsi@prodigy.net.mx Andrade-Ramos Miguel A miguelandrade@hotmail.com Bocanegra David jdbt.doc@live.com.mx Mercado-Pimentel Rodrigo rodrigo74mx@yahoo.com Arredondo Luis a.neur@yahoo.com Torres Dara dara-ofelias@hotmail.com Caniza Miguela A Miguela.Caniza@stjude.org Servicio de Hematología y Oncología Pediátrica, Unidad de Infectología, Hospital Civil de Guadalajara, Instituto de Investigación en Cáncer Infantil y de la Adolescencia, Universidad de Guadalajara, Guadalajara, Jalisco Mexico Laboratorio de Microbiología y Parasitología, Departamento de Microbiología y Patología, Universidad de Guadalajara, Guadalajara, Jalisco Mexico Servicio de Neurocirugía Pediátrica, Hospital Civil de Guadalajara, Guadalajara, Jalisco Mexico Servicio de Anatomía Patológica, Hospital Civil de Guadalajara, Guadalajara, Jalisco Mexico Servicio de Infectología Pediátrica, Hospital Civil de Guadalajara, Guadalajara, Jalisco Mexico Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN USA Unidad de Infectología, Servicio de Hematología y Oncología Pediátrica, Hospital Civil de Guadalajara “Dr. Juan I. Menchaca”, Salvador de Quevedo y Zubieta 750 Colonia Centro, Guadalajara, Jalisco 44340 Mexico 16 12 2014 2014 7 9194 8 2014 11 12 2014 © Escobedo-Meléndez et al.; licensee BioMed Central Ltd. 2014This article is published under license to BioMed Central Ltd. 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 credited. 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\nTuberculosis is a major health concern in Mexico, especially among the native population. Tuberculomas are a frequent and severe complication of pediatric tuberculosis, these are observed as tumors in neuroimaging studies but are often not diagnosed adequately.\n\nCase presentation\nWe present a case of a 12-year-old native Mexican girl Huichol ethnicity diagnosed with a large posterior fossa tuberculoma found by imaging. This tuberculoma was surgically removed. Histopathologic examination and staining with hematoxylin and eosin, and Ziehl-Neelsen techniques of the surgical specimen were performed. Cerebrospinal fluid was analyzed by using the newly available Xpert® MTB/RIF assay (Cepheid, Sunnyvale CA, USA). Granulomatous inflammation with central caseous necrosis surrounded by edematous brain with reactive gliosis and acid-fast bacilli were revealed on histopathologic analysis. Mycobacterium tuberculosis DNA susceptible to rifampicin was detected in the patient’s cerebrospinal fluid and the patient was started on anti-tuberculosis treatment. The girl continued to show severe neurologic damage despite surgery and anti-tuberculosis treatment, and she eventually died of respiratory complications.\n\nConclusion\nOur case highlights the need for early confirmation of tuberculoma diagnosis by molecular assay so that timely treatment can be initiated to prevent severe brain damage. Furthermore, it emphasizes the need to consider tuberculomas in the differential diagnosis of children with neurologic symptoms living in areas of high tuberculosis incidence and those belonging to native populations in developing countries.\n\nKeywords\nTuberculomaTuberculosisMolecular diagnosisHuichol childMexicoissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nPediatric tuberculosis (TB) is a global health threat [1], and tuberculomas are a frequent, severe complication of TB in developing countries [2, 3]. Intracranial tuberculomas occur in as many as 13% of children with neurotuberculosis [4]; these are observed as tumors in neuroimaging studies [5] but are often not detected at early stages, when antitubercular therapy offers a high likelihood of cure with minimal sequelae. Early diagnosis of tuberculomas can be difficult; they generally remain undetectable until they have grown sufficiently to cause neurologic signs and symptoms. Even a tumor detected by imaging cannot necessarily be attributed to TB because of frequent false-negative tuberculin skin tests (TSTs), and the difficulty of microscopic detection of TB in cerebrospinal fluid (CSF) and the slow growth of the bacilli in culture media [1, 2]. TB is a major health concern in Mexico [6], especially among the native population [7]. We report the unusual case of a native Huichol Mexican girl with a large posterior fossa tuberculoma; her TB was diagnosed by using the Xpert MTB/RIF assay, which amplifies DNA from Mycobacterium tuberculosis and detects rifampin resistance. The case presentation was approved by the Ethics Committee in Biomedical Research of Hospital Civil de Guadalajara.\n\nCase presentation\nA 12-year-old Huichol native Mexican girl was admitted to the infectious disease ward of Hospital Civil de Guadalajara on February 3, 2012. She had been brought in a stretcher by her grandparents, who were her care providers. She had a history of headache, nausea, vomiting, blurred vision, weakness, and ataxia. Four months before admission she had begun complaining of headaches, which became progressively more intense, and occasional nausea and vomiting. One month before admission she experienced blurred vision, progressive weakness, and difficulty in walking and doing other voluntary movement. She had no fever or cough. A physician at the local healthcare center referred her to Hospital Civil. Soon after referral she began experiencing brief, generalized tonic-clonic seizures then, became too weak to walk.\n\nThe patient had not received routine childhood immunizations, including BCG vaccine. Her household provided poor living conditions, and her diet included unpasteurized cow’s milk. At examination at the hospital, the patient appeared emaciated: weight, 26 kg; height, 150 cm; body mass index (BMI), 11.6 (reference BMI for age, 18.5 – 24.9, by http://www.nhlbi.nih.gov/guidelines/obesity/BMI/bmi-m.htm, accessed May 2, 2014). Her heart rate was 121/min, respiratory rate was 60/min, blood pressure was 70/40 mm Hg, and axillary temperature was 36.3°C. She was unconscious and unresponsive to verbal commands. The patient showed constricted pupils unresponsive to light with bilateral convergent esotropia, generalized weakness, and bilateral flexor plantar responses.\n\nCranial axial computed tomography (CT) with contrast revealed a posterior fossa mass and hydrocephalus, confirmed by cranial magnetic resonance imaging (MRI) with gadolinium. T1-weighted MRI revealed a large, well-defined, heterogeneous mass in the right posterior fossa with hyperdense rim enhancement and hydrocephalus measuring 61 × 69 × 62 mm3 (Figure 1A-D). The lesion was initially interpreted as a primary brain tumor obstructing CSF circulation. A ventriculo-peritoneal shunt was immediately placed. The patient received intravenous mannitol 2 g/kg to reduce presumed cerebral edema. A few days later, a spinal T1-weighted MRI revealed marked gadolinium enhancement of the cervical, thoracic, and lumbar dura, suggestive of an infectious process such as TB. However, the TST was negative and the CSF contained no leukocytes. The CSF protein concentration was 230 mg/dL; the CSF glucose (37 mg/dL) and plasma glucose (113 mg/dL) ratio was 0.32 (reference range, >0.6). Acid-fast bacilli (AFB) staining by the Ziehl–Neelsen technique and culture were negative.Figure 1 \nCranial magnetic resonance imaging of the tuberculoma and histopathologic studies of the surgical specimen. (A-B) T1-weighted and contrast-enhanced T1-weighted axial MRI revealed a large (61 × 69 × 62 mm) heterogeneous lesion that was contralaterally displacing the fourth ventricle and pons. (C-D) Sagittal views show an intensely gadolinium-enhanced lesion occupying the entire posterior fossa and causing hydrocephalus by compressing the fourth ventricle. (E) The surgical specimen comprised a caseous-appearing material. (F) Acid-fast bacilli observed by Ziehl–Neelsen staining (original magnification, ×100). (G) Lymphoplasmacytic inflammation containing epithelioid cells and multinucleated Langhans giant cells forming a granulomatous lesion. Hematoxylin and eosin staining (original magnification, ×10).\n\n\n\nBecause of the diagnostic uncertainty, the tumor was removed. It was revealed as a large, cheese-like mass (Figure 1E). Histopathology, using hematoxylin-eosin staining and Ziehl–Neelsen staining, revealed granulomatous inflammation with central caseous necrosis surrounded by edematous brain tissue with reactive gliosis and numerous AFB (Figure 1F-G). Rifampicin-susceptible M. tuberculosis was detected in the CSF by using the newly available Xpert MTB/RIF assay, confirming the diagnosis of central nervous system (CNS) TB. A chest CT, 10 days after admission, revealed consolidation in the basal left lung, but Ziehl–Neelsen staining and TB DNA amplification of bronchial and gastric aspirates with the Xpert MTB/RIF assay were negative for M. tuberculosis. Although her grandparents did not exhibit symptoms of TB, her community health department was notified to test other family members for TB (results not available).\n\nThe patient begun on 10 mg/kg/day isoniazid, 20 mg/kg/day rifampicin, 35 mg/kg/day pyrazinamide, and 20 mg/kg/day ethambutol. In addition, dexamethasone was added for the treatment of CNS TB. Serology was negative for human deficiency virus infection. One month after surgery and start of anti-TB treatment, the patient remained neurologically unchanged: unconscious, pupils unresponsive to light, bilateral esotropia, generalized weakness, and bilateral flexor plantar response. She was unable to communicate and was fed via orogastric tube. A cranial CT scan found no residual or new lesions or contrast enhancement at the original site.\n\nThe patient was cared for by team of infectious disease and multispecialty experts at Hospital Civil and medical care and medications were free. After three months, the grandparents requested a transfer to a hospital closer to her community. Six months after transfer, the patient died of respiratory complications. The Ethics Committee in Biomedical Research of Hospital Civil de Guadalajara granted permission and approval to review the patient’s clinical information.\n\nDiscussion\nIn Mexico, native ethnic groups comprise 10% of the population [8] and have a higher incidence of TB [7] for reasons including genetic predisposition, lifestyle, limited healthcare access, and poverty [9]. The case we present is unusually advanced, even in such a medically underserved population and illustrates how healthcare deficiencies can affect children in low-income populations, such as late access to appropriate medical care and TB prevention. At the same time, it demonstrates the importance of a rapid, highly sensitive and specific diagnostic test for neurotuberculosis.\n\nOur patient was severely malnourished, suggesting a long evolution of the disease. Thus, malnutrition, and consequently her immunocompromised condition, may explain her anergy to the TST. False-negative tuberculin reactions occur frequently in patients with advanced malnutrition [1, 2]. Our patient’s extent of neurological damage also indicated a long disease evolution. Her negative TST and the tuberculoma’s site may have delayed clinical suspicion until the CSF obstruction caused hydrocephalous [1]. Therefore, tuberculomas should be considered in the differential diagnosis of brain tumors in children living in TB-prone areas and in high-risk groups such as native populations in developing countries.\n\nThe patient’s neurologic symptoms evolved, in the absence of fever, for 4 months before hospitalization, consistent with the reported development of brain tuberculomas 2 to 6 months after TB infection [1]. Tuberculomas are granulomatous tumor-like mass that is not a cancer that results from infection with Mycobacterium tuberculosis. This lesion is composed of a central zone of caseation surrounded by collagenous tissue capsule that usually develop in the CNS or lungs [4, 5]. After hematogenous dissemination, the bacilli multiply locally and produce pathologic growth via chronic inflammation and aggregation of caseated granulomas [5]. A mass located in CNS structures frequently manifests as an intracranial space-occupying lesion [10, 11]. Therefore, tuberculoma should be a differencial diagnosis in patients with these intracranial lesions and severe neurologic damage where the risk TB is high, even in the absence of fever or other TB symptoms.\n\nCT and MRI revealed a large mass in the posterior fossa, despite a negative TST and acid-fast CSF stain. Fortunately, the newly available MTB/RIF assay revealed TB. Despite its high sensitivity (100%) and specificity (85.7%) in diagnosing tuberculoma, CT has a low positive predictive value (33%) [10]. CT and MRI images are suggestive of malignant tumors, but MRI offers greater inherent sensitivity and specificity [11]. Moreover, traditional microbiologic tests for TB in the CSF have low sensitivity (26% to 37%) [1] and mycobacteria grow slowly in culture [2]. Our patient’s CSF stain was negative for AFB until subsequent testing by Xpert MTB/RIF amplification. AFBs were detected in the excised tuberculoma and the histopathologic studies demonstrated caseating granulomas and mycobacteria [1]. These studies are recommended in all suspected cases of TB similar to our case. The Xpert MBT/RIF kit has moderate sensitivity (59.3% to 81.3%) and high specificity (99.5% to 100%) in CSF specimens [12, 13]. It also rapidly detects M. tuberculosis in CSF and tissue specimens and should be compared with histopathologic findings [1, 5]. In Mexico, as in many countries in the Americas, this TB diagnostic test was introduced as part of the programmatic management of multidrug-resistant TB (http://www.paho.org/hq/index.php?option=com_docman&task=doc_view&gid=24329&Itemid=). This assay is recommended for use in CSF and tissue specimens by the World Health Organization guidelines for national pediatric tuberculosis programs [14].\n\nDespite excision of the tuberculoma and treatment of the CSF obstruction and TB, our patient’s prognosis remained poor because of the tuberculoma’s size and neurologic sequelae. Her neurologic abnormalities were unremitting, and she died of respiratory complications, most likely related to chronic aspiration and infections. Risk factors for her poor outcome included the tuberculoma’s size, location, and lengthy evolution, and her malnourished condition. Other risk factors for an invasive TB and CNS infection is the lack of BCG vaccination, which has been reported to be protective for neurotuberculosis and miliary TB [1, 2]. Our case highlights the importance of BCG vaccination of children in TB-endemic regions and native ethnic groups in developing countries.\n\nConclusion\nTherefore, in areas with endemic TB, tuberculomas should be suspected in children with associated risk factors for TB infection [3, 5] and intracranial tumors. In clinically suspected cases, molecular assays now allow early diagnosis in CSF and tissues, facilitating timely treatment and prevention of severe brain damage and death.\n\nPatient consent\nWritten informed consent was obtained from the patient’s next to kin for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nTBTuberculosis\n\nTSTTuberculin skin test\n\nCSFCerebrospinal fluid\n\nBMIBody mass index\n\nCTComputed tomography\n\nMRIMagnetic resonance imaging\n\nAFBAcid-fast bacilli\n\nCNSCentral nervous system\n\nBCGBacillus calmette-guérin.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nGEM contributed in the initial design of the manuscript, the acquisition of the clinical data and was responsible for revising critically the manuscript for important intellectual content; LPG interpreted the results of the clinical data; MAAR, RMP and LA provided information of the surgical procedures; DT provided the patient clinical data; DB provided specialized histopathological data for the manuscripit; and MAC was responsible for designing and revising critically the manuscript for important intellectual content. All authors contributed to writing the final version of the paper. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank Dr. Vani Shanker and Sharon Naron for editorial assistance. This work was supported in part by the American Lebanese Syrian Associated Charities (ALSAC).\n==== Refs\nReferences\n1. Perez-Velez CM Marais BJ Tuberculosis in children N Engl J Med 2012 367 348 361 10.1056/NEJMra1008049 22830465 \n2. Newton SM Brent AJ Anderson S Whittaker E Kampmann B Paediatric tuberculosis Lancet Inf Dis 2008 8 498 510 10.1016/S1473-3099(08)70182-8 \n3. van Well GT Paes BF Terwee CB Spinger P Roord JJ Donald PR van Furth M Schoeman JF Twenty years of pediatric tuberculosis meningitis: a retrospective cohort study in the western cape of South Africa Pediatrics 2009 123 e1 e8 10.1542/peds.2008-1353 19367678 \n4. Anuradha HK Garg RK Sinha MK Agarwal A Verma R Singh MK Shukla R Intracranial tuberculomas in patients with tuberculous meningitis: predictors and prognostic significance Int J Tuberc Lung Dis 2011 15 234 239 21219687 \n5. DeLance AR Safaee M Oh MC Clark AJ Kaur G Sun MZ Tuberculoma of the central nervous system J Clin Neurosci 2013 20 1333 1341 10.1016/j.jocn.2013.01.008 23768968 \n6. World Health Organization Global Tuberculosis Control 2011 2011 Geneva Global, regional and country-specific data for key indicators. Region of the Americas 147 168 \n7. Oficina Regional de la Organización Mundial de la Salud III Reunión regional “Exitos y desafios en el control de la TB en los pueblos indigenas 2010 19 21 \n8. Instituto Nacional de Estadísticas, Geografía e Informática (INEGI) Censo general de Poblacion y Vivienda 2010, México 2010 \n9. Instituto Nacional de Estadísticas Geografía e Informática (INEGI) La poblacion indígena en México 2004 \n10. Selvapandian S Rajshekhar V Idikula J Chandy MJ Predictive value of computed tomography-based diagnosis of intracranial tuberculomas Neurosurgery 1994 35 845 850 10.1227/00006123-199411000-00007 7838332 \n11. Trivedi R Saksena S Gupta RK Magnetic resonance imaging in central nervous system tuberculosis Indian J Radiol Imag 2009 19 256 265 10.4103/0971-3026.57205 \n12. Lawn SD Zumbla AI Diagnosis of extrapulmonary tuberculosis using the Xpert MTB/RIF assay Expert Rev Anti Infect Ther 2012 10 631 635 10.1586/eri.12.43 22734954 \n13. Nhu NT Heemskerk D do Thu DA Chau TT Mai NT Nghia HD Loc PP Ha DT Merson L Thinh TT Day J Chau N Wolbers M Farrar J Caws M Evaluation of GeneXpert MTB/RIF for diagnosis of tuberculous meningitis J Clin Microbiol 2014 52 226 233 10.1128/JCM.01834-13 24197880 \n14. World Health Organization Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children 2014 2 Geneva, Switzerland WHO, Tuberculosis TB\n\n",
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"title": "Posterior fossa tuberculoma in a Huichol native Mexican child: a case report.",
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"affiliations": "Department of Pediatrics, Yokohama City University Medical Center, Minami-ku, Yokohama, Japan. k_ichi@yokohama-cu.ac.jp",
"authors": "Ichikawa|Kazushi|K|;Gakumazawa|Masayasu|M|;Inaba|Aya|A|;Shiga|Kentaro|K|;Takeshita|Saoko|S|;Mori|Masaaki|M|;Kikuchi|Nobuyuki|N|",
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{
"abstract": "A 53-year-old woman with end-stage renal impairment on hemodialysis was evaluated for recurrent episodes of Corynebacterium jeikeium bacteremia and endocarditis. Her recurrences occurred despite surgical debridement and extended courses of culture-directed antimicrobial therapy. The clinical course was complicated by the requirement of various endovascular prostheses for vascular access. To our knowledge this degree of relapse with guideline medical and surgical therapy is rare and challenges current practice and understanding of this group of infection.",
"affiliations": "Department of Internal Medicine, Bridgeport Hospital, Yale-New Haven Health System, Bridgeport, CT, 06610, USA.;Department of Internal Medicine, Bridgeport Hospital, Yale-New Haven Health System, Bridgeport, CT, 06610, USA.;Department of Infectious Diseases, Bridgeport Hospital, Yale-New Haven Health System, Bridgeport, CT, 06610, USA.",
"authors": "Clarke|John-Ross D|JD|;Abdur Rahman|Manal|M|;Saul|Zane|Z|",
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"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(19)30140-410.1016/j.idcr.2019.e00610e00610ArticleA case of recurrent Corynebacterium jeikeium endocarditis: Unanswered questions for the treatment of chronic endovascular infections Clarke John-Ross D. johnrossclarke@gmail.coma⁎Abdur Rahman Manal aSaul Zane ba Department of Internal Medicine, Bridgeport Hospital, Yale-New Haven Health System, Bridgeport, CT, 06610, USAb Department of Infectious Diseases, Bridgeport Hospital, Yale-New Haven Health System, Bridgeport, CT, 06610, USA⁎ Corresponding author at: 267 Grant Street, Bridgeport, CT, 06610, USA. johnrossclarke@gmail.com27 7 2019 2019 27 7 2019 18 e0061027 5 2019 25 7 2019 25 7 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Many factors confer increased risk of recurrent endocarditis.\n\n• Often many of these factors co-exist in the same host.\n\n• There is always the risk of residual infected endocardial tissue despite repeated debridement.\n\n• The traditional 4–6 week parenteral course in endocarditis accounts for bacterial tolerance and antimicrobial resistance.\n\n• The decision on antimicrobial therapy and duration are supported by evidence but should be individualized.\n\n\n\nA 53-year-old woman with end-stage renal impairment on hemodialysis was evaluated for recurrent episodes of Corynebacterium jeikeium bacteremia and endocarditis. Her recurrences occurred despite surgical debridement and extended courses of culture-directed antimicrobial therapy. The clinical course was complicated by the requirement of various endovascular prostheses for vascular access. To our knowledge this degree of relapse with guideline medical and surgical therapy is rare and challenges current practice and understanding of this group of infection.\n\nKeywords\nCorynebacterium jeikeium endocarditisInfective endocarditisRecurrent endovascular infection\n==== Body\nIntroduction\nInfective endocarditis is a biofilm associated disease. These biofilms can contribute to antimicrobial resistance and have been the probable cause of many recurrent implant-associated infections [1]. The Corynebacterium species was traditionally classified as culture contaminants, but have become associated with life-threatening infections in immunocompromised hosts [2,3]. Our case highlights many of the challenges with treating recurrent endovascular infections.\n\nCase presentation\nA 53-year-old woman was referred to our Emergency department (ED) after developing fever and rigors with worsening dyspnea three hours following an outpatient fluoroscopic Port-A-Cath® placement. This was to facilitate outpatient weekly transfusion of blood products. The patient denied any prior subjective fever, upper respiratory or gastrointestinal symptoms. Her co-morbidities included: end-stage renal disease related to focal segmental glomerulosclerosis (FSGS) on thrice weekly hemodialysis via a left brachia-axial polytetrafluoroethylene (PTFE) AV graft (created 5 years prior), native aortic and mitral, followed by subsequent prosthetic aortic valve Corynebacterium jeikeium endocarditis (six and three months prior) and a transfusion-dependent autoimmune hemolytic anemia and thrombocytopenia on daily prednisone 10 mg.\n\nOn arrival to the ED her blood pressure was 138/94 mmHg, pulse rate 144bpm, respiratory rate 36 breaths/min, oral temperature 98.5 °F and an oxygen saturation 98% on 3 L/min oxygen (90% on room air). Her clinical examination was consistent with decompensated biventricular failure with respiratory failure. The Port-A-Cath® site was clean and dry and the AV graft site was without erythema or discoloration. Complete blood count revealed a hemoglobin 7.3 g/dL, white blood cell (WBC) count 6,000 cells/μL with 85% neutrophils and a platelet count 46,000 cells/μL. Her comprehensive metabolic panel was at baseline approaching next hemodialysis session. Our patient was commenced on empiric antimicrobials with vancomycin and meropenem for possible health-care associated infection before being admitted to a critical care unit.\n\nAdmission peripheral blood cultures showed gram positive rods which later were identified as C. jeikeium. Transesophageal echocardiogram (TEE) revealed evidence of a 0.9 cm × 0.6 cm prosthetic aortic valve abscess. There was severe mitral regurgitation with a mobile mass present on the posterior mitral valve leaflet (Fig. 1). Clearance of bacteremia was achieved within 72 h. Antibiotics were deescalated to vancomycin monotherapy. Cardiothoracic surgical intervention was delayed pending investigation for a source of intermittent bacteremia. Indium-111 WBC scan showed abnormally increased uptake in the region of the heart in-keeping with infective endocarditis, without abnormal uptake in the area of the AV graft.Fig. 1 Timeline diagram outlining patient’s clinical course over two [2] year period.\n\nFig. 1\n\nUltimately, she underwent repeat surgery involving aortic valve replacement with a 21 mm Inspiris Edwards® biological valve, repair of perivalvular fistula with homologous pericardial patch, and replacement of mitral valve with a 25 mm Magna Ease® mitral valve prosthesis. Her post-operative course was complicated by thrombosis of her AV graft with subsequent successful thrombectomy. She required an internal jugular Ash Split Cath™ for interim hemodialysis (HD) and was discharged home to complete 6 weeks of vancomycin with HD.\n\nFour months later, she re-presented with evidence of decompensated heart failure. One week into her hospitalization she was persistently febrile and blood cultures grew C. jeikeium. She was started on daptomycin 6 mg/kg every 48 h (Fig. 1). TEE showed two mobile echogenic masses on the bioprosthetic mitral valve, most consistent with vegetation. Her bacteremia cleared within 72 h. The cardiothoracic team decided there was a high risk of re-infection of a replacement valve without removal of the AV graft. Final AV graft tissue cultures did not isolate bacteria.\n\nIsolate referral of her C. jeikeium species was sent to Yale New Haven Hospital, CT laboratory for susceptibility testing. The organism was identified as Corynebacterium jeikeium which was resistant to ciprofloxacin (MIC = 8 mcg/mL), ceftriaxone (MIC = 8mcg/mL), but sensitive to daptomycin (MIC = 0.38 mcg/mL), doxycycline (MIC = 0.50 mcg/mL) and vancomycin (MIC = 0.75 mcg/mL). She later completed a 6-week daptomycin course.\n\nFour weeks later blood cultures drawn while undergoing HD via a tunneled Ash Split Cath™ isolated gram-positive rods. Our patient was admitted and switched to vancomycin. TEE showed no vegetations. MRI of the lumbar spine showed no evidence of diskitis, osteomyelitis or epidural abscess. After confirmation of bacteremia clearance her dialysis catheter was changed. She was discharged on intravenous vancomycin with HD, with the aim of transitioning to oral suppressive therapy with doxycycline. However, after a 12-week course of vancomycin with negative cultures, she was observed for one month off antimicrobials before proceeding with surgery.\n\nAt the time of writing this report, she has undergone re-do mitral valve replacement and tricuspid repair. The post-op course has been uneventful and valve tissue cultures have not isolated bacteria.\n\nDiscussion\nCoryneform bacteria, or ‘diphtheroid’ species are pleomorphic, aerobic, non-sporulating gram-positive rods which are found as constituents of normal skin flora and have been traditionally regarded as contaminants when isolated in clinical specimens [4,5]. Corynebacterium endocarditis has a predilection for left-sided valves and over a third of patients have pre-existing valvular heart disease. Additional risk factors are previous episodes of endocarditis, end-stage-renal disease, presence of prosthetic devices, intravascular catheters and atrial-ventricular cerebrospinal fluid shunts [6,7].\n\nIt is often uncertain when the same organism is isolated on multiple occasions whether it represents relapse or reinfection [8]. It is reasonable given the time course between recurrences, that our patient has had ‘relapse’ of the same C. jeikeium bacteremia. A hypothesis is that despite extended courses of antimicrobial therapy, our patient maintained an endovascular site of bacterial colonization, resulting in repeated inoculation of prosthetic material. There is always the risk of residual infected tissue despite repeated debridement, and negative culture specimens. This is compounded by an almost non-existent ‘prosthetic-free interval’. This case generates a few questions: what is the source of relapse?; where was the original inoculum? what is the appropriate duration of antimicrobial therapy? and is there a role for life-long suppression therapy?\n\nIntraoperative contamination remains the most common cause of vascular graft infections (VGIs). One of the least common causes is bacteremia, and the risk of hematogenous seeding decreases after >2 months due to endothelization [9]. One hypothesis was that the PTFE graft was a nidus for recurrent bacterial seeding in our patient’s case. A negative tissue culture does not eliminate this possibility. However, the IE recurrence after graft removal raises the possibility of an alternative explanation.\n\nMany C. jeikeium species have shown susceptibility to vancomycin and daptomycin, which is similar to the sensitivity profile in our case. C. jeikeium species have shown resistance to many beta-lactam antimicrobials, doxycycline, ciprofloxacin, clindamycin and imipenem [10]. This resistance pattern makes the choice of a chronic oral suppression regimen very difficult. Two of the challenges in treating IE are bacterial tolerance and antimicrobial resistance [11]. Tolerance describes the survival of more resilient bacterial phenotypes in the presence of antimicrobial exposure. The traditional 4–6 week parenteral requirement for therapy was designed to account for the slow bactericidal effects of antimicrobials as well as the risk of tolerance.\n\nConclusion\nEndovascular infections present unique clinical challenges. The timing of any surgical intervention, as well as the decision on antimicrobial therapy and duration are supported by evidence but are often individualized. Patients with endovascular prostheses, immunocompromised states or frequent exposure to nosocomial pathogens, add to treatment complexity. Although our case is uncommon in its time course and relapse rate, it highlights many of the fundamental approaches to treatment as well as raises potential new considerations in this patient population.\n\nFunding source\nThe authors have no funding source to declare.\n\nEthical approval\nEthics approval was not applicable.\n\nAuthor statement\nAll authors have read and approved the final version of the manuscript for submission.\n\nCRediT authorship contribution statement\nJohn-Ross D. Clarke: Conceptualization, Writing - original draft. Manal Abdur Rahman: Writing - review & editing. Zane Saul: Writing - review & editing, Supervision.\n\nDeclaration of Competing Interest\nThe authors declare that they have no conflicts of interest.\n==== Refs\nReferences\n1 Neguț A.C. Streinu-Cercel A. Moțoi M.M. Bradu L. Berciu I. Streinu-Cercel O. Recurrent infective endocarditis due to probable biofilm formation on cardiac stimulator probe BMC Infect Dis 13 Suppl. 1 2013 \n2 Murray B.E. Karchmer A.W. Moellering R.C. Jr. Diphtheroid prosthetic valve endocarditis. A study of clinical features and infecting organisms Am J Med 69 6 1980 838 848 7446550 \n3 Berbari E.C.F. Steckelberg J. Infective endocarditis due to unusual or fastidious microorganisms Mayo Clin Proc 72 1997 532 542 9179137 \n4 von Graevenitz A. Punter V. Gruner E. Pfyffer G.E. Funke G. Identification of coryneform and other gram-positive rods with several methods APMIS 102 1994 381 389 8024740 \n5 Funke G. von Graevenitz A. Clarridge J.E. 3rd Bernard K.A. Clinical microbiology of coryneform bacteria Clin Microbiol Rev 10 1 1997 125 159 8993861 \n6 Chao C.T. Huang J.W. Yen C.J. A rare and under-recognized pathogen in peritoneal dialysis peritonitis: Corynebacterium jeikeium Perit Dial Int 33 5 2013 580 581 24133086 \n7 Knox K.H.A. Nosocomial endocarditis caused by Corynebacterium emycolatum and other nondiphtheriae corynebacteria Emerg Infect Dis 1 2002 97 99 \n8 Chu V.H. Sexton D.J. Cabell C.H. Reller L.B. Pappas P.A. Singh R.K. Repeat infective endocarditis: differentiating relapse from reinfection Clin Infect Dis 41 3 2005 406 409 16007540 \n9 Wilson W.R. Bower T.C. Creager M.A. Amin-Hanjani S. O’Gara P.T. Lockhart P.B. Vascular graft infections, mycotic aneurysms, and endovascular infections: a scientific statement from the American Heart Association Circulation 134 20 2016 e412–e60 \n10 Soriano F. Eva nieto antimicorbial susceptibilities of Corynebacterium species and other non-Spore-Forming gram-positive bacilli to 18 antimicocrobial agents Antimicrob Agents Chemother 39 1995 208 214 7695308 \n11 Cahill T.J. Baddour L.M. Habib G. Hoen B. Salaun E. Pettersson G.B. Challenges in infective endocarditis J Am Coll Cardiol 69 3 2017 325 344 28104075\n\n",
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"abstract": "BACKGROUND\nTo reduce treatment variability and facilitate comparative effectiveness studies, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published consensus treatment plans (CTPs) including one for juvenile proliferative lupus nephritis (LN). Induction immunosuppression CTPs outline treatment with either monthly intravenous (IV) cyclophosphamide (CYC) or mycophenolate mofetil (MMF) in conjunction with one of three corticosteroid (steroid) CTPs: primarily oral, primarily IV or mixed oral/IV. The acceptability and in-practice use of these CTPs are unknown. Therefore, the primary aims of the pilot study were to demonstrate feasibility of adhering to the LN CTPs and delineate barriers to implementation in clinical care in the US. Further, we aimed to explore the safety and effectiveness of the treatments for induction therapy.\n\n\nMETHODS\nForty-one patients were enrolled from 10 CARRA sites. Patients had new-onset biopsy proven ISN/RPS class III or IV proliferative LN, were starting induction therapy with MMF or IV CYC and high-dose steroids and were followed for up to 24 months. Routine clinical data were collected at each visit. Provider reasons for CTP selection were assessed at baseline. Adherence to the CTPs was evaluated by provider survey and medication logs. Complete and partial renal responses were reported at 6 months.\n\n\nRESULTS\nThe majority of patients were female (83%) with a mean age of 14.7 years, SD 2.8. CYC was used more commonly than MMF for patients with ISN/RPS class IV LN (vs. class III), those who had hematuria, and those with adherence concerns. Overall adherence to the immunosuppression induction CTPs was acceptable with a majority of patients receiving the target MMF (86%) or CYC (63%) dose. However, adherence to the steroid CTPs was poor (37%) with large variability in dosing. Renal response endpoints were exploratory and did not show a significant difference between CYC and MMF.\n\n\nCONCLUSIONS\nOverall, the immunosuppression CTPs were followed as intended in the majority of patients however, adherence to the steroid CTPs was poor indicating revision is necessary. In addition, our pilot study revealed several sources of treatment selection bias that will need to be addressed in for future comparative effectiveness research.",
"affiliations": "University of California, San Francisco, 550 16th Street, 5th Floor, San Francisco, CA, 94158, USA. jennifer.cooper@childrenscolorado.org.;Emory University School of Medicine/Children's Healthcare of Atlanta, 2015 Uppergate Dr, Atlanta, GA, 30322, USA.;Texas Scottish Rite Children's Hospital, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.;Stanford University, 725 Welch Rd, Palo Alto, CA, 94304, USA.;Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E. Chicago Ave, Chicago, IL, 60611, USA.;Ohio State University College of Medicine, 480 Medical Center Dr. S-2056, Columbus, OH, 43210, USA.;Duke University Medical Center, 2100 Erwin Rd, Durham, NC, 27705, USA.;Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.;Cohen Children's Hospital Medical Center, 1991 Marcus Ave, Lake Success, NY, 11042, USA.;University of Chicago Hospitals, 5841 S. Maryland Ave, MC 5044, Chicago, IL, 60637, USA.;Children's Hospital at Montefiore/Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY, 10467, USA.;Hackensack University Medical Center, 30 Prospect Ave, Hackensack, NJ, 07601, USA.;University of California, 200 UCLA Medical Plaza, Los Angeles, 90095, CA, USA.;Duke University Medical Center, 2400 Pratt, St. Durham, NC, 27705, USA.;Duke University Medical Center, 2400 Pratt, St. Durham, NC, 27705, USA.;University of California, San Francisco, 550 16th Street, 5th Floor, San Francisco, CA, 94158, USA.",
"authors": "Cooper|Jennifer C|JC|http://orcid.org/0000-0002-7673-6562;Rouster-Stevens|Kelly|K|;Wright|Tracey B|TB|;Hsu|Joyce J|JJ|;Klein-Gitelman|Marisa S|MS|;Ardoin|Stacy P|SP|;Schanberg|Laura E|LE|;Brunner|Hermine I|HI|;Eberhard|B Anne|BA|;Wagner-Weiner|Linda|L|;Mehta|Jay|J|;Haines|Kathleen|K|;McCurdy|Deborah K|DK|;Phillips|Thomas A|TA|;Huang|Zhen|Z|;von Scheven|Emily|E|;|||",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1186/s12969-018-0279-0",
"fulltext": "\n==== Front\nPediatr Rheumatol Online JPediatr Rheumatol Online JPediatric Rheumatology Online Journal1546-0096BioMed Central London 27910.1186/s12969-018-0279-0Research ArticlePilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis http://orcid.org/0000-0002-7673-6562Cooper Jennifer C jennifer.cooper@childrenscolorado.org 1Rouster-Stevens Kelly kelly.a.rouster-stevens@emory.edu 2Wright Tracey B tracey.wright@utsouthwestern.edu 3Hsu Joyce J joycehsu@stanford.edu 4Klein-Gitelman Marisa S klein-gitelman@northwestern.edu 5Ardoin Stacy P stacy.ardoin@nationwidechildrens.org 6Schanberg Laura E laura.schanberg@duke.edu 7Brunner Hermine I hermine.brunner@cchmc.org 8Eberhard B Anne BEberhard@northwell.edu 9Wagner-Weiner Linda lww@chicago.edu 10Mehta Jay metaj@email.chop.edu 11Haines Kathleen Kathleen.Haines@Hackensackmeridian.org 12McCurdy Deborah K dmccurdy@mednet.ucla.edu 13Phillips Thomas A Thomas.a.phillips@duke.edu 14Huang Zhen zhen.huang@duke.edu 14von Scheven Emily evonsche@ucsf.edu 1for the CARRA registry investigators 1 0000 0001 2297 6811grid.266102.1University of California, San Francisco, 550 16th Street, 5th Floor, San Francisco, CA 94158 USA 2 0000 0001 0941 6502grid.189967.8Emory University School of Medicine/Children’s Healthcare of Atlanta, 2015 Uppergate Dr, Atlanta, GA 30322 USA 3 Texas Scottish Rite Children’s Hospital, 5323 Harry Hines Blvd, Dallas, TX 75390 USA 4 0000000419368956grid.168010.eStanford University, 725 Welch Rd, Palo Alto, CA 94304 USA 5 0000 0004 0388 2248grid.413808.6Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E. Chicago Ave, Chicago, IL 60611 USA 6 0000 0001 2285 7943grid.261331.4Ohio State University College of Medicine, 480 Medical Center Dr. S-2056, Columbus, OH 43210 USA 7 0000000100241216grid.189509.cDuke University Medical Center, 2100 Erwin Rd, Durham, NC 27705 USA 8 0000 0000 9025 8099grid.239573.9Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229 USA 9 Cohen Children’s Hospital Medical Center, 1991 Marcus Ave, Lake Success, NY 11042 USA 10 0000 0000 8736 9513grid.412578.dUniversity of Chicago Hospitals, 5841 S. Maryland Ave, MC 5044, Chicago, IL 60637 USA 11 0000000121791997grid.251993.5Children’s Hospital at Montefiore/Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY 10467 USA 12 0000 0004 0407 6328grid.239835.6Hackensack University Medical Center, 30 Prospect Ave, Hackensack, NJ 07601 USA 13 0000 0000 9632 6718grid.19006.3eUniversity of California, 200 UCLA Medical Plaza, Los Angeles, 90095 CA USA 14 0000000100241216grid.189509.cDuke University Medical Center, 2400 Pratt, St. Durham, NC 27705 USA 22 10 2018 22 10 2018 2018 16 6523 5 2018 19 9 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\nTo reduce treatment variability and facilitate comparative effectiveness studies, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published consensus treatment plans (CTPs) including one for juvenile proliferative lupus nephritis (LN). Induction immunosuppression CTPs outline treatment with either monthly intravenous (IV) cyclophosphamide (CYC) or mycophenolate mofetil (MMF) in conjunction with one of three corticosteroid (steroid) CTPs: primarily oral, primarily IV or mixed oral/IV. The acceptability and in-practice use of these CTPs are unknown. Therefore, the primary aims of the pilot study were to demonstrate feasibility of adhering to the LN CTPs and delineate barriers to implementation in clinical care in the US. Further, we aimed to explore the safety and effectiveness of the treatments for induction therapy.\n\nMethods\nForty-one patients were enrolled from 10 CARRA sites. Patients had new-onset biopsy proven ISN/RPS class III or IV proliferative LN, were starting induction therapy with MMF or IV CYC and high-dose steroids and were followed for up to 24 months. Routine clinical data were collected at each visit. Provider reasons for CTP selection were assessed at baseline. Adherence to the CTPs was evaluated by provider survey and medication logs. Complete and partial renal responses were reported at 6 months.\n\nResults\nThe majority of patients were female (83%) with a mean age of 14.7 years, SD 2.8. CYC was used more commonly than MMF for patients with ISN/RPS class IV LN (vs. class III), those who had hematuria, and those with adherence concerns. Overall adherence to the immunosuppression induction CTPs was acceptable with a majority of patients receiving the target MMF (86%) or CYC (63%) dose. However, adherence to the steroid CTPs was poor (37%) with large variability in dosing. Renal response endpoints were exploratory and did not show a significant difference between CYC and MMF.\n\nConclusions\nOverall, the immunosuppression CTPs were followed as intended in the majority of patients however, adherence to the steroid CTPs was poor indicating revision is necessary. In addition, our pilot study revealed several sources of treatment selection bias that will need to be addressed in for future comparative effectiveness research.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12969-018-0279-0) contains supplementary material, which is available to authorized users.\n\nKeywords\nJuvenile systemic lupus erythematosusLupus nephritisCyclophosphamideMycophenolateCorticosteroidsConsensushttp://dx.doi.org/10.13039/100000980Arthritis Foundationhttp://dx.doi.org/10.13039/100002193Lupus Foundation of AmericaChildhood Arthritis and Rheumatology Research Allianceissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nSystemic lupus erythematous (SLE) is a chronic and complex autoimmune disease which causes systemic inflammation and may involve any part of the body. Individuals diagnosed in childhood or adolescence have more aggressive disease compared to adults, with lupus nephritis (LN) occurring in up to 80% of children [1]. The diagnosis of LN is established by kidney biopsy and classified according to the 2004 International Society for Nephrology/Renal Pathology Society (ISN/RPS) criteria [2]. Proliferative lesions are classified as class III if the lesion is focal or class IV if the lesion is diffuse, involving over half the sampled glomeruli. Treatment usually involves six months of aggressive induction immunosuppression to induce renal remission, followed by years of maintenance immunosuppression aimed at preventing disease flares. Progression to end-stage renal disease may occur despite therapy with class IV LN patients at the greatest risk, estimated at 44% over 15 years [3].\n\nData demonstrating optimal therapy for proliferative LN in children and adolescents are lacking. Thus, there is significant variability in the treatment of children and adolescents with LN as providers rely upon extrapolation from adult SLE studies, pediatric renal transplant literature, limited retrospective studies, and anecdotal experience to guide medical decision-making [4]. In an effort to reduce treatment variability and facilitate comparative effectiveness studies in pediatric rheumatic diseases, Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed Consensus Treatment Plans (CTPs) for several pediatric diseases, including one for proliferative LN [4]. However, there is little information about the acceptability and in-practice use of these CTPs.\n\nTherefore, the primary aim of the pilot study was to demonstrate feasibility of the LN CTPs in terms of adherence to the treatment regimens and to delineate barriers to implementation (reasons for not following the CTPs) in clinical care in the United States. Further, we aimed to explore the safety and effectiveness of the treatments rendered upon completion of induction therapy.\n\nMethods\nConsensus treatment plans of LN\nDetails about these plans have been previously published [4]. In brief, for induction therapy of proliferative LN, CARRA CTPs recommend either intravenous (IV) cyclophosphamide (CYC) 500–1000 mg/m2 (max 1500 mg) every 4 weeks × 6 months (6–7 doses) or mycophenolate mofetil (MMF) 600 mg/m2/dose BID (ma× 3000 mg/day) in addition to one of three high-dose corticosteroid (steroid) CTPs. Steroid CTP options include primarily oral, primarily IV, or mixed oral/IV regimens. High-dose pulse IV methylprednisolone 30 mg/kg (max 1000 mg/dose) × 3 doses is recommended at the start of therapy in the primarily IV and mixed oral/IV steroid CTPs and optional in the primarily oral steroid CTP. Tapering schedules for prednisone or prednisolone are outlined for each steroid regimen. Use of mesna, anti-emetics, gonadotropin releasing hormone agonists, and antimicrobials for Pneumocystis jiroveci prophylaxis are at the provider’s discretion. Maintenance immunosuppression CTP options include MMF, azathioprine (AZA), or quarterly IV CYC in addition to low-dose prednisone or prednisolone with a goal to taper to ≤10 mg/day by 12 months and to ≤5 mg/day by 24 months from the start of induction therapy.\n\nStudy design and patient population\nA multicenter prospective observational cohort study was conducted from May 2012 through October 2015. Patients at participating sites were enrolled in the CARRA registry and treated per the induction CTPs at the discretion of the pediatric rheumatology provider. Patients with complete or partial renal response at the 6-month visit were treated according to one of the three maintenance CTPs. Main study entry criteria included new diagnosis of biopsy-proven active proliferative LN (ISN-RPS class III or IV) with or without concurrent class V disease, fulfillment of ≥4 of 11 American College of Rheumatology revised classification criteria for SLE or presence of 3 criteria provided one is histological evidence of LN [5], age at diagnosis with SLE ≤ 16 years, and age at study enrollment ≤20 years. Exclusion criteria were: severe infection, pregnancy or lactation, presence of another chronic or genetic disease or organ involvement that significantly influenced treatment of LN, and treatment with MMF or CYC not indicated per provider.\n\nData collection\nStudy visits occurred at baseline and 3, 6, 9, 12, 18, and 24 months from the start of induction therapy. Standard-of-care clinical and laboratory data were captured at each visit. Data was collected using standardized case report forms through the InForm electronic data capture system managed by the Duke Clinical Research Institute. Patients or guardians were consented for data collection through the Legacy CARRA registry. The Legacy CARRA registry general protocol and consent was approved by Duke University institutional review board (IRB) and all participating site IRBs. Because the CTP study is not interventional and patients receive standard-of-care treatment at the discretion of their provider, only consent for data collection as a participant in the CARRA registry was required.\n\nReasons for CTP selection\nThe provider’s reasons for CTP selection were assessed using standardized responses (Table 1) with the ability to select multiple reasons. Reasons for induction immunosuppression and steroid CTP selection were assessed separately at baseline. Reasons for maintenance immunosuppression CTP selection were assessed in responders at the 6-month visit.Table 1 Standardized responses used to assess reasons for consensus treatment plan (CTP) selection\n\nInduction and maintenance immunosuppression CTPs\tSteroid CTPs\t\nThis is what I or my group always does\tThis is what I or my group always does\t\nThis treatment works best\tI think this steroid regimen works best\t\nThis treatment is safer\tI think this steroid regimen is safer\t\nThis treatment is better tolerated\tI am concerned about my patient’s adherence with oral meds\t\nI am concerned about my patient’s adherence with oral meds\tMy patient prefers oral meds\t\nThis is the only option covered by my patient’s insurance\tOther (free text)\t\nMy patient prefers this method of medication administration\t\t\nMy patient is very concerned about side effects\t\t\nOther (free text)\t\t\n\n\nFeasibility of LN CTPs\nAdherence to induction immunosuppression and steroid CTP regimens was assessed by medication log and provider-report. Medications used during the study period were recorded at every visit. Overall adherence to the induction CTPs was evaluated by providers at the 3- and 6-month visits by asking whether the CTP had been followed as intended. Reasons for not following a CTP were assessed by multiple choice with ability to select multiple reasons: patient non-adherence, patient-reported intolerance, physician drug adjustment due to intolerance, adverse event, disease flare, lack of response, laboratory abnormality, pregnancy, and other.\n\nRenal response\nRenal response was assessed by providers at the 6-month visit. Responder criteria were established as part of the previously published CARRA LN CTP and adapted from the 2006 ACR response criteria for proliferative and membranous renal disease in SLE clinical trials [4, 6]. Complete renal response (CR) was defined as normalization of estimated glomerular filtration rate (GFR), inactive urine sediment (< 5 WBC/hpf, < 5 RBC/hpf, and no cellular casts) and spot urine protein-to-creatinine ratio (UPCR) < 0.2 mg/mg. Partial renal response (PR) was defined as at least 50% improvement in two core renal parameters (GFR, urinary sediment, proteinuria), maximum UPCR of < 1.0 mg/mg, and no clinically relevant worsening of the remaining renal core parameters. Laboratory measures of renal function were collected at every visit. GFR was estimated using the modified Schwartz formula [7].\n\nDisease activity\nThe Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) score was reported at baseline and at each follow-up visit [8]. Providers assessed whether the patient had experienced a disease flare since the previous visit and whether the flare was renal or non-renal. Specific flare criteria were not provided.\n\nSafety\nAdverse Events (AEs) were graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0) [9]. AEs of grade two and higher and serious adverse events were recorded at each study visit. Serious AEs were defined as death, life-threatening, hospitalization, disability or permanent damage, congenital anomaly or birth defect, or event that does not fit the defined outcomes but may require intervention to prevent one of the defined outcomes.\n\nStatistical analyses\nThis was not a randomized study and comparisons of baseline characteristics between CTP groups were performed using Chi-square test, Fisher’s exact test, and Wilcoxon rank sum tests to evaluate for possible biases impacting CTP selection. To quantify deviation from the oral steroid tapers during induction therapy, the difference between the expected dose recommended per the chosen CTP and the reported daily dose was calculated for each patient. An average percent daily difference for each week of induction therapy was generated. Deviations from the IV pulse component of the primarily IV and mixed steroid CTPs were calculated similarly by taking the difference between the expected (per CTP) and recorded number of pulses in the medication log.\n\nExploratory analyses on clinical outcomes were performed using multivariate logistic regression and mixed effect models for repeated measures. The impact of induction immunosuppression treatment (CTP) on the renal response at the 6-month visit was evaluated by multivariate logistic regression analyses with adjustment of baseline characteristics including age (years), proteinuria (mg/dL), class of proliferative LN (III, IV), steroid CTP regimen (primarily IV, mixed IV/oral, primarily oral). Colinearity of continuous covariates were examined. Differences in longitudinal outcomes of GFR, proteinuria, and SLEDAI-2 K between induction immunosuppression CTPs were assessed using mixed models with repeated measures with adjustment for baseline characteristics including age, gender, time of scheduled visits, steroid CTP regimen, and baseline values of these outcomes. Study treatment (CTP) was considered a fixed effect and subjects were considered random effects. Missing data points were considered missing at random. Multiple variance structures were explored such as unstructured and spatial power. If convergence was reached with multiple covariance structures, standard goodness-of-fit measures were used to select the model with the best fit. Statistical analyses were conducted using STATA® 14.0 (StataCorp LLC) and SAS® 9.3 (SAS Institute Inc.). All tests are two-sided. P-values were not adjusted for multiple comparisons. Tests with p-values of < 0.05 were considered statistically significant.\n\nResults\nPatients\nEighty-five patients were screened with 41 patients ultimately enrolled at 10 CARRA sites. The most common reasons for not participating were failure to meet inclusion criteria (66%) and provider decision not to use a CTP to guide treatment (20%). Baseline demographic and clinical characteristics are shown in Table 2. Significantly more patients in the CYC group had class IV LN (79% vs. 35%, p = 0.005) and hematuria (96% vs. 47%, p = 0.001) compared to the MMF group.Table 2 Baseline characteristics overall and by induction immunosuppression CTP\n\n\tAll\nn = 41\tCYC\nn = 24\tMMF\nn = 17\tp-value\t\nDemographics\t\n Age at enrollment in years, mean (SD)\t14.7 (2.8)\t15.2 (2.9)\t14 (2.6)\t0.146\t\n Age at SLE diagnosis in years, mean (SD)\t13.8 (2.8)\t13.8 (2.9)\t13.7 (2.7)\t0.832\t\n SLE duration in weeks, median (IQR)\t6 (1–73)\t14 (3, 120)\t5 (1, 10)\t0.130\t\n Female, n (%)\t34 (83)\t18 (75)\t16 (94)\t0.109\t\n Race, n (%)\t\t\t\t0.889\t\n White\t16 (39)\t10 (42)\t6 (35)\t\t\n Black or African American\t11 (27)\t6 (25)\t5 (29)\t\t\n Asian or Pacific Islander\t6 (15)\t4 (17)\t2 (12)\t\t\n Other\t8 (19)\t4 (17)\t4 (24)\t\t\n Hispanic ethnicity, n (%)\t11 (27)\t6 (25)\t5 (29)\t0.753\t\n Parental Income in US $/year, n/total (%)\t0.798\t\n < 25,000\t6/26 (23)\t4/15 (27)\t2/11 (18)\t\n 25–49,999\t8/26 (31)\t3/15 (20)\t5/11 (45)\t\n 50–74,999\t2/26 (8)\t1/15 (7)\t1/11 (9)\t\n 75–99,999\t6/26 (23)\t4/15 (27)\t2/11 (18)\t\n 100–150,000\t2/26 (8)\t2/15 (13)\t0/11\t\n > 150,000\t2/26 (8)\t1/15 (7)\t1/11 (9)\t\n Insured, n (%)\t36 (88)\t20 (83)\t16 (94)\t0.382\t\nClinical and laboratory characteristics\t\n Lupus nephritis class, n (%)\t\t\t\t0.005\t\n ISN-RPS Class III, n (%)\t16 (39)\t5 (21)\t11 (65)\t\t\n ISN-RPS Class IV, n (%)\t25 (61)\t19 (79)\t6 (35)\t\t\n Concurrent ISN-RPS Class V LN, n (%)\t14 (34)\t6 (25)\t8 (47)\t0.142\t\n GFR in ml/min/1.73 m2, median (IQR)a\t94 (70–107)\t93 (79–107)\t95 (67–123)\t0.864\t\n Proteinuria in mg pr/mg cr, median (IQR)b\t1.9 (1.1–4.7)\t1.9 (1.3–4.6)\t1.8 (0.8–4.7)\t0.554\t\n Hematuria present, n/total (%)\t29/40 (73)\t22/23 (96)\t7/15 (47)\t0.001\t\n Hypertension, n/total (%)c\t23/37 (62)\t13/20 (65)\t10/17 (59)\t0.699\t\n ESR in mm/hr., mean (SD)\t50 (33)\t44 (27)\t60 (41)\t0.304\t\n Complement factor 3, median (IQR)\t51 (39–75)\t51 (39–71)\t55 (31–98)\t0.685\t\n Complement factor 4, median (IQR)\t6 (4–8)\t6 (3–8)\t6 (4–14)\t0.578\t\n Elevated dsDNA, n/total (%)\t32/36 (89)\t20/22 (91)\t12/14 (86)\t0.629\t\n Antiphospholipid antibody present, n/total (%)\t24/40 (60)\t14/24 (58)\t10/16 (63)\t0.792\t\n SLEDAI-2 K, median (IQR)\t12 (8–20)\t16 (10–20)\t12 (6–22)\t0.458\t\n PGA, scale 0–10, median (IQR)\t5 (3–6)\t5 (3–6)\t6 (2–6)\t0.707\t\n SLICC Damage Index, n/total (%)\t\t\t\t0.677\t\n Total Score 0\t30/37 (81)\t17/22 (77)\t13/15 (87)\t\t\n Total Score 1\t7/37 (19)\t5/22 (23)\t2/15 (13)\t\t\nAbbreviations: CTP consensus treatment plan, dsDNA double stranded DNA antibody, CR creatinine, GFR glomerular filtration rate, IQR interquartile range, ISN-RPS International Society of Nephrology-Renal Pathology Society, IQR interquartile range, PGA Physician’s global disease activity, PR protein, SD standard deviation, SLEDAI-2 K systemic lupus erythematosus disease activity index-2000, SLICC systemic lupus international collaborating clinics\n\naGFR estimated using modified Schwartz equation\n\nbProteinuria assessed by spot urine protein to creatinine ratio\n\ncHypertension defined as systolic or diastolic blood pressure ≥ 90th percentile, [21]\n\n\n\nStudy retention and visit timeliness\nAll patients completed at least 6 months of follow-up. Retention declined over time with 35 (85%) and 18 (44%) patients completing the 12- and 24-month visits respectively. Overall, 60% of visits occurred within four weeks before or after the target visit date.\n\nInduction CTP selection\nCYC was selected for 24 (59%) patients and MMF for 17 (41%) patients (Fig. 1). Most sites used both regimens (Fig. 2). The most common reasons for selecting CYC were “This is what I or my group always does” (54%) and “I think this treatment works best” (54%). Concern for patient non-adherence was the rationale for initiating CYC for 8 patients. The most common reason for MMF selection was “This is what I or my group always does” (41%).Fig. 1 Enrollment and induction CTP selection. Abbreviations: CTP = consensus treatment plan, CYC = cyclophosphamide, IV = intravenous, MMF = mycophenolate mofetil, IV = intravenous\n\nFig. 2 Induction CTP selection by study site. Abbreviations: CTP = consensus treatment plan, CYC = cyclophosphamide, MMF = mycophenolate mofetil\n\n\n\nOf the three steroid CTPs, the mixed regimen was the most commonly used (n = 17, 41%), followed by primarily IV (n = 15, 37%), and primarily oral (n = 22%). Several sites used only one regimen (Fig. 2). The most common reasons for CTP selection were: “I always select this regimen” (47%) and “This steroid regimen works best” (47%) for the mixed group, “This steroid regimen works best” (80%) for the primarily IV group, and “My patient prefers oral medications” (33%) for the primarily oral group. IV-based steroid CTPs (primarily IV and mixed) were more frequently used in conjunction with CYC (p = 0.002).\n\nAdherence to induction immunosuppression CTPs\nPer medication logs, adherence to the immunosuppression CTPs was acceptable. In the MMF group, 84% and 86% of patients were at the target dose of ≥600 mg/m2 BID by the 3- and 6-month visits respectively, In the CYC group, 63% received the expected number of 6 or 7 infusions; the median number of infusions was 6 (IQR 5–6). The median cumulative CYC dose was 6290 mg (IQR 5040-8700). The median number of infusions was 6 (IQR 5–6) with a median monthly dose of 1100 mg/m2 (IQR 849–1256).\n\nProviders reported the immunosuppression CTPs were followed as intended in 76% of patients at the 3-month visit and 64% at the 6-month visit. The most common reason for not following a CTP as intended was patient non-adherence (17%). Although many providers reported not following a CTP, the vast majority (95%) of patients stayed on the initially selected treatment during the first 6 months (Fig. 3). Two patients switched therapy; one switched to MMF after the first CYC infusion due to an allergic reaction and another switched to CYC from MMF due to patient non-adherence. Two patients were treated with additional immunosuppression during the induction period. Concurrent medications are described in Additional file 1.Fig. 3 Pattern of CYC and MMF use and duration of follow-up. Abbreviations: CYC = cyclophosphamide, MMF = mycophenolate mofetil\n\n\n\nAdherence to induction steroid CTPs\nOral steroid and IV pulse exposure through week 24 was highly variable, indicating poor adherence to the steroid CTPs (Table 3). For the primarily IV and mixed groups, there was a tendency to prescribe fewer IV pulses than outlined in the CTPs however, a substantial number of patients (n = 22) had incomplete IV records and were excluded from the IV analysis.Table 3 Induction corticosteroid exposure through week 24 by CTP*\n\nSteroid\tPrimarily IV\nN = 15\tMixed Oral/IV\nN = 17\tPrimarily Oral\nN = 9\t\nOral prednisone or prednisolone\t\n n patients with complete med loga\t14\t14\t9\t\n Total gm\t5.8 (4–8.4)\t8.4 (6.2–9.2)\t16.1 (7.7–17.7)\t\n Total mg/kg\t119 (72–142)\t144 (94–160)\t285 (114, 313)\t\n Difference from expected, mgb\t− 108 (− 685, + 65)\t+ 367 (− 692, + 1440)\t− 338 (− 2650, + 1620)\t\nIV methylprednisolone pulses\t\n n patient with complete med logsa\t9\t9\t5\t\n Total number of pulse doses\t12 (6–14)\t5 (3–8)\t1 (0, 3)\t\n Difference from expected, number of pulsesb\t− 1 (− 7, 0)\t−5 (− 5, 0)\t0 (0, 0)c\t\n*All values presented as median (interquartile range), Abbreviations: CTP = Consensus treatment plan, IV = intravenous\n\naPatients with incomplete steroid records were excluded from analysis\n\nbDifference from expected per CTP. A positive value (+) indicates more steroid was given than recommended per the CTP. A negative value (−) indicates less steroid was given per the CTP\n\ncIV pulses optional in the primarily oral CTP\n\n\n\nProviders reported adhering to the steroid CTPs in 68% of patients at 3 months and just 37% of patients at 6 months. Reasons for not following a steroid CTP were similar across the regimens; the most common reasons were patient non-adherence (22%) and other (17%). Review of free-text responses revealed a theme of tapering steroids more quickly than recommended.\n\nMaintenance CTP selection and steroid use\nPatients with CR or PR at the month 6 transitioned to a maintenance CTP (n = 30). Twenty-eight patients (93%) were treated with MMF, two (7%) with quarterly CYC, and none with AZA. The most common reasons for selecting MMF were “This is what I or my group always does” (54%) and “I think this treatment works best” (54%).\n\nThe median prednisone or prednisolone dose at 24 weeks for responders was 12 mg/day (IQR 10–20) or 0.2 mg/kg (IQR 0.2–0.3). Of patients with complete tapering data at 12 months, 74% were in alignment with the CTP tapering goal of ≤10 mg/day (median 7.7 mg/day or 0.2 mg/kg/day, IQR 0.1–0.2). By 24 months, 78% were on a dose of ≤5 mg/day (median 3.4 mg/day or 0.1 mg/kg/day, IQR 0–0.1).\n\nComplete/partial renal response\nProviders reported similar CR response rates for induction immunosuppression groups at 6 months; 46% of patients in the CYC group and 47% in the MMF group. Overall response (CR or PR) was reported in 83% (20/24) of patients in the CYC group vs. 59% (10/17) in the MMF group (p = 0.08). There was no significant difference between CYC and MMF and renal response (CR or PR) in multivariate logistic regression after controlling for age, gender, proliferative LN class, and steroid CTP.\n\nProvider assessment of renal response (CR, PR) was confirmed by laboratory values in 24 of 41 (59%) patients. However, we were unable to corroborate the provider’s assessment in 17 patients due to: missing laboratory data (n = 9) and inconsistency between the laboratory values and the reported response (n = 8). To conservatively estimate the proportion of patients achieving renal response (CR or PR) at the 6-month visit using only the reported laboratory data, we counted the nine patients with missing data as non-responders, resulting in a CR rate just above 40% for both CYC (10/24, 42%) and MMF (7/17, 41%) groups. The total proportion of responders (CR or PR) in the CYC group was 63% (15/24) and 53% (9/17) in the MMF group, p = 0.54. Courses of non-responders are summarized in Additional file 2.\n\nLongitudinal outcomes: Proteinuria, GFR, SLEDAI-2 K\nMedian GFR, proteinuria, and SLEDAI-2 K scores over the course of the study are shown in Fig. 4. Exploratory analyses evaluating the effect of induction immunosuppression CTP (CYC vs. MMF) on outcomes of proteinuria, GFR, and SLEDAI-2 K over the study period were conducted using mixed effects models. No significant differences were found between CYC and MMF groups and GFR, proteinuria, or SLEDAI-2 K over time.Fig. 4 Estimated GFR, proteinuria, and SLEDAI over the study period by induction immunosuppression CTP. Abbreviations: CTP = consensus treatment plan, GFR = estimated glomerular filtration rate, SLEDAI = systemic lupus erythematosus disease activity index-2 K, StdErr = standard error\n\n\n\nDisease flares\nOf the 30 patients with a CR or PR at month 6, four patients experienced disease flare (2 renal flares) by month 24; all four patients were on MMF at the time of flare.\n\nAdverse events\nAEs are summarized in Table 4. Two serious adverse events were reported during the 6-month induction period; one patient was hospitalized for depression and suicidal ideation and one patient developed an opportunistic infection. Study is available in Additional file 3.Table 4 Adverse Events\n\nPatient\tAE\tMedications at time of AE\tAE Grade\tSAE\tTiming\t\n1\tDepression with suicidal ideation\tCYC, Mixed CS\t3\tYes\tInduction\t\n2\tOpportunistic infection\tMMF, Mixed CS\t2\tYes\tInduction\t\n3\tInfusion reaction\tCYC, Primarily IV CS\t3\tNo\tInduction\t\n4\tSteroid intolerance\tMMF, Mixed CS\t2\tNo\tInduction\t\n5\tHypertension\tMMF, Mixed CS\t3\tYes\tMaintenance\t\n6\tAcute appendicitis\tMMF\t3\tYes\tMaintenance\t\n7\tChest pain\tMycophenolic acid, low-dose prednisone*\t2\tNo\tMaintenance\t\n8\tGastroenteritis\tMMF. low-dose prednisone*\t2\tNo\tMaintenance\t\n9\tPyelonephritis\tMMF, low-dose prednisone*\t2\tYes\tMaintenance\t\nAbbreviations: AE adverse event, CS corticosteroid, CYC cyclophosphamide, MMF mycophenolate mofetil, SAE Serious adverse event\n\n*Low-dose prednisone = 10 mg/day or less\n\n\n\nDiscussion\nOur pilot study illustrates the feasibility of adhering to the CARRA LN CTPs in clinical practice and collecting observational longitudinal data across ten US pediatric rheumatology centers. Most importantly, this study elucidates the need for revision of the steroid CTPs to reduce treatment variability and support future comparative effectiveness research as adherence to the steroid CTPs was poor (37% at 6 months) with large variability in dosing. The original CTP development process utilized case-based surveys to assess current practice of the CARRA membership and it is possible that the theoretical cases used to develop the CTPs did not allow for assessment of real-life nuance, treatment practices have changed, or the providers in this pilot study were not representative of those surveyed during the initial consensus process. Thus, as the current steroid CTPs do not seem to be representative of common use we recommend revision to include a faster tapering option for patients with early response to therapy or for those with dose-limiting steroid toxicity or intolerance.\n\nWe characterized physician decision-making and identified treatment biases that will be important to consider when designing future comparative effectiveness studies. Overall, the most common reason for selecting a particular CTP was “This is what I or my group always does” suggesting that although the aim was develop CTP options that were considered equivalent in effectiveness and would be equally acceptable as standard-of-care, providers may still have strong treatment preferences. Perhaps not surprisingly, there was a tendency to treat patients with class IV LN (vs. class III), hematuria, and compliance concerns with CYC. In addition, we observed increased use of the IV-based steroid CTPs (primarily IV and mixed) in the CYC group. While this is not surprising from a practical standpoint because it is more convenient for patients already receiving one IV medication to receive another, it may also reflect a tendency to treat patients with more severe disease and/or poor compliance with IV medications. Strategies to reduce the effects of confounding by indication such as cluster (site) randomization or statistical adjustment with propensity matching could be implemented in future CTP studies.\n\nAnother potential barrier to CTP implementation highlighted in this study will be developing a process to efficiently update CTPs as practice patterns evolve. Although 90% of pediatric rheumatologists surveyed during the CTP development process endorsed using CYC first-line for induction treatment of proliferative LN, the CYC CTP was used in 63% of patients [4]. In addition, the vast majority (93%) of patients received MMF for maintenance therapy. Taken together, these results likely reflect increased use of MMF by pediatric rheumatologists since development of the LN CTPs. In addition, the lack of AZA use for maintenance therapy is surprising given the comparable effectiveness to MMF demonstrated in adults [10–12], lower cost, and option for once daily dosing. During the LN CTP development process, the low-dose “Euro-lupus” IV CYC regimen was not included as an option because of the lack of dosing guidelines for children and because the CTPs are designed to reflect current practice and the Euro-lupus regimen was not commonly used by CARRA pediatric rheumatologists. In recent years, several U.S. pediatric rheumatology centers have begun using the Euro-lupus regimen in adolescents in light of data in adults demonstrating comparable long-term renal outcomes and lower risk of ovarian toxicity compared to conventional dosing [13, 14].\n\nAs the main objectives of this pilot study were to assess feasibility of adhering to the CTPs in clinical practice, the study was not powered to assess differences in clinical response between treatment groups. In an exploratory analysis estimating renal response using laboratory data and with patients with missing data as non-responders, both CYC and MMF groups had a CR rate just above 40% at the 6-month visit. Renal response criteria for LN are far from standardized however, when similar CR criteria (proteinuria < 500 mg/24 h, no worsening of GFR at 6 months) were applied to raw data sets from three large adult LN trials (Aspreva Lupus Management Study, Abatacept and Cyclophosphamide Combination Efficacy and Safety Study, and Euro-lupus Nephritis Trial), response rates for MMF, high-dose IV CYC, and low-dose IV CYC all groups showed CR rates of approximately 20%, substantially lower than our study [15–18]. Several factors that may contribute to this finding. First, this study included only new-onset proliferative LN patients while most adult proliferative LN trials do not exclude patients with prior LN flares and these patients may be less likely to achieve a CR. Second, many patients in the current study had their 6-month visit assessment late, leading to more time on therapy before outcome assessment, which could have favorably affected the response rate.\n\nOur pilot study has several limitations. We were unable to corroborate provider assessment of renal response in many patients, most often due to missing laboratory values but there were also instances where the provider’s assessment did not match the reported laboratory data, raising concern regarding future use of provider response ascertainment. The inconsistency may indicate that the response criteria is difficult to apply in clinical practice and highlights the challenge of using research assessment tools designed for use in RCTs in the pragmatic study setting. Importantly, since this study was conducted, the CARRA registry has implemented measures to reduce missing data and improve data quality. In addition to known biases, this study is subject to bias from unmeasured confounders. Examples of potential unmeasured confounders in the current study are renal histopathology disease activity and chronicity and patient adherence. Baseline renal biopsy detail regarding activity and chronicity was not systematically collected but may have influenced provider decision-making regarding CTP selection. Poor medication adherence has been associated with poor renal outcomes in adults [19, 20] and although provider concern for poor adherence to oral medications was found to influence CTP selection, individual patient adherence data was not recorded and is difficult to measure. Lastly, given the small sample size, results from this feasibility study should be interpreted with caution.\n\nConclusions\nIn summary, our pilot study demonstrates that the general approach of using the CARRA LN CTPs in clinical practice for observational research is feasible, however we identified several key issues to consider going forward, particularly revision of the steroid CTPs, determination of renal response, and strategies to reduce effects of confounding by indication.\n\nAdditional files\n\nAdditional file 1: Concurrent medication use. (DOCX 12 kb)\n\n \nAdditional file 2: Course of Non-responders. (DOCX 11 kb)\n\n \nAdditional file 3: Weight gain. (DOCX 12 kb)\n\n \n\n\nAbbreviations\nACRAmerican College of Rheumatology\n\nAEAdverse event\n\nCARRAChildhood Arthritis and Rheumatology Research Alliance\n\nCRComplete response\n\nCSCorticosteroid\n\nCTPConsensus treatment plan\n\nCYCCyclophosphamide\n\nESRErythrocyte sedimentation rate\n\nGFRGlomerular filtration rate\n\nIQRInterquartile range\n\nIRBInstitutional review board\n\nISN/RPSInternational Society of Nephrology-Renal Pathology Society\n\nIVIntravenous\n\nLNLupus nephritis\n\nMMFMycophenolate mofetil\n\nPGAPhysician’s global assessment\n\nPRPartial response\n\nSAESerious adverse event\n\nSLEDAI-2 kSystemic lupus erythematosus disease activity index-2000\n\nStd ErrStandard error\n\nUPCRUrine protein to creatinine ratio\n\nAcknowledgements\nThe authors wish to acknowledge CARRA, and the ongoing Arthritis Foundation financial support of CARRA. The authors wish to acknowledge Marilynn Punaro for her contributions to study conception and design. In addition, the authors thank Jane Winsor, B.A. (DCRI) for database programming and the following CARRA Registry site coordinators: Sally Brinkman, Rebecca Puplava, Marilynn Punaro.\n\nFunding\nThis work was supported by the following: Arthritis Foundation Innovative Research Award (PI EVS), Lupus Foundation of America, Michael John Barlin Pediatric Research Program (PI EVS), CARRA Publication Grant (PI EVS), and the CARRA Registry.\n\nAvailability of data and materials\nThe datasets analyzed during the current study are available from the corresponding author after obtaining permission from the CARRA data and sample sharing committee.\n\nAuthors’ contributions\nThe study was conceived of and designed by EVS, KRS, MSKG, SPA, JJH, HIB, LES, BAE, LWW, JM, KH, DKM. Funding was obtained by EVS, HIB, LES, and BAE. Data acquisition: JCC, KRS, TBW, JJH, MSKG, SPA, LES, HIB, LWW, BAE, and EVS. Data cleaning, interpretation and analysis: JCC, EVS, TAP, ZH. Manuscript was drafted by JCC with critical revision provided by KRS, TBW, MSKG, SPA, LES, HIB, BAE, LWW, JM, KH, DKM, TAP, ZH, EVS. All authors have given final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy and integrity of any part of the work are appropriately investigated and resolved.\n\nEthics approval and consent to participate\nThe CARRA registry general protocol and consent was approved by the Duke University IRB and at all participating site IRBs.\n\nConsent for publication\nN/A\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Tamirou F Long-term follow-up of the MAINTAIN nephritis trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis Ann Rheum Dis 2016 75 3 526 531 10.1136/annrheumdis-2014-206897 25757867 \n11. Houssiau FA Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN nephritis trial Ann Rheum Dis 2010 69 12 2083 2089 10.1136/ard.2010.131995 20833738 \n12. Tian SY Immunosuppressive therapies for the maintenance treatment of proliferative lupus nephritis: a systematic review and network Metaanalysis J Rheumatol 2015 42 8 1392 1400 10.3899/jrheum.141650 26077406 \n13. Houssiau FA The 10-year follow-up data of the euro-lupus nephritis trial comparing low-dose and high-dose intravenous cyclophosphamide Ann Rheum Dis 2010 69 1 61 64 10.1136/ard.2008.102533 19155235 \n14. Tamirou F Brief Report: The Euro-Lupus Low-Dose Intravenous Cyclophosphamide Regimen Does Not Impact the Ovarian Reserve, as Measured by Serum Levels of Anti-Mullerian Hormone Arthritis Rheumat (Hoboken, N.J.) 2017 69 6 1267 1271 10.1002/art.40079 \n15. Wofsy D Diamond B Houssiau FA Crossing the Atlantic: the Euro-Lupus Nephritis regimen in North America Arthritis Rheumat (Hoboken, NJ) 2015 67 5 1144 1146 10.1002/art.39067 \n16. Appel GB Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis J Am Soc Nephrol 2009 20 5 1103 1112 10.1681/ASN.2008101028 19369404 \n17. Group, A.T Treatment of lupus nephritis with abatacept: the Abatacept and cyclophosphamide combination efficacy and safety study Arthritis Rheumatol 2014 66 11 3096 3104 10.1002/art.38790 25403681 \n18. Houssiau FA Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the euro-lupus nephritis trial Arthritis Rheum 2004 50 12 3934 3940 10.1002/art.20666 15593207 \n19. Bruce IN Gladman DD Urowitz MB Factors associated with refractory renal disease in patients with systemic lupus erythematosus: the role of patient nonadherence Arthritis Care Res 2000 13 6 406 408 10.1002/1529-0131(200012)13:6<406::AID-ART11>3.0.CO;2-2 14635317 \n20. Adler M An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period Rheumatology (Oxford) 2006 45 9 1144 1147 10.1093/rheumatology/kel039 16527882 \n21. National High Blood Pressure Education Program Working Group on High Blood Pressure in, C. and Adolescents The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents Pediatrics 2004 114 2 Suppl 4th Report 555 576 15286277\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1546-0096",
"issue": "16(1)",
"journal": "Pediatric rheumatology online journal",
"keywords": "Consensus; Corticosteroids; Cyclophosphamide; Juvenile systemic lupus erythematosus; Lupus nephritis; Mycophenolate",
"medline_ta": "Pediatr Rheumatol Online J",
"mesh_terms": "D000293:Adolescent; D002648:Child; D015331:Cohort Studies; D032921:Consensus; D003520:Cyclophosphamide; D005240:Feasibility Studies; D005260:Female; D005938:Glucocorticoids; D019983:Guideline Adherence; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D008181:Lupus Nephritis; D008297:Male; D009173:Mycophenolic Acid; D010865:Pilot Projects; D011446:Prospective Studies; D012042:Registries; D012074:Remission Induction; D012219:Rheumatology; D016896:Treatment Outcome",
"nlm_unique_id": "101248897",
"other_id": null,
"pages": "65",
"pmc": null,
"pmid": "30348175",
"pubdate": "2018-10-22",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "9324032;25757867;15593207;20833738;19116979;19155235;15286277;14635317;19369404;19820136;25779381;16453282;22162255;25403681;14717922;11838846;28235250;26077406;26815601;16527882",
"title": "Pilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis.",
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