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{
"abstract": "Myelodysplastic syndrome with myelofibrosis (MDS-F) is a disease with a poor prognosis, and patients with this condition are at an increased risk of engraftment failures after allogeneic hematopoietic stem cell transplantation (SCT). Azacitidine (AZA) is effective in high-risk MDS patients. However, the effects of AZA on MDS-F have not been elucidated. AZA was administered to a 62-year-old male with MDS-F for 7 days at a dose of 75 mg/m2. Hematological improvements were observed after only 1 course of treatment. No suitable donor was found through the Japan Marrow Donor Program; therefore, the patient underwent umbilical cord blood transplant (UCBT). Neutrophil engraftment was observed on day 21 after the transplant procedure. He developed acute graft versus host disease (GVHD) of the skin (stage 3/grade II), but it could be controlled using prednisolone. Chronic GVHD was not observed and he was discharged in good general condition on day 68. While treatment prior to allogeneic SCT of MDS-F has not been established, in the present case, the hematological improvement brought about by AZA likely contributed to the patient's positive response to UCBT.",
"affiliations": "Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital.;Department of Clinical Oncology and Hematology, The Jikei University Hospital.",
"authors": "Ohba|Rie|R|;Usui|Noriko|N|;Ito|Yuta|Y|;Yamauchi|Hirofumi|H|;Machishima|Tomohito|T|;Ishii|Hiroto|H|;Fukushima|Ryoko|R|;Yokoyama|Hiroki|H|;Shiota|Yuko|Y|;Yahagi|Yuichi|Y|;Yano|Shingo|S|;Dobashi|Nobuaki|N|;Aiba|Keisuke|K|",
"chemical_list": "D001374:Azacitidine",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.601",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(6)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Azacitidine; MDS-F; Umbilical cord blood cell transplantation",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D001374:Azacitidine; D036101:Cord Blood Stem Cell Transplantation; D005312:Fetal Blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D055728:Primary Myelofibrosis; D014184:Transplantation, Homologous",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "601-606",
"pmc": null,
"pmid": "28679989",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Myelodysplastic syndrome with myelofibrosis in which azacitidine therapy was effective and cord blood transplantation was carried out.",
"title_normalized": "myelodysplastic syndrome with myelofibrosis in which azacitidine therapy was effective and cord blood transplantation was carried out"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-20170904668",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": "3",
"drugadministrationroute": "058",
"drugauthorizationnumb": "050794",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "75 MILLIGRAM/SQ. METER",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELODYSPLASTIC SYNDROME",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "75",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "AZACITIDINE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "80 MILLIGRAM/SQ. METER",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELODYSPLASTIC SYNDROME",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "80",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MELPHALAN."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "GRAFT VERSUS HOST DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHOTREXATE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "150 MILLIGRAM/SQ. METER",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELODYSPLASTIC SYNDROME",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "150",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUDARABINE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELODYSPLASTIC SYNDROME",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": null,
"patientonsetage": "62",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Bronchopulmonary aspergillosis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Myelodysplastic syndrome",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Acute graft versus host disease in skin",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "OHBA R. MYELODYSPLASTIC SYNDROME WITH MYELOFIBROSIS IN WHICH AZACITIDINE THERAPY WAS EFFECTIVE AND CORD BLOOD TRANSPLANTATION WAS CARRIED OUT. THE JAPANESE JOURNAL OF CLINICAL HEMATOLOGY.",
"literaturereference_normalized": "myelodysplastic syndrome with myelofibrosis in which azacitidine therapy was effective and cord blood transplantation was carried out",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20170919",
"receivedate": "20170919",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13988611,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171128"
}
] |
{
"abstract": "BACKGROUND\nVariable response after clopidogrel is well documented and may affect major adverse clinical events after stroke. Impact of CYP2C19 genetic polymorphisms is an established marker linked to variable response after clopidogrel. However, the association of certain genetic polymorphisms with prediction of major adverse clinical events following stroke still remains controversial, especially in Caucasians.\n\n\nOBJECTIVE\nThe primary aim was to evaluate the impact of CYP2C19 allele *2 in heterozygote form on major adverse clinical events in Caucasian poststroke survivors treated with clopidogrel. The secondary aim was to analyze the potential link between CYP2C19 genetic polymorphism and variable response after clopidogrel.\n\n\nMETHODS\nOne hundred thirty patients of Caucasian origin following documented ischemic stroke were included. Platelet reactivity was assessed by light transmittance aggregometry (LTA) and matched with various CYP2C19 loss-of-function genetic polymorphisms and major adverse clinical events (composite of vascular deaths, stroke/transient ischemic attack, and myocardial infarction).\n\n\nRESULTS\nOver the mean follow-up of 14.9 months, 19 patients experienced major adverse clinical events. The risk of major adverse clinical events was nearly 3-fold in loss-of-function allele carriers (hazard ratio = 2.904; 95% confidence interval, 1.083-7.786; P = 0.013), whereas the risk of ischemic stroke or transient ischemic attack alone was also higher (hazard ratio = 3.170; 95% confidence interval, 1.281-7.849; P = 0.034). Platelet activity was strongly associated with allele *2 status (rs = 0.21, P = 0.016) but not with other genetic polymorphisms. Carriers of allele*2 exhibited lower platelet response to adenosine diphosphate-mean LTA (30.1% vs. 42.0%; P = 0.017). There were no significant differences in LTA results with other agonists. Strong association of increase in adenosine diphosphate-induced aggregation with diabetes mellitus (rs = 0.20, P = 0.023), increasing age (rs = 0.23, P = 0.008), and conversely diminishing over increased weight (rs = 0.23, P = 0.009) was also detected. The carriers of other gene allele variants lack uniformed impact on variable response after clopidogrel.\n\n\nCONCLUSIONS\nEven heterozygous CYP2C19*2 allele carriers among Caucasian patients after ischemic stroke had a higher risk of major adverse clinical events. The LTA, however, did not predict major adverse clinical events. The exact clinical utility of these findings is still uncertain and requires large outcome-driven randomized trial in Caucasians for proof of concept.",
"affiliations": "Department of Neurology, 2nd Faculty of Medicine, Charles University, Prague and Motol University Hospital, Prague, Czech Republic.;Molecular Genetics Laboratory, Hospital Na Homolce, Prague, Czech Republic.;Faculty of Pharmacology, Veterinary University Brno, Brno, Czech Republic.;Department of Neurology, 2nd Faculty of Medicine, Charles University, Prague and Motol University Hospital, Prague, Czech Republic.;Department of Neurology, 2nd Faculty of Medicine, Charles University, Prague and Motol University Hospital, Prague, Czech Republic.;Department of Neurology, 2nd Faculty of Medicine, Charles University, Prague and Motol University Hospital, Prague, Czech Republic.;Department of Neurology, 2nd Faculty of Medicine, Charles University, Prague and Motol University Hospital, Prague, Czech Republic.;Department of Neurology, 2nd Faculty of Medicine, Charles University, Prague and Motol University Hospital, Prague, Czech Republic.;Department of Neurology, 2nd Faculty of Medicine, Charles University, Prague and Motol University Hospital, Prague, Czech Republic.;Department of Hematology, 2nd Faculty of Medicine, Charles University, Prague and Motol University Hospital, Prague, Czech Republic.;Molecular Genetics Laboratory, Hospital Na Homolce, Prague, Czech Republic.;Molecular Genetics Laboratory, Hospital Na Homolce, Prague, Czech Republic.;Molecular Genetics Laboratory, Hospital Na Homolce, Prague, Czech Republic.;Department of Neurology, Johns Hopkins University, Baltimore, MD.",
"authors": "Tomek|Aleš|A|;Matʼoška|Václav|V|;Frýdmanová|Alena|A|;Magerová|Hana|H|;Šrámek|Martin|M|;Paulasova-Schwabová|Jaroslava|J|;Růžičková|Tereza|T|;Janský|Petr|P|;Šarbochová|Ivana|I|;Hadačová|Ivana|I|;Kaplan|Vojtěch|V|;Lacinová|Zuzana|Z|;Táborský|Luděk|L|;Serebruany|Victor|V|",
"chemical_list": "D015415:Biomarkers; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000416",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "25(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D015415:Biomarkers; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D002546:Ischemic Attack, Transient; D000073658:Loss of Function Mutation; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D018570:Risk Assessment; D020521:Stroke; D017741:Survivors; D013988:Ticlopidine; D016896:Treatment Outcome; D044465:Whites",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e202-e212",
"pmc": null,
"pmid": "29509167",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impact of CYP2C19 Polymorphisms on Clinical Outcomes and Antiplatelet Potency of Clopidogrel in Caucasian Poststroke Survivors.",
"title_normalized": "impact of cyp2c19 polymorphisms on clinical outcomes and antiplatelet potency of clopidogrel in caucasian poststroke survivors"
} | [
{
"companynumb": "US-TEVA-2018-US-972150",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "076999",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANTIPLATELET THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CLOPIDOGREL"
}
],
"patientagegroup": null,
"patientonsetage": "47",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Lower gastrointestinal haemorrhage",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TOMEK A, MAT^OSKA V, FRYDMANOVA A, MAGEROVA H, SRAMEK M, PAULASOVA-SCHWABOVA J, ET AL. IMPACT OF CYP2C19 POLYMORPHISMS ON CLINICAL OUTCOMES AND ANTIPLATELET POTENCY OF CLOPIDOGREL IN CAUCASIAN POSTSTROKE SURVIVORS. AM-J-THER 2018?25(2):E202-E212.",
"literaturereference_normalized": "impact of cyp2c19 polymorphisms on clinical outcomes and antiplatelet potency of clopidogrel in caucasian poststroke survivors",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "CZ",
"receiptdate": "20181107",
"receivedate": "20181107",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 15590911,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190205"
}
] |
{
"abstract": "BACKGROUND\nBecause standard chemotherapy for advanced gastric cancer consists of oral fluoropyrimidines plus platinum as first-line therapy, with paclitaxel plus ramucirumab as the second line, irinotecan is usually positioned as third-line chemotherapy in clinical practice in Japan.\n\n\nMETHODS\nA retrospective evaluation was conducted to determine the efficacy and safety of irinotecan as third-line chemotherapy for advanced gastric cancer in patients refractory or intolerant to fluoropyrimidines, platinum, and taxanes.\n\n\nRESULTS\nBetween February 2008 and December 2013, 52 patients received third-line irinotecan monotherapy. Among the 32 patients with measurable lesions, 1 patient achieved a confirmed partial response and 6 patients had stable disease. The overall response rate was 3% and the disease control rate was 22%. Median progression-free survival was 2.3 months [95% confidence interval (CI), 1.8-2.8] and median overall survival was 4.0 months (95% CI, 2.6-5.3). The most common adverse events of grade 3 severity or higher were neutropenia (27%), febrile neutropenia (12%), anorexia (12%), and diarrhea (6%). Although no treatment-related deaths occurred, 2 patients (4%) died of disease progression within 30 days after the last administration of irinotecan.\n\n\nCONCLUSIONS\nIrinotecan monotherapy appears to be tolerated but was shown to have modest activity as third-line chemotherapy for advanced gastric cancer.",
"affiliations": "Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. siwasa@ncc.go.jp.;Department of Global Clinical Research, Graduate School of Medicine, Chiba University, Chiba, Japan.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.",
"authors": "Nishimura|Takashi|T|;Iwasa|Satoru|S|;Nagashima|Kengo|K|;Okita|Natsuko|N|;Takashima|Atsuo|A|;Honma|Yoshitaka|Y|;Kato|Ken|K|;Hamaguchi|Tetsuya|T|;Yamada|Yasuhide|Y|;Shimada|Yasuhiro|Y|;Boku|Narikazu|N|",
"chemical_list": "D000970:Antineoplastic Agents; D004338:Drug Combinations; D017671:Platinum Compounds; D043823:Taxoids; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D000069287:Capecitabine; D000077146:Irinotecan; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10120-016-0670-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1436-3291",
"issue": "20(4)",
"journal": "Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association",
"keywords": "Gastric cancer; Irinotecan; Third-line chemotherapy",
"medline_ta": "Gastric Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D002166:Camptothecin; D000069287:Capecitabine; D018572:Disease-Free Survival; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid; D017671:Platinum Compounds; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016879:Salvage Therapy; D013274:Stomach Neoplasms; D043823:Taxoids; D005641:Tegafur; D016896:Treatment Outcome",
"nlm_unique_id": "100886238",
"other_id": null,
"pages": "655-662",
"pmc": null,
"pmid": "27858180",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": "24190112;17298958;21742485;19358705;22412140;18172173;23266882;21431297;21340668;16099596;20159816;17695430;23341787;16557431;25240821;18282805;19596975;20047125;20037789;21677484;15492562;18971936;19097774;20150573;19153121;21844504;11156391;17558305;15007088;20221831;20728210",
"title": "Irinotecan monotherapy as third-line treatment for advanced gastric cancer refractory to fluoropyrimidines, platinum, and taxanes.",
"title_normalized": "irinotecan monotherapy as third line treatment for advanced gastric cancer refractory to fluoropyrimidines platinum and taxanes"
} | [
{
"companynumb": "JP-PFIZER INC-2018161295",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "020571",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "150 MG/M2, CYCLIC (90-MIN INTRAVENOUS INFUSION EVERY 2 WEEKS)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "GASTRIC CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "150",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "IRINOTECAN HCL"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Neuropathy peripheral",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
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"abstract": "OBJECTIVE\nOur aim was to replicate and extend the recently found association between acetaminophen use during pregnancy and ADHD symptoms in school-age children.\n\n\nMETHODS\nParticipants were members of the Auckland Birthweight Collaborative Study, a longitudinal study of 871 infants of European descent sampled disproportionately for small for gestational age. Drug use during pregnancy (acetaminophen, aspirin, antacids, and antibiotics) were analysed in relation to behavioural difficulties and ADHD symptoms measured by parent report at age 7 and both parent- and child-report at 11 years of age. The analyses included multiple covariates including birthweight, socioeconomic status and antenatal maternal perceived stress.\n\n\nRESULTS\nAcetaminophen was used by 49.8% of the study mothers during pregnancy. We found significantly higher total difficulty scores (Strengths and Difficulty Questionnaire parent report at age 7 and child report at age 11) if acetaminophen was used during pregnancy, but there were no significant differences associated with any of the other drugs. Children of mothers who used acetaminophen during pregnancy were also at increased risk of ADHD at 7 and 11 years of age (Conners' Parent Rating Scale-Revised).\n\n\nCONCLUSIONS\nThese findings strengthen the contention that acetaminophen exposure in pregnancy increases the risk of ADHD-like behaviours. Our study also supports earlier claims that findings are specific to acetaminophen.",
"affiliations": "Department of Paediatrics, The University of Auckland, Auckland, New Zealand.;School of Psychology, The University of Auckland, Auckland, New Zealand.;Discipline of Nutrition, The University of Auckland, Auckland, New Zealand.;Department of Medicine, The University of Auckland, Auckland New Zealand.;Department of Paediatrics, The University of Auckland, Auckland, New Zealand.",
"authors": "Thompson|John M D|JM|;Waldie|Karen E|KE|;Wall|Clare R|CR|;Murphy|Rinky|R|;Mitchell|Edwin A|EA|;|||",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
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"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, USA 25251831PONE-D-14-2123610.1371/journal.pone.0108210Research ArticleBiology and Life SciencesPsychologyMedicine and Health SciencesPediatricsSocial SciencesAssociations between Acetaminophen Use during Pregnancy and ADHD Symptoms Measured at Ages 7 and 11 Years Acetaminophen Use during Pregnancy and ADHDThompson John M. D. \n1\nWaldie Karen E. \n2\n\n*\nWall Clare R. \n3\nMurphy Rinky \n4\nMitchell Edwin A. \n1\nthe ABC study group \n¶\n\n1 \nDepartment of Paediatrics, The University of Auckland, Auckland, New Zealand\n\n2 \nSchool of Psychology, The University of Auckland, Auckland, New Zealand\n\n3 \nDiscipline of Nutrition, The University of Auckland, Auckland, New Zealand\n\n4 \nDepartment of Medicine, The University of Auckland, Auckland New Zealand\nHashimoto Kenji Editor\nChiba University Center for Forensic Mental Health, Japan\n* E-mail: k.waldie@auckland.ac.nzCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: JMDT KEW CW RM EAM. Performed the experiments: JMDT KEW CW RM EAM. Analyzed the data: JMDT. Contributed reagents/materials/analysis tools: JMDT. Wrote the paper: JMDT KEW CW RM EAM. The ABC study group: ER DB CW. Collected data: GG BR HN.\n\n¶ Members of the ABC study group can be found in the acknowledgments.\n\n2014 24 9 2014 9 9 e10821012 5 2014 21 8 2014 © 2014 Thompson et al2014Thompson et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Objective\nOur aim was to replicate and extend the recently found association between acetaminophen use during pregnancy and ADHD symptoms in school-age children.\n\nMethods\nParticipants were members of the Auckland Birthweight Collaborative Study, a longitudinal study of 871 infants of European descent sampled disproportionately for small for gestational age. Drug use during pregnancy (acetaminophen, aspirin, antacids, and antibiotics) were analysed in relation to behavioural difficulties and ADHD symptoms measured by parent report at age 7 and both parent- and child-report at 11 years of age. The analyses included multiple covariates including birthweight, socioeconomic status and antenatal maternal perceived stress.\n\nResults\nAcetaminophen was used by 49.8% of the study mothers during pregnancy. We found significantly higher total difficulty scores (Strengths and Difficulty Questionnaire parent report at age 7 and child report at age 11) if acetaminophen was used during pregnancy, but there were no significant differences associated with any of the other drugs. Children of mothers who used acetaminophen during pregnancy were also at increased risk of ADHD at 7 and 11 years of age (Conners’ Parent Rating Scale-Revised).\n\nConclusions\nThese findings strengthen the contention that acetaminophen exposure in pregnancy increases the risk of ADHD-like behaviours. Our study also supports earlier claims that findings are specific to acetaminophen.\n\nThe initial study was funded by the Health Research Council of New Zealand. The 12 month postal questionnaire was funded by Hawkes Bay Medical Research Foundation. The 3.5 year follow-up study was funded by Child Health Research Foundation, Becroft Foundation and Auckland Medical Research Foundation. The 7 year follow-up study was funded by Child Health Research Foundation. The 11 year follow-up was funded by Child Health Research Foundation and the National Heart Foundation. E. A. Mitchell and J. M. D. Thompson are supported by Cure Kids. The 3½, 7 and 11 year follow-ups were conducted in the Children’s Research Centre which is supported in part by the Starship Foundation and the Auckland District Health Board. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityThe authors confirm that all data underlying the findings are fully available without restriction. Data are from the Auckland Birthweight Collaborative Study whose authors may be contacted at The University of Auckland Department of Paediatrics (Prof. EA Mitchell).Data Availability\nThe authors confirm that all data underlying the findings are fully available without restriction. Data are from the Auckland Birthweight Collaborative Study whose authors may be contacted at The University of Auckland Department of Paediatrics (Prof. EA Mitchell).\n==== Body\nIntroduction\n\nJAMA Pediatrics recently published a potentially alarming finding: Acetaminophen taken during pregnancy increased the risk of attention-deficit/hyperactivity disorder (ADHD) symptoms in their 7 year old offspring [1]. The use of acetaminophen in pregnancy led to an increased likelihood of offspring taking prescribed ADHD medications (e.g., methylphenidate) and an increased likelihood of hyperkinetic disorder (a severe form of ADHD). ADHD is the most common neurodevelopmental disorder, affecting over 5–10% of the school age population, and is characterised by inattention, hyperactivity and impulsivity [2]. Despite having an early onset, ADHD is most commonly diagnosed and treated between the ages 7 and 12 years [3] and is reported to persist through to adolescence and beyond in about 80% of cases [4].\n\nThe finding that even low doses of acetaminophen (indicated by the number of weeks of drug exposure) can affect behaviour 7 years later is alarming because acetaminophen (paracetamol) is the most commonly used antenatal drug [5]. If supported, understanding the biological mechanism underlying the acetaminophen-behaviour link would likely take precedent in tandem with efforts to inform the general public of the newly identified risks of this commonly used over-the-counter drug. The finding is also noteworthy because of the many strengths of the above study. Firstly, the sample consisted of a large cohort of mothers (64 322 individuals enrolled in the Danish National Birth Cohort) and multiple child outcomes were included (Strengths and Difficulties Questionnaire [SDQ], medication use for ADHD, and hospital records for hyperkinetic disorder. Secondly, the longitudinal research was sampled prospectively, meaning that the results were unlikely affected by recall bias. Finally, the analyses controlled for a wide range of factors that might influence both medication-taking in pregnant mothers (e.g., reported fever, inflammatory problems) and ADHD symptoms in offspring (e.g., birthweight, antenatal smoking and alcohol use).\n\nIn an Editorial in the same issue of JAMA Pediatrics, Cooper et al. [6] underscore the importance of the acetaminophen findings but also highlight some of the study weakness. They rightly stress that the correlational design of the study (among other factors) does not permit us to infer causation. As such, the authors urge caution when interpreting the study results until the findings are replicated and extended. One such recommendation by the authors to extend the study was to examine other drugs taken during pregnancy to determine if the drug-ADHD association was specific to acetaminophen.\n\nTowards this end, the aim of the present study was to determine the association between drugs commonly taken during pregnancy, including acetaminophen, and ADHD in child members of the prospective Auckland Birthweight Collaborative (ABC) longitudinal study. Aspirin, antacids, and antibiotics were the other drugs, besides acetaminophen, that were analysed in relation to SDQ total difficulties (and sub-scales) at 7 and 11 years of age. We also measured ADHD symptoms with more specificity than the SDQ by using the Conners’ Behavioural Rating Scale: Revised (CRS:R) parent report at ages 7 and 11 years. Our analyses included multiple covariates, including those controlled for in the Danish study. We also included other factors previously shown to be related to SDQ in our study, including antenatal maternal perceived stress. Children of mothers who report antenatal stress have been shown to have a range of poorer neurodevelopmental outcomes, including ADHD [7], [8].\n\nMethods\nParticipants\nThe Auckland Birthweight Collaborative (ABC) Study has been described in detail elsewhere [9]. In brief, the study originally selected children at birth, between October 1995 and November 1997. Children were selected over the entire time period from the Auckland District Health Board, and from October 1995 to August 1997 in the Waitemata District Health Board. All small for gestational age (SGA) infants (< = 10th percentile for gestation and sex) and a random selection of appropriate for gestational age infants (AGA) were selected during the study, such that the number in each group were approximately equal. Infants were excluded from the study if they were not resident and born in the designated study regions, were preterm, were from multiple births or had congenital abnormalities likely to affect subsequent growth or development.\n\nThe study consisted of 1714 children at birth of which 871 had mothers who were self-identified as being of European ethnicity. The study has followed the children at 1 year (via a postal questionnaire), and with face to face assessments at 3.5, 7 and 11 years of age. Only European children were followed up after 3.5 due to the poor response rate for other ethnic groups at the previous time point. At all follow-ups mothers of respondents have been found to be more likely than non-respondents to have a tertiary education (p = 0.05), to be married (p<0.0001), to have high socio-economic status (p<0.0001), not to have smoked during their pregnancy (p<0.0001) and to be older (p = 0.0001). Respondents and non-respondents did not differ in other obstetric and social variables, including the gestational age, birthweight and gender of their infant, parity, type of delivery, maternal social support or maternal stress levels.\n\nAt birth, demographics and information about maternal health, perceived stress, drug use, and other lifestyle factors during pregnancy was collected by maternal interview and obstetric records. When children were aged approximately 12 months information about feeding practices, home environment, physical development of the child and maternal parenting stress and social support was collected via postal questionnaire. Children aged 3.5 years were assessed on measures of cognitive and physical development. Mothers were interviewed regarding the child’s health, diet and development during the early years of life and demographic information was collected regarding the child’s family environment, including socio-economic status [10]. When children were aged 7 years, information was again collected from maternal interview about children’s physical activity, diet, behaviour and health. Mothers and children were assessed when the child was aged 11 years. Maternal interview collected demographic information, information about physical activity, diet and health of the child and maternal measures of stress and social support. Children completed questionnaires regarding bullying, self esteem, depression, headaches, behaviour and emotional difficulties.\n\nThe study received ethical approval at each phase from the Northern regional ethics committee. Signed consent for the study was given by the parents of the children and assent also given by the child.\n\nMeasures\nDrug Use\nData on paracetemol use was obtained by interviewer-administered questionnaires with the mother soon after the birth of her child. Specifically, ascertainment of drug use was obtained by the following question “Did you have any of these medicines or treatments during your pregnancy”. Amongst this list were: a) anti-inflammatories; b) aspirin based pain killers e.g. Aspro, Disprin) other pain killers e.g. Panadol (acetaminophen); d) antacids.\n\nStrengths and Difficulties Questionnaire\nSymptoms of ADHD were measured at ages 7 and 11 years using the parent format of the Strengths and Difficulties Questionnaire (SDQ) and also using the child format at age 11 [11].\n\nCompared with other child behaviour rating scales the SDQ is considered to be a brief measure of child behaviour which inquires about 25 positive and negative emotional and behavioural attributes. Each child is given a score for 5 subscales each consisting of 5 items. The subscales relate to difficulties in conduct, emotion, hyperactivity-inattention, peer group relationships and pro-social behaviour. Each item is scored on a 3 point Likert scale of 0 = ‘not true’, 1 = ‘somewhat true’ and 2 = ‘certainly true’. The total scores for each subscale are calculated by summing scores on items relevant to a particular problem. The SDQ has a test-retest stability of 0.62 after 4 to 6 months and the internal consistencies of the subscales range from 0.62 to 0.75 [12].\n\nThe Total Difficulties score is calculated by summing all four deficit focused subscales (Emotional symptoms; Hyperactivity; Conduct problems; Peer problems). Scores range from 0 to 40. A total of 587 children age 7 years and 614 age 11 years had available data on all five SDQ scales.\n\nConners’ Behavioural Rating Scale: Revised - Long Format (CRS:R-L)\nThe CRS:R-L is a measure of child and adolescent behaviour which is available for children age 6 to 17 years [13]. The CRS: R-L parent questionnaire, used here, consists of 80 items and each item is scored on a four point Likert scale. Responses indicate the extent to which each symptom applies to the target child. Symptoms are scored 0 = ‘not at all true’ 1 = ‘just a little true’, 2 = ‘pretty much true’ and 3 = ‘very much true’. Three of the CRS:R-L subscales relate to the DSM-IV diagnostic criteria for (1) ADHD Inattentive type, (2) ADHD Hyperactive-Impulsive type, and (3) ADHD Combined type. Three subscales referred to as Conners Global Indices (CGI) are also provided (Restless-Impulsive subscale, Emotional Liability, Total subscale reflecting general problematic behaviour). The Conners’ ADHD Index is used to identify a probable diagnosis of ADHD. Total raw scores for each of the CRS: R-L subscales are summed and converted to T-scores, which are standardised by a child’s age and sex [14].\n\nThe CRS-R is one of the most popular of the DSM-IV based rating scales used in research and clinical settings. The parent versions of the CRS:R-L was used here to measure child behaviour, particularly symptoms of ADHD. A total of 575 children aged 7 years had scorable data for the CRS:R-L parent version and 617 children aged 11 years had scorable data.\n\nStatistical analysis\nWe analysed SDQ and Conners scores continuously in univariable analysis using t-tests and logistic regression and for multivariable analysis using generalised linear models to control for potential confounders to assess the differences between those with each medication use during pregnancy and those without. Distributions of both the SDQ and Conners were skewed so we also undertook analyses using log transformed data to confirm the results found using the untransformed data.\n\nMultivariable models were controlled for variables that we have previously reported to be related to ADHD symptoms in children and variables considered to be potential confounders in the relationship between medication use and ADHD symptoms.\n\nAll statistical analyses were carried out for this paper was generated using SAS/STAT software, Version 9.3 of the SAS System for Windows (SAS Institute Inc., Cary, NC, USA). and were tested with a significance level set at p<0.05.\n\nResults\nWe investigated the relationships of the use of acetaminophen (49.8%), anti-inflammatories (1.3%), aspirin (5.3%), antacids (17.4%), and antibiotics (23.5%) in relation to the strengths and difficulties questionnaire at 7 years of age (parent) and 11 years of age (parent and child).\n\nPresented in Table 1 are the descriptive statistics for the SDQ Total Difficulties scores at 7 and 11 years of age by medication taken during pregnancy. We found significantly higher total scores on all 3 SDQ formats if acetaminophen was used during pregnancy, but there were no significant differences associated with any of the other drugs. Additionally to provide a direct comparison with the original analyses we analysed the relationship with the categorical cutoff for defining borderline/abnormal scores. Our power is reduced for this analysis though we found stronger odds ratios at the univariable level than the original study SDQ at 7 (OR = 2.1 95% CI = (0.0, 5.0)), but smaller odds ratios with parent SDQ at 11 (OR = 1.2 95% CI = (0.6, 2.5)) and child SDQ at 11 (OR = 1.0 95% CI = (0.6, 1.6)).\n\n10.1371/journal.pone.0108210.t001Table 1 Means (standard deviations) and differences with 95% confidence intervals (CI) of Strengths and Difficulties Questionnaire (SDQ) Total Difficulties scores at 7 and 11 years of age by medication taken during pregnancy.\n\tPrevalence\tParent SDQ Total at 7\t\tParent SDQ Total 11\t\tChild SDQ Total at 11\t\t\n\t\tYes µ (s.d)\tNo µ (s.d)\tDifference 95% CI\tYes µ (s.d)\tNo µ (s.d)\tDifference 95% CI\tYes µ (s.d)\tNo µ (s.d)\tDifference 95% CI\t\nParecetamol\t49.8%\t8.0 (5.0)\t6.7 (4.6)\t\n1.2 (0.4, 2.0)\n\t7.6 (5.2)\t6.7 (5.0)\t\n0.8 (0.0, 1.6)\n\t10.3 (5.0)\t9.3 (5.0)\t\n0.9 (0.1, 1.7)\n\t\nAnti-inflamatories\t1.3%\t6.2 (3.5)\t7.5 (4.9)\t−1.3 (−3.5, 0.9)\t7.5 (6.8)\t7.2 (5.1)\t0.3 (−2.7, 3.2)\t10.7 (5.3)\t9.9 (5.0)\t0.8 (−2.1, 3.7)\t\nAspirin\t5.3%\t7.9 (5.5)\t7.4 (4.8)\t0.5 (−1.5, 2.4)\t7.8 (6.4)\t7.2 (5.1)\t0.6 (−1.8, 3.0)\t10.2 (5.7)\t9.9 (5.0)\t0.3 (−1.8, 2.4)\t\nAntacids\t17.4%\t7.3 (5.0)\t7.5 (4.8)\t−0.1 (−1.0, 0.7)\t7.3 (5.4)\t7.2 (5.1)\t0.1 (−0.8, 1.0)\t9.6 (4.8)\t10.0 (5.1)\t−0.4 (−1.3,0.5)\t\nAntibiotics\t23.5%\t7.8 (4.8)\t7.3 (4.9)\t0.5 (−0.4, 1.4)\t7.8 (5.3)\t7.0 (5.0)\t0.8 (−0.1, 1.7)\t10.2 (5.0)\t9.8 (5.0)\t0.4 (−0.5, 1.3)\t\nWe further analysed the relationship of acetaminophen on the sub-scales of the SDQ, in univariable and multivariable analyses (controlling for all potential confounders, see Table 2). Notably the acetaminophen use group had higher scores at each age for all difficulty sub-scales and lower scores for the pro-social scales. We found a consistent effect with the total difficulties scale, though the parental scale at 11 did not quite reach statistical significance at the 5% level. Similarly consistent negative effects were seen for the emotional sub-scale with similar effects for the parental SDQ at 7 and 11. Lower scores were also seen for the conduct subscale on the parental SDQ at 7 and the child SDQ at 11.\n\n10.1371/journal.pone.0108210.t002Table 2 Univariable and Multivariable differences of continuous Strengths and Difficulties Questionnaire (SDQ) scores between the offspring of mothers who took acetaminophen in pregnancy and those that did not at 7 and 11 years of age (95% confidence intervals in parentheses).\n\tParent SDQ at 7\tParent SDQ at 11\tChild SDQ at 11\t\n\tUnivariable\tMultivariable*\n\tUnivariable\tMultivariable*\n\tUnivariable\tMultivariable*\n\t\nTotal difficulties\t\n1.2 (0.2, 1.4)\n\t\n1.1 (0.2, 2.0)\n\t\n0.8 (0.0, 1.6)\n\t0.8 (−0.1, 1.8)\t\n0.9 (0.1, 1.7)\n\t\n1.1 (0.2, 2.0)\n\t\nEmotion\t\n0.4 (0.1, 0.7)\n\t\n0.4 (0.0, 0.7)\n\t\n0.5 (0.2, 0.8)\n\t\n0.5 (0.1, 0.9)\n\t\n0.3 (0.0, 0.6)\n\t0.2 (−0.2, 0.6)\t\nConduct\t\n0.3 (0.0, 0.5)\n\t\n0.2 (0.0, 0.5)\n\t0.0 (−0.2, 0.3)\t0.0 (−0.3, 0.3)\t0.1 (−0.2, 0.3)\t\n0.3 (0.0, 0.6)\n\t\nHyperactivity\t0.3 (−0.1, 0.7)\t0.4 (−0.1, 0.8)\t0.1 (−0.2, 0.5)\t0.1 (−0.3, 0.6)\t\n0.4 (0.0, 0.7)\n\t\n0.4 (0.0, 0.8)\n\t\nPeer Esteem\t\n0.3 (0.0, 0.5)\n\t0.1 (−0.2, 0.4)\t0.1 (−0.1, 0.4)\t0.2 (−0.1, 0.5)\t0.2 (−0.1, 0.4)\t0.2 (−0.1, 0.5)\t\nProsocial\t−0.1 (−0.4, 0.2)\t−0.1 (−0.5, 0.2)\t−0.1 (−0.4, 0.2)\t−0.1 (−0.4, 0.3)\t0.0 (−0.2, 0.3)\t0.0 (−0.3, 0.3)\t\n *Controlled for SGA status, sex, age mother left school, maternal smoking during pregnancy, paternal smoking during pregnancy, marital status at birth, parity, socio-economic status, maternal pre-pregnancy BMI, maternal stress in the last month of pregnancy, alcohol consumption in the first trimester, living with the child’s biological father at 3.5 and child activity levels at 3.5, high fever during pregnancy, visiting GP for psychological conditions including depression and anxiety, taking medication during pregnancy for psychological conditions.\n\nAdditionally the effects of acetaminophen on the Conners scales showed similar results at 7 years of age (see Table 3). This showed consistently higher (poorer) scores for all but the DSM IV inattentive score and DSM IV inattentive symptoms at 7 years of age. Likewise there were higher scores with all scales for the acetaminophen group for the 11 year old data. However, only the DSM IV- hyperactive impulsive scores at 11 showed a statistically significant difference at the univariable level.\n\n10.1371/journal.pone.0108210.t003Table 3 Univariable and Multivariable differences of continuous parental Conners’ scores between the offspring of mothers who took acetaminophen in pregnancy and those that did not at 7 and 11 years of age (95% confidence intervals in parentheses).\n\tParent Conners at 7\tParent Conners at 11\t\n\tUnivariable\tMultivariable*\n\tUnivariable\tMultivariable*\n\t\nConners ADHD index\t\n1.6 (0.3, 2.9)\n\t1.5 (−0.1, 3.0)\t0.8 (−0.5, 2.1)\t0.5 (−1.1, 2.1)\t\nCGI restless-impulsive\t\n2.1 (0.7, 3.6)\n\t\n2.1 (0.4, 3.7)\n\t0.3 (−1.1, 1.6)\t−0.1 (−1.7, 1.6)\t\nCGI emotional lability\t\n2.6 (1.1, 4.1)\n\t\n3.0 (1.3, 4.7)\n\t1.2 (−0.3, 2.6)\t0.6 (−1.1, 2.4)\t\nCGI total\t\n2.5 (1.1, 3.9)\n\t\n2.6 (1.0, 4.2)\n\t0.6 (−0.7, 1.9)\t0.1 (−1.5, 1.8)\t\nDSM IV inattentive\t1.1 (−0.2, 2.4)\t0.7 (−0.8, 2.2)\t0.6 (−0.8, 2.0)\t0.2 (−1.5, 1.9)\t\nDSM IV- hyperactive impulsive\t\n2.0 (0.5, 3.5)\n\t\n2.0 (0.3, 3.6)\n\t\n1.2 (0.0, 2.5)\n\t1.3 (−0.2, 2.7)\t\nDSM-IV total\t\n1.6 (0.3, 3.0)\n\t1.5 (−0.1, 3.0)\t1.0 (−0.3, 2.3)\t0.8 (−0.7, 2.3)\t\nDSM inattentive symptoms\t0.0 (−0.1, 0.2)\t0.0 (−0.2, 0.1)\t0.0 (−0.1, 0.2)\t0.0 (−0.2, 0.2)\t\nDSM hyperactive-impulsive symptoms\t\n0.2 (0.0, 0.4)\n\t\n0.2 (0.0, 0.4)\n\t\n0.1 (0.0, 0.2)\n\t0.1 (−0.1, 0.2)\t\n *Controlled for SGA status, sex, age mother left school, maternal smoking during pregnancy, paternal smoking during pregnancy, marital status at birth, parity, socio-economic status, maternal pre-pregnancy BMI, maternal stress in the last month of pregnancy, alcohol consumption in the first trimester, living with the child’s biological father at 3.5 and child activity levels at 3.5, high fever during pregnancy, visiting GP for physchological conditions includingdepression and anxiety, taking medication during pregnancy for psychological conditions.\n\nDiscussion\nIn this New Zealand birth cohort study with prospective follow up we found that the children of mothers who used acetaminophen during pregnancy were at increased risk of having symptoms of ADHD as defined by screening questionnaires (the SDQ and Connors Rating System) at 7 and 11 years of age. These findings strengthen the contention that acetaminophen exposure in pregnancy increases the risk of ADHD-like behaviours, as published by Liew et al [1]. Our study also supports the earlier report that the findings are specific to acetaminophen, as there were no associations found with other commonly used drugs in pregnancy (aspirin, antacids and antibiotics).\n\nMore specifically, there was a significant effect of acetaminophen use on parent scored SDQ total difficulties at age 7 after controlling for potential confounders. Particularly problematic at age 7 were emotional and conduct problems. Child- but not parent-reported total difficulties at age 11 remained significant in multivariable analyses. Child-reported problems with conduct and hyperactivity/inattention were particularly salient. The hyperactivity-inattention subscale consists of the following items: ‘restless, overactive, cannot stay still for long’, ‘constantly fidgeting or squirming’, ‘easily distracted, concentration wanders’, ‘can stop and think things out before acting’ and ‘sees tasks through to the end, good attention span’.\n\nThere was also a significant effect of acetaminophen use on parent scored CRS:R-L ADHD symptoms at age 7 after controlling for the potential confounders. These were specific to subscales relating to the DSM-IV diagnostic criteria for ADHD Hyperactive-Impulsive type. Other subscales showing a significant multivariable effect included the CGI Restless-Impulsive subscale (indicates symptoms of restlessness, impulsivity and inattentiveness) and the CGI Emotional Liability subscale (identifies individuals who are prone to emotional responses and behaviours than would be expected to be typical, such as outbursts of crying or anger). Interestingly, for the CRS:R-L the association between acetaminophen use during pregnancy and parent-reported ADHD symptoms was not consistent at 11 years. It is not clear why the finding did not remain significant.\n\nIt is also not clear why the SDQ child reported ADHD symptoms remained significant at age 11 but not parent-reported problems. Self-reported problem behaviour has been shown to be a more valid indicator of mental and physical health than parent-reported problems [15]–[17]. It is also well known that ADHD has a complex etiology. It could be that other, more positive and enriching, environmental exposures begin to dilute the neurological outcome of acetaminophen over time. Acetaminophen was hypothesized to act as a hormone disrupter and thus alter fetal brain development [1]. Unfortunately we do not yet have data relating to ADHD symptoms measured after puberty. We also did not have information on dosage of acetaminophen use or trimester of use. Early life acetaminophen exposure may be significant determinants ADHD only at higher doses of the pain killer. In addition, other environmental factors not measured may also act through epigenetics to modify disease risk and neurological outcomes. More research is needed to provide a more precise assessment of risk and consequences of acetaminophen use during pregnancy.\n\nOther limitations should be considered while interpreting our results. Firstly, the follow-up rate of 59 to 70% of the original population is clearly a potential source of bias. Nonetheless, this is unlikely to cause any systematic bias because the percentage of SGA and AGA children remained steady at all phases of the study- at 41and 59% respectively. Secondly, because data was only obtained from European mothers and offspring, generalization of the results should be limited to children of European ethnicity. Thirdly, selection bias may be a problem if one or both of the parents also had ADHD. Unfortunately we have no information on the ADHD status of the parents.\n\nA strength of this study is that the longitudinal design of the research was sampled prospectively and the analyses controlled for a wide range of factors that might influence medication-taking in pregnant mothers (e.g., reported fever, inflammatory problems) and ADHD symptoms in offspring (e.g., birthweight, antenatal smoking and alcohol use). Interestingly controlling for all these factors had little effect on the size of the effect. In addition to the Danish study, we were also able to support the outcomes of the SDQ with more specificity by using the CRS-R parent report at both 7 and 11years. We were also were able to control for the effect of antenatal perceived stress.\n\nThere is a balance of weighing up the risk associated with taking acetaminophen during pregnancy and that of not taking it in the presence of potentially serious conditions such as maternal fever. In this study the reported prevalence of maternal fever in pregnancy was less than 5%, compared to approximately 50% who took acetaminophen during pregnancy.\n\nThe ABC study group also includes Mrs Elizabeth Robinson, Dr David Becroft and Professor Chris Wild. We acknowledge the assistance of Gail Gillies, Barbara Rotherham, and Helen Nagels for contacting or assessing the participants. We sincerely thank the parents and children for participating in this study.\n==== Refs\nReferences\n1 Liew Z, Riutz B, Rebordosa C, Lee PC, Olsed J (2014) Acetaminophen use during pregnancy, behavioural problems, and hyperkinetic disorders. JAMA Pediat. Doi:10.1001/jamapediatrics.2013.4914.\n2 \nLinnet KM , Wisborg K , Agerbo E , Secher N-J , Thomsen PH , et al (2006 ) Gestational age, birth weight, and the risk of hyperkinetic disorder . Arch Dis Child \n91 : 655 –660 .16754656 \n3 \nBhutta AT , Cleves MA , Casey PH , Cradock MM , Anand K (2002 ) Cognitive and behavioral outcomes of school-aged children who were born preterm - A meta-analysis . JAMA \n288 : 728 –737 .12169077 \n4 \nMannuza S , Klein RG , Moulton JL , Kessler RC , Aguilar-Gaxiola S , et al (2003 ) Persistence of attention-deficit hyperactivity disorder into adulthood: What have we learned from the prospective follow-up studies? \nJ Atten Disord \n7 : 93 –100 .15018358 \n5 \nWerler MM , Mitchell AA , Hernandez-Diaz S , Honein MA (2005 ) Use of over-the-counter medications during pregnancy . Am J Obstet Gynecol \n193 : 771 –777 .16150273 \n6 Cooper M, Langley K, Thapar A (2014) Antenatal acetaminophen use and attention-deficit/hyperactivity disorder: An interesting observed association but too early to infer causality. JAMA Pediat. Doi:10.1001/jamapediatrics.2013.4914.\n7 \nVan den Bergh B , Marcoen A (2004 ) High antenatal maternal anxiety is relatied to ADHD symptoms, externalizing problems and anxiety in 8- and 9-year-olds . Child Development \n75 : 1085 –1097 .15260866 \n8 \nRodriguez A , Bohlia G (2005 ) Are maternal smoking and stress during pregnancy related to ADHD symptoms in children? \nJ Child Psych Psychiatr \n46 : 246 –254 .\n9 \nThompson JM , Clark PM , Robinson E , Becroft DM , Pattison NS , et al (2001 ) Risk Factors for Small-For-Gestational-Age Babies: The Auckland Birthweight Collaborative Study . J Pediatr Child Health \n37 : 369 –375 .\n10 \nElley WB , Irving JC (1985 ) The Elley-Irving socioeconomic index 1981 census revision . NZ J Ed Studies \n20 : 115 –128 .\n11 \nGoodman R (1999 ) The extended version of the Strengths and Difficulties Questionnaire as a guide to child psychiatric caseness and consequent burden . J Child Psych Psychiatr Allied Disciplines \n40 : 791 –799 .\n12 \nGoodman R (2001 ) Psychometric Properties of the Strengths and Difficulties Questionnaire . J American Child Adolesc Psychiatr \n40 : 1337 –1345 .\n13 Conners CK (2001) Development of the CRS-R. In Conners CK, Ed. Conners’ Rating Scales-Revised (pages 83–98). North Tonawanda, NY: Multi-Health Systems.\n14 \nConners CK , Sitarenios G , Parker JD , Epstein JN (1998 ) The revised Conners’ Parent Rating Scale (CPRS-R): factor structure, reliability, and criterion validity . J Abnorm Child Psychol \n26 : 257 –268 .9700518 \n15 \nMcDougall J , Bedell G , Wright V (2013 ) The youth report version of the Child and Adolescent Scale of Participation (CASP): Assessment of psychometric properties and comparison with parent report . Child: Care, Health & Development \n39 : 512 –522 .\n16 \nShoval G , Mansbach-Kleinfeld I , Farbstein I , Kanaaneh R , Lubin G , et al (2013 ) Self versus maternal reports of emotional and behavioral difficulties in suicidal and non-suicidal adolescents: an Israeli nationwide survey . European Psychiatr: J Assoc European Psychiatrists \n28 : 235 –239 .\n17 \nAchenbac T , McConaughy S , Howell C (1987 ) Child and adolescent behavioural and emotional problems: implications of cross-informant correlations for situational specificity . Psychol Bull \n101 : 2 .\n\n",
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"title": "Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years.",
"title_normalized": "associations between acetaminophen use during pregnancy and adhd symptoms measured at ages 7 and 11 years"
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{
"abstract": "Intravitreous injections of anti-vascular endothelial growth factor (VEGF) agents are associated with a sustained increase in intraocular pressure. This sustained elevated intraocular pressure could lead to higher rates of glaucoma surgery to lower this pressure.\n\n\n\nTo determine the risk of glaucoma surgery following repeated intravitreous bevacizumab injections.\n\n\n\nThis nested, case-control study acquired and analyzed data from large, population-based, linked health databases supported by the British Columbia Ministry of Health in Canada. Study participants included all patients with ophthalmic issues in British Columbia, such as those of the Provincial Retinal Diseases Treatment Program, who had received intravitreous bevacizumab injections for exudative age-related macular degeneration between January 1, 2009, and December 31, 2013. Cases were identified using glaucoma surgical codes for trabeculectomy, complicated trabeculectomy, glaucoma drainage device, and cycloablative procedure. For each case, 10 controls were identified and matched for age, preexisting glaucoma, calendar time, and follow-up time. The number of intravitreous bevacizumab injections received per year-3 or fewer, 4 to 6, or 7 or more-was determined for both cases and controls. Data analysis was performed from February 23, 2016, to November 14, 2016.\n\n\n\nRisk of glaucoma surgery compared with the number of intravitreous bevacizumab injections per year in cases and controls. Rate ratios were adjusted for covariates (diabetes mellitus, myocardial infarction, stroke, and verteporfin use).\n\n\n\nSeventy-four cases of glaucoma surgery and 740 controls were identified, with a mean (SD) age of 81.3 (8.4) years for cases and 81.4 (7.9) for controls. The case group had more males than the control group (38 [51.4%] vs 272 [36.8%]). The adjusted rate ratio of glaucoma surgery among those who received 7 or more injections per year was 2.48 (95% CI, 1.25-4.93). There was a 10.3% higher number of 7 or more injections among cases compared with controls. The adjusted rate ratio for those who received 4 to 6 injections per year compared with those who received 3 or fewer was 1.65% (95% CI, 0.84-3.23).\n\n\n\nFindings from this large, pharmacoepidemiologic study suggest that 7 or more intravitreous injections of bevacizumab annually is associated with a higher risk of glaucoma surgery and that 4 to 6 injections per year show a nonstatistically significant rate ratio in the same direction.",
"affiliations": "Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.;Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada3Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada4Pharmaceutical Outcomes Programme, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.;Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.",
"authors": "Eadie|Brennan D|BD|;Etminan|Mahyar|M|;Carleton|Bruce C|BC|;Maberley|David A|DA|;Mikelberg|Frederick S|FS|",
"chemical_list": "D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaophthalmol.2017.0059",
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"issue": "135(4)",
"journal": "JAMA ophthalmology",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D001955:British Columbia; D016022:Case-Control Studies; D005260:Female; D005901:Glaucoma; D020327:Glaucoma Drainage Implants; D006801:Humans; D007429:Intraocular Pressure; D058449:Intravitreal Injections; D008297:Male; D017891:Pharmacoepidemiology; D019919:Prosthesis Implantation; D019233:Retreatment; D012307:Risk Factors; D014130:Trabeculectomy; D042461:Vascular Endothelial Growth Factor A; D057135:Wet Macular Degeneration",
"nlm_unique_id": "101589539",
"other_id": null,
"pages": "363-368",
"pmc": null,
"pmid": "28301639",
"pubdate": "2017-04-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20381871;20187807;19700194;23084240;26522708;19525685;19376495;7851330;18425523;22791273;23173135;17021319;26820610;24814167;22788585;22330964;25233052;25719991;21159147;17386270;20702430;17021318;24406814;26701272;19485295;24141714;22474205;25369256;17962821;25692915;22990314;22440275;20398941;21836409",
"title": "Association of Repeated Intravitreous Bevacizumab Injections With Risk for Glaucoma Surgery.",
"title_normalized": "association of repeated intravitreous bevacizumab injections with risk for glaucoma surgery"
} | [
{
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"reaction": [
{
"reactionmeddrapt": "Glaucoma",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
"summary": null
},
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"literaturereference": "EADIE B, ETMINAN M, CARLETON B, MABERLEY D AND MIKELBERG F. ASSOCIATION OF REPEATED INTRAVITREOUS BEVACIZUMAB INJECTIONS WITH RISK FOR GLAUCOMA SURGERY. JAMA OPHTHALMOLOGY 2017 MAR 16;:E1-E6.",
"literaturereference_normalized": "association of repeated intravitreous bevacizumab injections with risk for glaucoma surgery",
"qualification": "1",
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},
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{
"abstract": "Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.",
"affiliations": "University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;MD Anderson Cancer Center, Houston, TX, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA.;University of Washington, Seattle, WA, USA. achapuis@fredhutch.org.",
"authors": "Paulson|K G|KG|;Voillet|V|V|;McAfee|M S|MS|;Hunter|D S|DS|;Wagener|F D|FD|;Perdicchio|M|M|;Valente|W J|WJ|http://orcid.org/0000-0002-9330-944X;Koelle|S J|SJ|;Church|C D|CD|;Vandeven|N|N|;Thomas|H|H|;Colunga|A G|AG|;Iyer|J G|JG|;Yee|C|C|;Kulikauskas|R|R|;Koelle|D M|DM|http://orcid.org/0000-0003-1255-9023;Pierce|R H|RH|;Bielas|J H|JH|;Greenberg|P D|PD|;Bhatia|S|S|;Gottardo|R|R|http://orcid.org/0000-0002-3867-0232;Nghiem|P|P|http://orcid.org/0000-0003-2784-963X;Chapuis|A G|AG|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D061025:Costimulatory and Inhibitory T-Cell Receptors",
"country": "England",
"delete": false,
"doi": "10.1038/s41467-018-06300-3",
"fulltext": "\n==== Front\nNat CommunNat CommunNature Communications2041-1723Nature Publishing Group UK London 630010.1038/s41467-018-06300-3ArticleAcquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA Paulson K. G. 123Voillet V. 2McAfee M. S. 2Hunter D. S. 2Wagener F. D. 2Perdicchio M. 26http://orcid.org/0000-0002-9330-944XValente W. J. 2Koelle S. J. 12Church C. D. 1Vandeven N. 1Thomas H. 1Colunga A. G. 1Iyer J. G. 1Yee C. 4Kulikauskas R. 1http://orcid.org/0000-0003-1255-9023Koelle D. M. 125Pierce R. H. 2Bielas J. H. 12Greenberg P. D. 12Bhatia S. 123http://orcid.org/0000-0002-3867-0232Gottardo R. 12http://orcid.org/0000-0003-2784-963XNghiem P. 123Chapuis A. G. achapuis@fredhutch.org 1231 0000000122986657grid.34477.33University of Washington, Seattle, WA USA 2 0000 0001 2180 1622grid.270240.3Fred Hutchinson Cancer Research Center, Seattle, WA USA 3 0000 0004 0431 6950grid.430269.aSeattle Cancer Care Alliance, Seattle, WA USA 4 0000 0001 2291 4776grid.240145.6MD Anderson Cancer Center, Houston, TX USA 5 0000 0001 2219 0587grid.416879.5Benaroya Research Institute, Seattle, WA USA 6 0000 0004 0374 1269grid.417570.0Present Address: Roche, Basel, Switzerland 24 9 2018 24 9 2018 2018 9 386811 5 2018 15 8 2018 © The Author(s) 2018Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor–immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.\n\nAcquired resistance is a major problem in cancer immunotherapy. Here the authors report a study of two patients with Merkel cell carcinoma under immunotherapy treatment who develop resistance after deep responses for >1 year and identified a novel mechanism of acquired, gene-specific transcriptional suppression of HLAs.\n\nissue-copyright-statement© The Author(s) 2018\n==== Body\nIntroduction\nImmunotherapy has recently entered the cancer mainstream with the widespread use of immune checkpoint inhibitors (ICIs)1–4. However, despite many impressive responses, the majority of cancers treated are either unresponsive or develop late/acquired resistance5–7. Understanding resistance is critical but complex, as tumor–immune interfaces include multiple cell populations and many target antigens8. Among the small number of cancers for which resistance mechanisms have been conclusively determined, genetic loss of antigen presentation to CD8+ T cells has often been identified9. Intriguingly, a recent report suggested that, in low antigen burden tumors, genetic loss of a single human leukocyte antigen (HLA) allele is associated with checkpoint inhibitor resistance, supporting the concept that T cells recognizing very few epitopes may mediate an immunotherapy response10. However, most tumors resistant to checkpoint inhibitor immunotherapy lack a readily identifiable genetic means of resistance, suggesting transcriptional (and potentially reversible) escape mechanisms may be at play.\n\nAdoptive cellular immunotherapy for solid tumors offers a defined T cell population and a defined antigen, and we thus hypothesized that detailed longitudinal investigation of patients who developed late/acquired resistance to autologous endogenous T cell therapy combined with ICIs might help broadly inform immunotherapy resistance. We focused on patients with Merkel cell carcinoma (MCC), an aggressive skin cancer typically caused by the Merkel cell polyomavirus (MCPyV)11–13, because of the immunotherapy responsiveness6,14,15, exceptionally low mutational/neoepitope burden16–18 and highly expressed, defined conserved viral antigens11,19,20. We first interrogated tumors from a discovery/index patient: a 59-year-old man with widely metastatic heavily pre-treated MCC whom we treated with autologous ex vivo expanded CD8+ T cells recognizing a newly described HLA-B restricted allele of MCPyV followed by checkpoint inhibitors. After a 22 month response, tumors relapsed. The targeted antigen, infused T cells, and immunohistochemistry staining for pan-HLA-ABC were all present, rendering the mechanism of escape occult. We then performed single cell RNA sequencing that revealed selective loss of HLA-B at the time of acquired resistance, which we found to be transcriptional and reversible. In a second validation patient, treated with HLA-A restricted CD8+ T cells and ICIs, MCC relapsed after an 18 month response with transcriptional loss of HLA-A, supporting the reproducibility of this escape. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and has implications for the design of effective immunotherapy combinations to rescue patients from late/acquired immunotherapy resistance.\n\nResults\nTreatment of discovery patient with MCPyV-specific T cells\nUsing a peptide pool based screening approach, we identified a novel HLA-B*3502-restricted epitope in MCPyV sT-Ag oncoprotein (MCPyV-sT83-91; Methods; Supplementary Fig. 1)20. A 59-year-old man expressing HLA-B*3502+ (referred for simplicity as discovery patient, 2586-4) presented with widely metastatic MCPyV-associated MCC that was refractory to >5 prior therapies, including one infusion of pembrolizumab, an anti-PD-1 ICI6. The patient underwent leukapheresis, from which MCPyV-sTAg-specific polyclonal endogenous CD8+ T cells were expanded by stimulation with autologous dendritic cells pulsed with the MCPyV-sT83-91 (NCT01758458; Supplementary Fig. 2)21. Several metastases were irradiated to upregulate pan class I HLA (Methods; Supplementary Fig. 3)21,22, with remaining disease unmanipulated for monitoring. MCPyV-specific CD8+ T cells were infused (1010 cells per m2) on day 0 and again 33 days later. Toxicities included transient fevers lasting <24 h, requiring only supportive care on the general ward (Supplementary Table 1). Since his tumors enlarged, pembrolizumab and ipilimumab23, an anti-CTLA-4 ICI, were added, followed by regression (Fig. 1a, b, Supplementary Fig. 3). Tumors shrank by >90%, with symptomatic improvement, and the patient returned to work. Twenty-two months after T cell infusion and in the context of ongoing ICI therapy, the patient relapsed, indicating late/acquired immunotherapy resistance.Fig. 1 Acquired resistance to combination immunotherapy. T cell infusions indicated by dashed lines. a Clinical course. b Immunotherapy treatments. c T cell persistence. CD8+ T cell persistence by MCPyV-sT83-91 tetramer is on left axis (green line) and frequency of dominant infused clone by CDR3-beta sequencing on right axis (blue line; this clonotype was 85% of the infusion product). d Evaluation of tumor at acquired resistance/late relapse (post-treatment day + 832): Left: Immunohistochemistry demonstrating expression of MHC class I (pan-HLA–ABC) in tumor (T) and epidermis (E) and MCPyV T antigen in tumor. Scale bar indicates approximately 100 micrometers. Right: sequence of the targeted MCPyV-sT83-91 epitope was unmutated. Discovery patient (2586-4) is shown\n\n\n\nInfused CD8+ T cells persisted in peripheral blood at relapse\nDuring the clinical response, infused, virus-specific CD8+ cells persisted in the peripheral blood (Fig. 1c, Supplementary Fig. 4) and no other virus-specific CD8+ or CD4+ T cells recognizing alternate epitopes in MCPyV were detected (Supplementary Fig. 5)19,20. At relapse, antigen-experienced MCPyV-specific CD8+ cells abundantly persisted in the peripheral blood (>25% of CD8+ cells) and their immunophenotype was similar to the time of response (Fig. 1c, Supplementary Fig. 4).\n\nTumor resistance mechanism remained unclear by standard evaluations\nBiopsy of a relapsed tumor (new tumor on lower leg; day + 832; not previously irradiated) revealed preserved expression of HLA-ABC and of MCPyV oncoproteins by immunohistochemistry (Fig. 1d). DNA sequencing (whole exome and MCPyV) detected several tumor-associated/somatic mutations (e.g., PTEN) in the pre-treatment tumor, but no additional mutations explaining immune escape at acquired resistance, including no mutations or loss of-heterozygosity in the HLA-B gene, sequenced HLA-B promoter region, or targeted MCPyV epitope (Fig. 1d, Supplementary Data 1, Supplementary Table 2). Given the absence of an identifiable genomic basis, we explored transcriptional regulation as a mechanism for tumor escape.\n\nscRNAseq of blood revealed T cell activation at response\nWe first assessed the activity of infused T cells by performing single cell RNA sequencing (scRNAseq) with whole-transcriptome expression analysis on serial PBMCs using the 10x Genomics platform24 (n = 11,021 cells; Methods). Overlay of analyses at four time-points (pre-treatment, early post treatment day + 27, responding post treatment day + 376, relapse/acquired resistance post treatment day + 614) revealed overlap of all clusters, indicating similarity between the processed cells and endogenous CD8+ T cells (Supplementary Fig. 6). Unsupervised clustering distinguished CD8+, CD4+, NK, B, and dendritic cells, and monocytes (Fig. 2a, Supplementary Fig. 7)25. Three CD8+ T cell clusters were identified: naïve/central memory, effector memory/effector, and an activated effector population significantly enriched at response, which overexpressed glycolysis (GAPDH, mitochondrial RNAs) and other activation (IL32; actin) transcripts relative to the effector memory/effector cells (Fig. 2b–d; Supplementary Table 3)26–28, while maintaining an expression profile otherwise consistent with traditional effector CD8+ T cells (expression of granzymes and perforins without CCR7 or IL7R expression; Supplementary Fig. 7).Fig. 2 scRNAseq of PBMC identifies an activated CD8+ T cell population at response. Four peripheral blood time points are shown, all from the discovery patient (2586-4): pre-treatment, early post-treatment (day + 27), treatment response (day + 376), and late/acquired resistance (day + 614). a t-Stochastic Neighbor Embedding (tSNE) visualization of clustering of peripheral blood. Peripheral blood mononuclear cells (PBMC; n = 11,021) clustered into populations as indicated. Representative marker genes shown in Supplementary Fig. 7. b, c Enrichment of cluster of activated CD8+ lymphocytes (red cluster, arrow) at response to immunotherapy. Clustering biostatistical analysis described in detail in the Methods, and proportion of CD8+s in each cluster at the various time points compared with Fisher’s exact test. d Heat map of selected significantly differentially expressed genes comparing CD8+ T cells in the red activated cluster (n = 170) to those in the blue effector/EM cluster (n = 429) at response (day + 376). For full list of all 45 differentially expressed genes, see Supplementary Table 3\n\n\n\nActivated CD8+ T cells infiltrated the responding tumor\nIn tumor biopsies at time of treatment response and concurrent to the presence of activated CD8+ cells in blood (day + 349), CD8+ T cells expressing the activation marker HLA-DR newly infiltrated the previously T cell “cold”, now shrinking MCC (Fig. 3a, b)29,30. The dominant CD8+ cell clonotype in the infusate identified by its unique CDR3-beta was also dominant in regressing metastases (Fig. 3c)31, implicating infused CD8+ cells as the likely mediators of tumor regression. At a later biopsy after acquired resistance (day + 832), CD8+ T cells were absent from the relapsing tumor. This finding, combined with the presence of quiescent T cells in the peripheral blood identified by scRNAseq, suggests tumor specific CD8+ T cells were no longer encountering antigen (Figs. 2 and 3).Fig. 3 Activated CD8+ T cell infiltration into tumor at the time of treatment response. a Multiplex immunohistochemistry showing representative peritumoral and intratumoral CD8+ infiltrates. Arrows indicate CD3+CD8+ cells (not all indicated). Dark blue = DAPI (nuclei), Light blue = CD56 (MCC tumor), Red = CD3+CD8–, Green = CD8+, Purple = HLA-DR. Three timepoints are shown from the discovery patient (2586-4): pre-treatment, post-treatment response (day + 349), and late/acquired resistance (day + 832). b Quantification of density of peritumoral and intratumoral CD8 cells. Three representative microscope scan areas were digitally scored for each patient, and significant differences in density determined with student’s T test. c Detection of infused T cell clonotypes in tumor at time of treatment response by sequencing of TCR CDR3-beta\n\n\n\nscRNAseq of relapsed tumor revealed HLA-B downregulation\nTo define the mechanism of late/acquired resistance, scRNAseq was performed on viably frozen tumor digests (Fig. 4a; n = 7431 cells), from pre-treatment and acquired resistance (D + 615) time points. Although bulk/unsorted cells were assessed together, scRNAseq tSNE unsupervised clustering permitted segregation and simultaneous analysis of tumor, macrophage, B lymphocyte, T lymphocyte, fibroblast and endothelial populations (Supplementary Fig. 8). The transcriptome of non-tumor clusters before and at late/acquired resistance were superimposable, implying changes in these microenvironment cells were not driving immune evasion. In contrast, MCC tumor cells demonstrated marked transcriptional change, visualized by distinct spatial separation of pre-treatment and relapsed tumor cells in tSNE plots (Fig. 4a, b), with 255 differentially expressed genes (Methods; Supplementary Data 2). These included many expected to be overexpressed in a multiply-recurrent cancer (e.g., cell cycle), but also defined the immune escape. Specifically, MCC tumor significantly downregulated HLA-B, but not HLA-A at acquired resistance (Fig. 4c, d, Supplementary Fig. 9). This implies intense immunologic and selective pressure from the transferred HLA-B*3502-restricted CD8+ cells. HLA-B loss was exclusive to tumor cells and undetectable by standard HLA-ABC immunohistochemistry (Fig. 1d). To exclude sampling bias, tumor from a second post-resistance biopsy (day + 832) was obtained and qPCR reaffirmed HLA-B downregulation (Fig. 4e).Fig. 4 scRNAseq of tumor biopsies. a–e Discovery patient (2586-4). f, g Validation patient (9245-3). h Both patients. a tSNE of viably frozen cells (n = 7431) from tumor biopsies obtained pre-treatment (blue) and at late relapse/acquired resistance (day + 615; orange). Marked spatial separation of tumor cells from the two timepoints indicates substantial transcriptional change. b Heat map of selected significantly differentially expressed genes (DEGs) in tumor clusters. For full table of DEGs, see Supplementary Data 2. c tSNE of HLA-B expression. d Differential change in scRNAseq expression of HLA-A, -B by tumor cells. HLA (HLA-A, HLA-B) and time point (pre: pre-treatment, rel: acquired resistance/relapse) are indicated below. e qPCR validation and reversibility of HLA-B downregulation on a repeat tumor biopsy at time of acquired resistance, day + 832, graphed on a log2 scale. Tumor cells were cultured ex vivo for 48 h before RNA collection with either vehicle control (–), interferon gamma (1000 IU/mL; IFN) or the hypomethylating agent 5-azacytidine (1 μM; 5-aza) as indicated below. Bars represent mean and error bars represent range of two experimental runs, each performed with triplicate wells. f tSNE of specimens from late relapse in the validation patient (day + 565 post treatment). Viably frozen cells (n = 11267) from PBMC (pink) and tumor biopsy (blue) at late relapse/acquired resistance. Patient had received HLA-A-restricted CD8+ T cells with 18 months response followed by relapse (Supplemental Figures 10 and 11). g tSNE of HLA-A expression. h Differential expression of targeted and non-targeted HLA on relapsed tumor for both patients. Proportion MCC cells expressing gene by scRNAseq are indicated. Data for discovery patient (2586-4) are reproduced from panel 4d for clarity. Please see Methods section for details of scRNAseq biostatistical analysis and determination of DEGs\n\n\n\nHLA-B transcription was restored with hypomethylating agents\nWe next sought to determine whether transcriptional downregulation of HLA-B was reversible. We were able to successfully establish short term ex vivo cultures but not a cell line. In ex vivo cultures, HLA-B loss was reversible with either pharmacologic doses of interferon-γ or the hypomethylating agent 5-azacitadine, consistent with transcriptional downregulation22,32.\n\nIdentification of and clinical course of second validation patient\nTo validate our findings, we sought to perform similar analyses on a second patient, preferably treated with MCPyV-specific T cells restricted to a different class I HLA. Out of all patients previously treated at our institution with both MCPyV-specific T cells and ICIs, we identified one additional patient with early response and late/acquired immunotherapy resistance. Patient 9245-3, referred to as validation patient for simplicity, was treated with MCPyV-specific CD8+ T cells and checkpoint inhibition, this time with T cells restricted to HLA-A2 and avelumab (anti-PD-L1) as checkpoint inhibition (Supplementary Fig. 10; NCT0258482)14,15. This validation patient had an 18 month response to combined immunotherapy, during which he achieved complete regression by radiographic and pathologic assessment. However, at the 18 month time point, he relapsed at a single tumor site, and tumors were excised (day + 565 post-treatment). Resistant tumor expressed MCPyV T antigen and had detectable pan-HLA-ABC by immunohistochemistry (Supplementary Fig. 10).\n\nT cells infiltrated tumor during treatment response in the validation patient\nWe interrogated the T cell infiltration in the microenvironment for the validation patient. Prior to T cell therapy, the tumor was T cell cold (Supplementary Fig. 11). However, during response (day + 14), the tumor became T cell hot with intratumoral enrichment of tumor-specific CD8+ T cells (Supplementary Fig. 11). At acquired resistance (day + 565), CD8+ T cells were no longer infiltrating intratumorally but instead were excluded to the tumor periphery. At that time, infused HLA-A2 restricted T cell persisted at low levels in the microenvironment (Supplementary Fig. 11).\n\nscRNAseq of tumor revealed HLA-A transcriptional downregulation\nFor the validation patient, tumor tissue was only available in viably frozen format from a time of late/acquired resistance (day + 565). Therefore, scRNAseq using the 10x genomics 5′ platform was performed on this resistant tumor (n = 5397 cells), along with matched peripheral blood (n = 5870 cells; day + 559; Fig. 4f-h, Supplementary Fig. 12) to provide additional comparative tissue. We again observed selective transcriptional downregulation of the targeted HLA (HLA-A; Fig. 4g) in the tumor cells, without changes in the HLA-A DNA sequence as determined by whole exome sequencing (Supplementary Table 4). Attempts to culture tumor from the validation patient were unsuccessful in both short term and long-term cultures, and thus reversibility with interferon-γ and 5-azacitidine could not be tested.\n\nDiscussion\nLate/acquired resistance stands as a barrier to immunotherapy cure. We performed detailed investigation on two patients who had received T cell immunotherapy along with ICIs; these patients both had sustained immunotherapy responses followed by late/acquired resistance. We observed infiltration of infused CD8+ T cells into shrinking MCC tumors, supporting T cell mediated regression. In both cases, when tumors relapsed, there was apparent selective transcriptional downregulation of the HLA restricting the targeted MCPyV epitope.\n\nImmune avoidance by genetic loss of single or all class I HLAs has been described as a mechanism of resistance to cellular immune therapies33 and anti-PD-1 checkpoint inhibitors9,10.\n\nImmunotherapy escape by genetic HLA loss is important to distinguish from immunotherapy escape by transcriptional HLA loss as we observed here. In the former, the HLA alleles are deleted and new T cell responses must necessarily be targeted to alternate HLAs to overcome immunotherapy resistance. In the latter, tumor-specific HLA suppression is potentially reversible with drug therapy. Transcriptional suppression of all class I HLA genes in a coordinated fashion has been described previously by our group and others for MCC22,32. This has also been described as a mechanism of melanoma early34 and, in a single case, late immunotherapy resistance35. Differential transcriptional suppression of the targeted class I HLA genes as a mechanism of late immunotherapy resistance demonstrates immunotherapy responses can be driven by T cells restricted to a single HLA. Additionally, such resistance cannot be readily detected by pan-HLA-ABC immunohistochemistry, indicating this mechanism might have been underappreciated previously.\n\nOur study had limitations. Attempts to generate tumor-derived cell lines for additional functional studies were unsuccessful on both patients. We could not differentiate if acquired resistance represented immunoediting, i.e., outgrowth of a pre-existing previously rare or quiescent clone, or was new transcriptional suppression that developed after immunotherapy. In either scenario, immune pressure from the transferred CD8+ T cells revealed selective HLA downregulation that was transcriptional, and in at least one patient reversible.\n\nHere we employ scRNAseq on thousands of cells to demonstrate strong immune pressure mediated by ICIs and transferred CD8+ T cells recognizing a single tumor epitope, and identify a novel mechanism of immunotherapy escape by selective transcriptional loss of the targeted HLA under T cell pressure, which is rendered possible based on established differential regulation of HLA-A and -B genes36. This has therapeutic implications for rescue as it is potentially reversible (e.g., hypomethylating agents). Transcriptional loss of antigen presentation deserves further evaluation in immunotherapy resistance, as these targetable escape mechanisms are likely active in additional tumor types.\n\nMethods\nIdentification of HLA-B*3502-restricted epitope of MCPyV\nTumor infiltrating lymphocytes (TIL) from a testicular metastasis of a 64-year-old man with advanced MCC (separate from featured case) were non-specifically expanded for 2 weeks with IL-2 and IL-15 cytokine support and screened against peptide pools (13 mers overlapping by 9) tiling across the entirety of expressed portion of MCPyV T antigens by Elispot20. Confirmation of reactivity to the small T antigen pool (containing peptides spanning the C-terminal domain of MCPyV small T antigen), identification of minimal epitope as MCPyV-sT83-91 (Supplementary Fig. 1), and restriction to HLA-B*3502 was determined by interferon-gamma intracellular cytokine stain, using autologous irradiated PBMC pulsed with peptide at final concentration of 1 microgram per milliliter as antigen presenting cells. This peptide was then confirmed to also be held by HLA-B*3501 and HLA-B*3503 alleles, which are highly similar to HLA-B*3502. For sequence comparison analyses, all Merkel cell polyomavirus small T antigen protein sequences available in NCBI were downloaded on August 21, 2017 in FASTA format and aligned using MUSCLE37.\n\nClinical protocols\nAll clinical investigations were performed in compliance with the Declaration of Helsinki principles. The first treated patient (primary focus of manuscript, 2586-4) was enrolled on protocols #2586/NCT01758458 (T cell infusion treatment), #6585 and #1765 (biological sample collection) at the Fred Hutchinson Cancer Research Center (FHCRC, Seattle, WA), all research activities were approved by the FHCRC Institutional Review Board and the Food and Drug Administration. The patient provided written informed consent. The second, “validation” patient was enrolled on protocol #9245/NCT0258482 as well as the sample collection protocols as above (9245-3). The third patient from whom the HLA-B*3502-restricted epitope was identified was enrolled on protocol #6585 (biological sample collection) and also provided written informed consent.\n\nThe primary patient (2586-4) received hypofractionated radiation for HLA upregulation to some but not all disease sites: 21 Gy in 6 fractions to pelvic nodes, 8 Gy in 1 fraction to retroperitoneum (previously heavily irradiated and recurrent post radiation), 8 Gy in 1 fraction to one of the thigh tumors. Other sites of disease, including orbit, mediastinum (bulky), bladder, lumbar spine, and other lower extremity tumors were not irradiated. Twenty-four hours thereafter the first of his two infusions of HLA-B3502 restricted CD8+ T cells targeting Merkel cell polyomavirus was administered. The second infusion was 33 days after the first. Cell dose was at 10 billion cells per m2 for a total dose of 26 billion cells. After initial progression, pembrolizumab followed by ipilimumab were added. Please see Fig. 1 for schematic of infusions. Tumor volumes were determined by mWHO criteria38.\n\nThe second validation patient (9245-3) is a 59-year-old man with metastatic MCC that had initially presented as stage IIIB disease, now metastatic at multiple sites. He had developed multiple relapses that had previously been treated with radiation; trial interventions were first systemic therapy. He received avelumab (anti-PD-L1) 10 mg/kg every two weeks15, and four infusions of MCPyV-specific T cells at dosages ranging from 0.8-3.9 billion (dose target of 1010 cells per m2 (23.5 billion) was not met for technical reasons). Two HLA-upregulation interventions were performed as detailed in Supplementary Fig. 10 including injection of intralesional interferon-beta 0.1 mg once into a single tumor lesion prior to first cycle of infusions, and irradiation of a single pelvic lymph node with an 8 Gy radiation fraction prior to second infusion. Cells were of two specificities: HLA-B35/FPW, and HLA-A0201 recognizing the “KLL” epitope39, however only HLA-A0201 cells persisted.\n\nGeneration of tetramer\nAllophycocyanin-conjugated MCPyV-specific antigen pMHC multimers (FHCRC Immune Montoring Core Facility) were used to confirm purity of the cellular product as well as detect transferred CTL in PBMCs, with a staining sensitivity of 0.05% of total CD8+ T cells19.\n\nIsolation and expansion of MCC-specific CTLs\nFor the primary patient described (2586-4), peripheral blood mononuclear cells (PBMCs) were collected by leukapheresis, and all ensuing ex vivo manipulations were performed in the clinical Good Manufacturing Practices Cell Processing Facility at the FHCRC. Patient PBMCs were collected by leukapheresis and depleted of CD25+ T cells to eliminate regulatory T cells31. Cells were cultured with cytokines (IL-2, IL-7, IL-15 and IL-21) stimulated twice for 7–10 day cycles with autologous DCs pulsed with the HLA B*3502-restricted Merkel cell polyomavirus (MCPyV) MCPyV-sT83-91 epitope peptide FPWEEYGTL21,23. Cultures containing >5% specific CD8+ cells (as assessed by tetramer binding) were GMP flow-sorted and then expanded to sufficient numbers for infusion using two cycles of the Rapid Expansion Protocol21,23,40. Cell products bound the MCPyV sT-Ag epitope MCPyV-sT83-91 peptide-HLA tetramer and secreted IFN-gamma when exposed to the cognate antigen (Supplementary Fig. 2).\n\nFor the validation patient (9245-3), identical methods were used, with the exception that a second culture was also performed using the MCPyV-T antigen (sT15-23 and LT15-23) peptide KLLEIAPNC as stimulus. This is restricted to HLA A*0201, as previously described39. Cells of both specificities were mixed together immediately prior to infusion in a 1:1 ratio.\n\nFlow cytometry on patient peripheral blood samples\nBlood samples were collected at the indicated time points, PBMCs isolated through the research cell bank at FHCRC by standard Ficoll-Hypaque gradient, and viably cryopreserved. Cells were analyzed by flow cytometry after permeabilization, fixation and staining with fluorochrome-conjugated monoclonal antibodies to CD4 (SK3; Becton Dickinson), CD8 (3B5; Invitrogen), CD19 (H1B19; Becton Dickinson), CD16 (3G8; Becton Dickinson), CCR7 (G043H7; Biolegend), CD45RO (UCHL1; Becton Dickinson), CD28 (CD28.2; Biolegend), KLRG1 (SA231A2; Biolegend), CD27 (L128; Biolegend), CXCR3 (G025H7; Biolegend), CD127 (A019D5; Biolegend), PD1 (ED12.2H7; Biolegend), Lag3 (2DS223H; eBioscience), 4-1BB (4B4-1; Biolegend), BCL2 (100; Biolegend), CTLA-4 (L3D10) and the above described tetramers. Cells were analyzed on a Fortessa cytometer (Becton Dickinson) and data analysis performed with FlowJo. Staining, acquisition and analyses were performed on all samples in a batch on same day and negative controls included.\n\nEpitope spreading assessments\nFor the analyses of epitope spreading in Supplementary Fig. 5, PBMCs were cultured for 72 h with MCPyV peptide pools (13 mers overlapping by 9)20, and responses detected with interferon gamma intracellular cytokine stain.\n\nTCR beta CDR3 sequencing\nDNA was extracted from tetramer-sorted infusion product and unsorted PBMCs using a Qiagen DNEasy Blood and Tissue kit per manufacturers instruction. These samples and tumor biopsies were submitted to Adaptive Biotechnologies (Seattle, WA) for DNA amplification and sequencing of TCRB CDR3 using the immunoSEQ platform41,42.\n\nImmunohistochemistry\nFormalin-fixed paraffin-embedded tissues were sectioned and baked per standard protocol.\n\nMCPyV large T antigen was detected using the CM2B4 antibody (Santa Cruz, dilution 1 :50) and HLA-ABC using clone EMR8-5 (MBL, dilution 1 :1500 for slides from discovery patient and dilution 1 :8000 for slides from validation patient; antibody lots titered on normal tissues with endothelial cells serving as on-slide positive control)22,43. For multiplex immunohistochemistry, slides were dewaxed and stained on a Leica Bond Rx stainer using Leica Dewax solution, antigen retrieval, and antibody stripping and rinsing after each step (bond wash solution). A high stringency wash was performed after the secondary and tertiary applications using high-salt TBST solution (0.05 M Tris, 0.3 M NaCl, and 0.1% Tween-20, pH 7.2–7.6). OPAL Polymer HRP Mouse plus Rabbit (PerkinElmer, Hopkington, MA) was used for all secondary applications. Antigen retrieval and antibody stripping steps were performed at 100 °C with all other steps at ambient temperature. Endogenous peroxidase was blocked with 3% H2O2 for 8 min followed by protein blocking with TCT buffer (0.05 M Tris, 0.15 M NaCl, 0.25% Casein, 0.1% Tween 20, pH 7.6 + /- 0.1) for 30 min. The first primary antibody (position 1) was applied for 60 min followed by the secondary antibody application for 10 min and the application of the tertiary amplification reagent (PerkinElmer OPAL fluor) for 10 min. The primary and secondary antibodies were stripped with retrieval solution for 20 min before repeating the process with the second primary antibody (position 2) starting with a new application of 3% H2O2. Antibodies included CD8 (clone 144B; Dako; opal fluor 520, concentration 0.2 microgram/mL), CD56 (clone 123c3.d5; Bio SB; opal fluor 540, 1 ug/mL), CD3 (clone SP7; Thermo, opal fluor 650, concentration 1 :400), and HLA-DR (clone EP96; Bio SB; opal fluor 690; concentration 0.125 ug/mL). Slides were removed from the stainer and stained with Spectral DAPI (Perkin Elmer) for 5 min, rinsed for 5 min, and coverslipped with Prolong Gold Antifade reagent (Invitrogen/Life Technologies, Grand Island, NY). Slides were cured for 24 h at room temperature, then representative images from each slide were acquired on PerkinElmer Vectra 3.0 Automated Imaging System. Images were spectrally unmixed using PerkinElmer inForm software and exported as multi-image TIFF’s for analysis. Quantitative image analysis was performed in HALO software (Indica Labs, Corrales, NM). For each slide, three representative sections were scored. CD56 staining readily identified tumor. Layers were manually drawn for intratumoral (within tumor borders) and peritumoral (edge of tumor to 100 micron beyond tumor border) regions. Three sections were counted for each slide and comparisons between time points were made using the Student’s t test.\n\nExome sequencing\nFor both patients 2586-4 (discovery) and 9245-3 (validation), DNA was isolated from PBMC as germline control, and from tumor time point pre-immunotherapy and at acquired resistance as tumor specimens (DNA from frozen tumor specimens), using a Qiagen QIAAmp DNA extraction kit under manufacturer’s recommended conditions. Quality was confirmed with spectrophotometry and Qubit (Fisher Biosciences). For patient 2586-4 samples were submitted for exome sequencing through the FHCRC Genomics Core. Library prep was performed with standard procedures using Agilent SureSelect Human All Exon V6 and sequencing performed on an illumina HiSeq 2500 per Agilent recommendations. Samples were aligned to hg19 reference using annovar44 and somatic mutations determined using MuTect45. For patient 9245-3, samples were submitted for exome sequencing through the University of Washington Northwest Clinical Genomics Laboratory research sequencing service. Library preparation was with xGen technology and sequencing on an illumina HiSeq 4000 at 100x coverage. Samples were aligned to hg19 with BWA46 and variants identified with GATK47 as per the NCGL standard pipeline.\n\nGeneration of single cell tumor digests\nTumor material not required for clinical pathology analysis was placed in RPMI. Tumor was mechanically minced with scissors and forceps into small pieces and then resuspended in 20 mL freshly prepared digestion medium (20 mL RPMI plus 0.002 g DNAse (Worthington Biochemical) plus 0.008 g collagenase (Worthington Biochemical) plus 0.002 g hyaluronidase (Worthington Biochemical) in a 10 cm dish. Digesting tumor was incubated in 37 degree tissue culture incubator for 3 h with occasional manual rocking. After incubation, tumor digest was strained through a 70 micron cell strainer, cells were centrifuged, counted, and assessed for single cellularity and viability, and resuspended in freeze medium (50% human serum, 45% RPMI, 5% DMSO). Cells were frozen overnight at -80C in a styrofoam sandwich then transferred to liquid nitrogen for long-term storage.\n\nSingle cell RNA sequencing (scRNAseq)\nFor samples from patient 2586-4, cells were thawed, washed, and labeled in a single cell fashion using the 10x genomics 3’ Chromium v2.0 platform24 as per manufacturer’s instructions. Library preparation was performed as per manufacturer’s protocol with no modifications. Library quality was confirmed with illumina TapeStation high sensitivity (evaluates library size), qubit (evaluates dsDNA quantity), and KAPA qPCR analysis (KAPA Biosystems, evaluates quantity of amplifiable transcript). Samples were mixed in equimolar fashion and sequenced on an illumina hiSeq 2500 “rapid run” mode according to standard 10x genomics protocol.\n\nFor samples from patient 9245-3, scRNAseq was performed using the 10x Genomics 5’ V(D)J and gene expression chromium platform, with cell washing, barcoding, and library preparation as per manufactures instruction. Library quality was confirmed as above. Samples were sequenced on an Illumina NovaSeq 6000 (gene expression) and HiSeq 4000 (V(D)J) as per 10x genomics protocol for this instrument.\n\nTranscriptome alignment, barcode assignment and UMI counting\nThe Cell Ranger Single-Cell Software Suite (versions 2.0.0 and 2.1.0 for the discovery and validation patients respectively) were used to perform sample demultiplexing, barcode processing and single-cell gene counting (http://10xgenomics.com/). First, raw base BCL files were demultiplexed using the Cell Ranger mkfastq pipeline into sample-specific FASTQ files. Second, these FASTQ files were processed individually using the Cell Ranger count pipeline, which made use of the STAR software48 to align cDNA reads to the hg38 human reference genome (Ensembl) and the Merkel cell polyomavirus sequence (HM011556.1). Aligned reads were then filtered for valid cell barcodes and unique molecular identifiers (UMIs). Cell barcodes with 1-Hamming-distance from a list of known barcodes were considered. UMIs with sequencing quality score >10% and not homopolymers were retained as valid UMIs. A UMI with 1-Hamming-distance from another UMI with more reads, for a same gene and a same cell was corrected to this UMI with more reads. Tumor and PBMC samples were, respectively, aggregated together using the Cell Ranger aggr pipeline resulting in two gene-barcode count matrices (tumor and PBMC) to be used for downstream analyses. A correction for sequencing depth was also performed during the aggregation19.\n\nBiostatistical analysis—data normalization and correction\nUMI normalization was performed as in Zheng et al.19. Only genes with at least one UMI count detected in at least one cell were retained for analysis. A library-size normalization was performed for each cell. UMI counts were scaled by the total number of UMI in each cell and multiplied by the median of the total UMI counts across cells. The data were then log2-transformed and corrected for unwanted sources of variation (number of detected UMIs) using the ScaleData R function as described in the Seurat manual49. The corrected-normalized gene-barcode matrix was used as input for dimension reduction and clustering analysis, whereas the normalized gene-cell barcode matrix was used for the MAST analysis as described below.\n\nGene expression analysis: discovery patient tumor\nFollowing sequence alignment and filtering, a total of 7431 tumor cells (2243 cells before and 5188 cells after T cell therapy) were analyzed. The corrected-normalized gene-barcode matrix was used to perform principal component analysis (PCA) and t-distributed stochastic neighbor embedding (tSNE) analyses. First, the top 873 most variable genes selected by Seurat (log-mean expression values greater than 0.0125 and dispersion (variance/mean) greater than 0.5) were kept for PCA. The first top 10 principal components (PCs) were then down selected for tSNE visualization. One thousand iterations of tSNE using a perplexity value of 30 were performed. Cell classification and clustering were done according to the expression of established MCC tumor markers: NCAM1, ENO2, CHGA and KRT20 and also TILs markers. There were a total of 1984 cancer cells before, and 5131 cancer cells at the acquired resistance time point. Differential expression analysis between tumor cells before and after T cell therapy was performed using the R package MAST50. The normalized gene-cell barcode was used as input. The model included the cellular detection rate (CDR) as a covariate to correct for biological and technical nuisance factors that can affect the number of genes detected in a cell (e.g., cell size and amplification bias). Genes were declared significantly differentially expressed at a false discovery rate (FDR) of 5% and a fold-change >1.3.\n\nGene expression analysis: discovery patient PBMC\nFollowing sequence alignment and filtering, a total of 12,874 cells were analyzed. As for the tumor samples, the corrected-normalized gene-barcode matrix was used to run PCA and t-distributed stochastic neighbor embedding (tSNE) analyses. First, the top 1203 most variable genes selected by Seurat (log-mean expression values greater than 0.0125 and dispersion (variance/mean) greater than 0.5) were kept for PCA. Again, the first top 10 PCs were then down selected for tSNE visualization. One thousand iterations of tSNE using a perplexity value of 30 were performed. Cell clustering was performed using a graph-based clustering method implemented in Seurat (FindClusters R function—share nearest neighbor (SNN) modularity optimization based clustering algorithm). Thirteen distinct clusters of cells were identified using the top 10 PCs with a neighborhood size of 40 and resolution of 0.6. Based on the clustering results, we removed cells belonging to three different distinct clusters enriched for expression of red blood cell and megakaryocyte markers that were likely the result of blood contamination (leaving total of 11,021 cells for analysis). Clusters were labeled according to enrichment of specific markers (FindMarkers R function implemented in Seurat). This analysis resulted in nine distinct clusters: CD4+ T cells, CD8+ T cells, CD8+ effector T cells, B cells, NK cells, CD14+ monocytes, CD16+ monocytes, myeloid cells and dendritic cells. Differential expression analysis between CD8+ and CD8+ effector T cells for the third time point was performed using the R package MAST50 as described in the previous section. R code is attached in Supplementary Data 3. Data submitted to NCBI Gene Expression Omnibus (GEO), accession GSE 117988.\n\nGene expression analysis: validation patient\nThe aggregated corrected-normalized gene-barcode matrix was used to first run PCA and t-distributed stochastic neighbor embedding (tSNE) analyses. The top 2450 most variable genes selected by Seurat (log-mean expression values greater than 0.05 and dispersion (variance/mean) greater than 0.5) were kept for PCA. The top 10 PCs were used for tSNE visualization. One thousand iterations of tSNE using a perplexity value of 50 were performed. As described in the previous section, cell clustering was performed using a graph-based clustering method implemented in Seurat (FindClusters R function). Nineteen distinct clusters of cells were identified using the top 10 PCs with a neighborhood size of 20 and resolution of 0.6. Clusters were labeled according to enrichment of specific markers. R code is attached in Supplementary Data 4, and data submitted to NCBI GEO, accession 118056.\n\nTreatment with hypomethylating agents\nEx vivo tumor was mechanically dissociated, filtered and cultured for 48 h in RPMI supplemented with 20% FBS and pen/strep antibiotics. Untreated tumor was compared to tumor treated with 5-azacytidine (Toronto Research Chemicals, concentration 1 μM final) or gamma-interferon (final concentration 1000 IU/mL). RNA was isolated using directzol and reverse transcription performed. qPCR was performed using RT2 SYBR mastermix and commercially available primer sets to the indicated genes (Qiagen). Each condition was run in triplicate and qPCR repeated twice.\n\nElectronic supplementary material\n\nSupplementary Information\n\n \nPeer Review File\n\n \nDescription of Additional Supplementary Files\n\n \nSupplementary Data 1\n\n \nSupplementary Data 2\n\n \nSupplementary Data 3\n\n \nSupplementary Data 4\n\n \n\n\nPublisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThese authors contributed equally: P. Nghiem, A.G. Chapuis.\n\nElectronic supplementary material\nSupplementary Information accompanies this paper at 10.1038/s41467-018-06300-3.\n\nAcknowledgements\nWe thank the patients and their families, Kristina Lachance, Kieu-Thu Bui, Natalie Miller, Olga Afanasiev, Erika Kiem, Marcus Lindberg and FHCRC core facilities: Immunohistochemistry, Flow Cytometry, Cell Processing, Immune Monitoring, and Genomics.\n\nAuthor Contributions\nK.G.P. contributed to the conception, design, and implementation of immunohistochemistry, flow cytometry, exome, and scRNAseq experiments, and assembly of data. K.G.P. and A.G. Chapuis wrote the manuscript. V.V., S.J.K. and R.G. conducted the biostatistical analyses. M.P. and F.D.W. performed flow cytometry. D.S.H., W.J.V., and J.H.B. performed, assisted, and provided critical infrastructure and guidance for scRNAseq, respectively. C.D.C., N.V., H.T., A.G. Colunga, M.S.M., and R.K. acquired/processed the clinical specimens and assisted in implementation of clinical trial. J.G.I. and D.M.K. identified the MCPyV-sT83-91 epitope. C.Y. developed the protocol for cellular product preparation. R.H.P. was the pathologist. P.D.G. contributed immunologic expertise and critical analysis. S.B. contributed to the protocol development, patient treatment, and collection of clinical samples. P.N. and A.G. Chapuis conceived the protocol and project, designed experiments, and served as principal investigators on the trial. Funding: NIH-5R01CA176841 and NIH-K24CA139052 (P.N.), NIH-5K08CA169485 (A.G. Chapuis), NIH-5T32CA009515 (K.G.P.), Immunotherapy Integrated Research Center at FHCRC (A.G. Chapuis), Damon Runyon (A.G. Chapuis), MCC gift fund at UW (P.N.), P30 CA015704 (FHCRC), EMD Serono, and 10X Genomics.\n\nData availability\nSingle cell RNA sequencing data from the discovery patient submitted to National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO), accession GSE 117988 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE117988] and R code to generate tSNE plot using Seurat software package51,52 attached in Supplementary Data 3. Single cell RNA sequencing data from the validation patient submitted to NCBI GEO, accession GSE 118056 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE118056] and R code attached in Supplementary Data 4.\n\nCompeting Interests\nA.G. Chapuis has received support from Juno therapeutics. P.D.G. has received support and has ownership interest in Juno Therapeutics, Immune Design, and Innate Pharma. P.N. has received consulting fees from EMD Serono, Pfizer, Merck Sharpe and Dohne, Amgen, Incyte, Takeda, Mallinckrodt and research support from EMD Serono and Bristol-Meyers Squibb. A.G.C., M.S.M., D.M.K., K.G.P., C.D.C., and P.N. and their institutions have intellectual property related to T cell receptors recognizing Merkel cell polyomavirus. S.B. has received advisory board honoraria from Genentech and EMD-Serono; his institution (University of Washington) has received research funding from EMD-Serono, Merck, BMS, Oncosec, and Immune Design. A.G. Chapuis and K.G.P. have received reagents from 10X genomics. R.G. received consulting fees from Juno Therapeutics. The authors declare no other competing interests.\n==== Refs\nReferences\n1. Boussiotis VA Molecular and biochemical aspects of the PD-1 checkpoint pathway N. Engl. J. Med. 2016 375 1767 1778 10.1056/NEJMra1514296 27806234 \n2. Wolchok JD Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma N. Engl. J. 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"fulltext_license": "CC BY",
"issn_linking": "2041-1723",
"issue": "9(1)",
"journal": "Nature communications",
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"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D018414:CD8-Positive T-Lymphocytes; D015266:Carcinoma, Merkel Cell; D061025:Costimulatory and Inhibitory T-Cell Receptors; D015972:Gene Expression Regulation, Neoplastic; D005805:Genes, MHC Class I; D006801:Humans; D016219:Immunotherapy, Adoptive; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D059965:Merkel cell polyomavirus; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D027601:Polyomavirus Infections; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D012878:Skin Neoplasms; D013736:Testicular Neoplasms; D014158:Transcription, Genetic; D014182:Transplantation, Autologous; D019139:Tumor Escape; D014412:Tumor Virus Infections",
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"title": "Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA.",
"title_normalized": "acquired cancer resistance to combination immunotherapy from transcriptional loss of class i hla"
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"literaturereference": "PAULSON KG, VOILLET V, MCAFEE MS, HUNTER DS, WAGENER FD, PERDICCHIO M, ET AL.. ACQUIRED CANCER RESISTANCE TO COMBINATION IMMUNOTHERAPY FROM TRANSCRIPTIONAL LOSS OF CLASS I HLA. NATURE COMMUNICATIONS. 2018?9(1):1-10",
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{
"abstract": "Thrombosis after cessation of anticoagulation, also named rebound thrombosis, is a matter of concern and controversy. There are only few published data about occurrence of rebound thrombosis associated with non-vitamin K-antagonist oral anticoagulant drugs (NOACs). We report on a 58-year-old male with paroxysmal atrial fibrillation (AF) with a CHA2DS2VASC score of 4 who developed central pulmonary embolism four days after interruption of rivaroxaban because of parotid surgery. He had received 40 mg enoxaparin/d. The parotid gland was partially resected within 6 hours without blood loss. Pulmonary embolism and AF occurred on the first postoperative day. He recovered with low-molecular-weight heparin in therapeutic dosages and amiodarone and was discharged with phenprocoumon. The relevance of a rivaroxaban rebound phenomenon, manifesting as arterial embolism, stroke or venous thromboembolism should be clarified. It should be assessed if rebound-phenomena also exist for the NOACs dabigatran, apixaban and edoxaban. Thus, the randomized trials and registries investigating patients with AF or venous thromboembolism should be re-analysed and, based on these data, recommendations should be developed for situations in which NOAC-therapy has to be interrupted or ceased.",
"affiliations": "Univ. Prof. Dr. Claudia Stöllberger, Steingasse 31/18, A-1030 Wien, Österreich, Tel.: 0043 676 403 11 87, Fax: +43 1 71165 2209, Email: claudia.stoellberger@chello.at.",
"authors": "Göndör|Gabor|G|;Stöllberger|Claudia|C|",
"chemical_list": "D006495:Heparin, Low-Molecular-Weight; D000069552:Rivaroxaban; D000638:Amiodarone; D010644:Phenprocoumon",
"country": "Germany",
"delete": false,
"doi": "10.5482/HAMO-17-01-0005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0720-9355",
"issue": "37(4)",
"journal": "Hamostaseologie",
"keywords": "Non-vitamin K-antagonist; atrial fibrillation; oral anticoagulants; pulmonary embolism; rivaroxaban rebound phenomenon",
"medline_ta": "Hamostaseologie",
"mesh_terms": "D000284:Administration, Oral; D000638:Amiodarone; D001281:Atrial Fibrillation; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D008297:Male; D008875:Middle Aged; D010306:Parotid Gland; D019990:Perioperative Care; D010644:Phenprocoumon; D011183:Postoperative Complications; D011655:Pulmonary Embolism; D000069552:Rivaroxaban",
"nlm_unique_id": "8204531",
"other_id": null,
"pages": "302-306",
"pmc": null,
"pmid": "28853765",
"pubdate": "2017-10-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary embolism four days after interruption of therapy with rivaroxaban.",
"title_normalized": "pulmonary embolism four days after interruption of therapy with rivaroxaban"
} | [
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"companynumb": "AT-JNJFOC-20170907227",
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{
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],
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{
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"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "STLLBERGER C, GANDAR G. PULMONARY EMBOLISM FOUR DAYS AFTER INTERRUPTION OF THERAPY WITH RIVAROXABAN. HAMOSTASEOLOGIE 2018:38.",
"literaturereference_normalized": "pulmonary embolism four days after interruption of therapy with rivaroxaban",
"qualification": "1",
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},
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"receiptdate": "20170912",
"receivedate": "20170912",
"receiver": {
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"receivertype": "6"
},
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"sendertype": "2"
},
"serious": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171128"
}
] |
{
"abstract": "Chediak-Higashi syndrome is a rare immunodeficiency disorder for which hematopoietic stem cell transplant (HSCT) is the only curative treatment option. HSCT only corrects the hematologic and immunologic manifestations of the disease but neurologic complications may still progress after transplant. Haploidentical HSCT (haplo-HSCT) has evolved as a feasible alternative for patients with primary immunodeficiency. More recently, there has been use of haplo-HSCT with post-transplant cyclophosphamide. However, only 4 cases of Chediak-Higashi syndrome have been reported using this approach. Here, the authors describe a case of a 17-month-old boy who was successfully treated by haplo-HSCT with reduced-toxicity conditioning (fludarabine/treosulfan/melphalan) and post-transplant cyclophosphamide.",
"affiliations": "Department of Hematology, Pediatric Hemato-Oncology and Bone Marrow Transplant, Fortis Memorial Research Institute (FMRI), Gurugram, Haryana, India.",
"authors": "Sachdev|Mansi|M|;Bansal|Minakshi|M|;Chakraborty|Sohini|S|;Hamal|Sushma|S|;Bhargava|Rahul|R|;Dua|Vikas|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001977",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e1030-e1032",
"pmc": null,
"pmid": "33093354",
"pubdate": "2021-10-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Haploidentical Stem Cell Transplant With Post-transplant Cyclophosphamide for Chediak-Higashi Syndrome: A Very Rare Case Report.",
"title_normalized": "haploidentical stem cell transplant with post transplant cyclophosphamide for chediak higashi syndrome a very rare case report"
} | [
{
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},
{
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},
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"medicinalproduct": "CYCLOPHOSPHAMIDE."
},
{
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"activesubstancename": "MELPHALAN"
},
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"drugdosagetext": "140 MG/M2 ON DAY ?2",
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"drugindication": "BONE MARROW CONDITIONING REGIMEN",
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"medicinalproduct": "MELPHALAN."
}
],
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"reaction": [
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
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"abstract": "The intellectual disability syndrome characterized by seizures and dysmorphic features was initially described in 2017 and was associated with genetic variants in the OTUD6B gene, identified by exome sequencing (ES) in a large cohort. This multisystem disorder primarily affects the central nervous system, the gastrointestinal, and the skeletal systems. In this article, we describe the first Mexican patient diagnosed by ES. The homozygous c.433C>T (p.Arg145*) variant of the OTUD6B gene confirmed this intellectual disability syndrome. In addition to seizures and other more frequently reported manifestations of this condition, this is the third patient with associated hypothyroidism and hypogammaglobulinemia, underscoring the value of screening for these conditions in other patients. The current challenge with this patient is to ensure medical management of his seizures and provide him with a better quality of life. The possibilities of additional therapeutic approaches may increase by understanding the physiopathology of the involved pathways.",
"affiliations": "Clínica Nova de Monterrey, San Nicolas de los Garza, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico.;Clínica Nova de Monterrey, San Nicolas de los Garza, Nuevo Leon, Mexico.;Genomi-k SAPI de CV, Monterrey, Nuevo Leon, Mexico.;Clínica Nova de Monterrey, San Nicolas de los Garza, Nuevo Leon, Mexico.;Clínica Nova de Monterrey, San Nicolas de los Garza, Nuevo Leon, Mexico.",
"authors": "Romero-Ibarguengoitia|Maria Elena|ME|0000-0002-2572-4043;Cantú-Reyna|Consuelo|C|0000-0003-4432-9177;Gutierrez-González|Dalia|D|;Cruz-Camino|Héctor|H|0000-0002-2815-6619;González-Cantú|Arnulfo|A|;Sanz Sánchez|Miguel Angel|MA|",
"chemical_list": "D010450:Endopeptidases; C559912:OTUD6B protein, human",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620957777\n10.1177_2324709620957777\nCase Report\nComparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case\nhttps://orcid.org/0000-0002-2572-4043Romero-Ibarguengoitia Maria Elena MD, MS, PhD1 https://orcid.org/0000-0003-4432-9177Cantú-Reyna Consuelo MD, MS23 Gutierrez-González Dalia MD1 https://orcid.org/0000-0002-2815-6619Cruz-Camino Héctor BS34 González-Cantú Arnulfo MD, MSC1 Sanz Sánchez Miguel Angel MD1 1 Clínica Nova de Monterrey, San Nicolas de los Garza, Nuevo Leon, Mexico\n2 Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico\n3 Genomi-k SAPI de CV, Monterrey, Nuevo Leon, Mexico\n4 Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico\nMaria Elena Romero-Ibarguengoitia, MD, MS, PHD, Clínica Nova de Monterrey, Av. del Bosque 139, Cuauhtémoc, San Nicolás de los Garza, Monterrey, Nuevo Leon 66450, Mexico. Email: mromeroi@novaservicios.com.mx\n13 9 2020 \nJan-Dec 2020 \n8 23247096209577778 6 2020 7 8 2020 11 8 2020 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).The intellectual disability syndrome characterized by seizures and dysmorphic features was initially described in 2017 and was associated with genetic variants in the OTUD6B gene, identified by exome sequencing (ES) in a large cohort. This multisystem disorder primarily affects the central nervous system, the gastrointestinal, and the skeletal systems. In this article, we describe the first Mexican patient diagnosed by ES. The homozygous c.433C>T (p.Arg145*) variant of the OTUD6B gene confirmed this intellectual disability syndrome. In addition to seizures and other more frequently reported manifestations of this condition, this is the third patient with associated hypothyroidism and hypogammaglobulinemia, underscoring the value of screening for these conditions in other patients. The current challenge with this patient is to ensure medical management of his seizures and provide him with a better quality of life. The possibilities of additional therapeutic approaches may increase by understanding the physiopathology of the involved pathways.\n\nintellectual disabilitywhole-exome sequencingabnormalitiesseizuresOTUD6Bcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nThe intellectual developmental disorder characterized by a dysmorphic facies, seizures, and distal limb anomalies (OMIM 617452), also known as OTUD6B-related disorder, was initially described in 2017 by Santiago-Sim et al, who associated the role of genetic variants in the OTUD6B gene,1 identified by exome sequencing (ES) in a large cohort. Later, 3 other cases were detected after a genetic research odyssey was undertaken, also by ES.2-4\n\nThis syndrome is a serious multisystemic disorder characterized by poor general growth, developmental delay, early-onset seizures, intellectual disability, as well as dysmorphic craniofacial and distal extremity features. The phenotypic manifestations are variable, whereby the most severe include a neurodevelopmental disorder with microcephaly, the lack of speech, and an inability to walk, as well as the need for feeding probes. Other manifestations include congenital heart disease or nonspecific abnormalities of the brain. In some cases, intellectual disability is mild to moderate with normal speech and motor development.1\n\nAccording to the reported cases, an autosomal recessive inheritance pattern has been established.1 The OTUD6B (ovarian tumor domain-containing 6B) gene is located on chromosome 8q21.3 and encodes a deubiquitinating enzyme (DUB).5 DUBs can recycle ubiquitin as components of the 26S proteasome and recover proteins from the degradation pathway by deubiquitination. In addition, this enzyme regulates central biological processes, including DNA repair, apoptosis, oncogene expression and function, and checkpoint regulation.6 This gene is expressed in the brain, lungs, liver, gastrointestinal tract, skin, testicles, cardiovascular system, adipose tissue, adrenal glands, thyroid, pancreas, and lymphocytes.7\n\nThe OTUD6B gene regulates protein synthesis in cells by operating downstream from the mammalian target of rapamycin complex 1 (mTORC1).8 The mTOR has been shown to integrate intracellular signals to control cell growth, nutrient metabolism, and protein translation. This pathway regulates neural stem cell differentiation, neural progenitor migration, dendrite development, and neuron maturation.9\n\nCurrently, only 7 different genetic variants have been described (ie. nonsense, missense, and intronic site variants) in 15 cases (9 families) affected by this syndrome, of which the truncating c.433C>T variant (rs368313959) has been identified as the most common (12 of 30 alleles).1-3 After random mating calculation, the prevalence of this variant in the homozygous state in a Latino population is estimated to be 1/145 000.1\n\nIn this article, we herein report the first Mexican case of OTUD6B-related disorder. The clinical history is provided, and a comparison is made with other cases in the literature.\n\nCase Report\nThe index case is a 10-year-old Mexican male with unrelated healthy parents. He is the first and only son. The parents came to the clinic searching for treatment of their son’s refractory epilepsy and insomnia. The patient was born by cesarean section at 38 weeks gestation. During the pregnancy, there was no intrauterine growth restriction; at birth, the patient’s weight was 3 200 g and his length was 52 cm, with an APGAR score of 9-9. Four hours after birth, the patient developed perioral cyanosis and was transferred to the intensive care unit with a probable diagnosis of neonatal sepsis. During his hospital stay, an echocardiogram reported patent ductus arteriosus that closed spontaneously. The newborn screening was reported as normal. He was discharged after 11 days.\n\nSince the first days of life, the patient presented recurrent pulmonary infections associated with multiple hospital admissions, severe gastroesophageal reflux, and breast milk intolerance. At 6 months, he underwent a Nissen fundoplication and gastrostomy.\n\nFrom the age of 7 months until now, the patient has presented atonic seizures and childhood spasms that are difficult to control. He initially responded well to valproic acid, but developed Fanconi syndrome as a secondary adverse event. He also had a good response to oxcarbazepine but developed severe hyponatremia, so both medications had to be withdrawn. Other prescribed medications included phenobarbital, phenytoin, atomoxetine, aripiprazole, quetiapine fumarate, haloperidol, sertraline, pregabalin, olanzapine, topiramate, levetiracetam, mirtazapine, and ethyl loflazepate, but these medications could not control the seizures either or led to adverse reactions such as irritability, insomnia, tremors, and hallucinations, among others. He is currently treated with lacosamide, clobazam, brivaracetam, and acetazolamide, which have decreased the number of seizures (5 events/month). He recently developed hypokalemia secondary to the use of acetazolamide but was successfully treated with potassium supplementation.\n\nSince his first year of life, his weight, height, and head circumference have been below the third percentile. In addition, at 18 months of age, the patient was diagnosed with subclinical hypothyroidism and selective immunodeficiency of immunoglobulin (Ig)G and IgA, as well as nephrocalcinosis.\n\nThe primary dysmorphic features included microcephaly, elongated eyelid fissures with eversion of the outer third of the lower eyelid, arched and broad eyebrows, a depressed nasal tip with a short columella, small and spaced teeth, and micrognathia. He had large cup-shaped ears with low implantation, and bilateral retroauricular pits. Polydactyly of the right hand and left foot were present from birth and were treated surgically. He also had bilateral palmar aberrant folds (dermatoglyphics) and a sacral dimple. This clinical picture fulfilled the findings of a suspected diagnosis of Kabuki syndrome (OMIM 147920); however, sequencing the KMT2D gene—the most commonly associated—ruled out the diagnosis.\n\nSince this diagnostic possibility was excluded, ES was performed. It was only carried out in the patient’s amplifying exome (>98% of the coding regions); mitochondrial DNA was sequenced with an Illumina platform. ES resulted in a homozygous variant in the OTUD6B gene, c.433C>T (p.Arg145*). This nonsense variation (rs368313959) has been described in Clinvar and Baylor Genetics as pathogenic, and other databases have reported an allelic frequency of 0.00014 (Genome Aggregation Database) and 0.00015 (Exome Sequencing Project). No other relevant findings were identified. According to the ACMG scoring guidelines,10 it appears to be a rare variant fulfilling PVS1, PM2, and PP5 criteria, which could be classified as pathogenic.\n\nCurrently, the patient weighs 24 kg (below p3) and measures 1.24 m (below p3). He has presented delayed overall development in terms of head support, sitting with support, and with no gait development, he only emits sounds, and obeys simple commands. He is receiving solid foods orally and liquids by gastrostomy. Furthermore, he is well controlled with levothyroxine and gamma globulin for the management of subclinical hypothyroidism and selective immunodeficiency, respectively. Recently, the patient was diagnosed with insulin resistance and allergic colitis. Figure 1 shows the patient’s current facial and hand features.\n\nFigure 1. Clinical features of the patient. Photographs illustrating the phenotype of the patient. (A) Front face; (B) lateral face; (C) back of the left hand back; (D) palm of the left hand.\n\nDiscussion\nWe report the case of a Mexican child with severe intellectual disability, seizures, and dysmorphic features, with a molecular diagnosis obtained by ES of a homozygous pathogenic variant in the OTUD6B gene, c.433C>T (p.Arg145*).\n\nDue to the rarity of this syndrome and the scarce literature available, Table 1 presents the clinical and molecular findings of the 16 patients described to date,1-4 including the present case. This aids in visualizing the similarities and differences among patients in terms of the variants reported previously. In general, the central nervous system, gastrointestinal, and skeletal systems are the most compromised when genetic variants are present in OTUD6B. Moreover, craniofacial dysmorphism, cardiologic malformations, and recurrent respiratory infections are frequently associated clinical features and appear to be dependent on a specific variant (ie, c.433C>T).1,3\n\nTable 1. Comparative Table of Clinical and Molecular Characteristics Present in Patients With Pathogenic Variants Within OTUD6B.\n\n\tFam1 (1)1\tFam2 (1)1\tFam3 (3)1\tFam4 (2)1\tFam5 (2)1\tFam6 (3)1\tFam7 (1)2\tFam8 (1)3\tFam9 (1)4\tFam10 (1)—IP\t\nHomozygous Genetic Variant (except Fam7)\tc.433C>T\tc.433C>T\tc.433C>T\tc.469_473delTTAAC\tc.173-2A>G\tc.647A>G\tc.324 + 1G>C/c.405+1G>A\tc.433C>T\tc.631G>T\tc.433C>T\t\nProtein change\tp.Arg145*\tp.Arg145*\tp.Arg145*\tp.Leu157Argfs*8\tIntronic variant\tp.Tyr216Cys\tIntronic variant\tp.Arg145Ter\tp.E211*\tp.Arg145Ter\t\nGender\tF\tM\tM (3)\tM (3)\tF (2)\tM (2), F (1)\tF\tF\tF\tM\t\nEthnic origin\tHispanic\tHispanic/Italy\tEgypt\tSyria\tPalestine\tTurkey\tItaly\tSpain\tSaudi Arabia\tMexico\t\n\nClinical manifestations\n\t\nCentral nervous system\t\n Intellectual disability\tSevere\tSevere\tSevere (3)\tSevere (2)\tSevere (2)\tModerate (2)\nMild (1)\tMild\tPresent\tNot assessed\tSevere\t\n Seizures\t+\t+\t+ (3)\t+ (2)\t+ (2)\t+ (3)\t+\t+\t−\t+\t\n Speech delay/absence\t+\t+\t+ (3)\t+ (2)\t+ (2)\t− (3)\t+\t+\tNot assessed\t+\t\n Hypotonia\t+\t+\t+ (3)\t+ (2)\t+ (2)\t− (3)\t+\t+\tNA\t+\t\n Gross motor delay\t+\t+\t+ (3)\t+ (2)\t+ (2)\t− (3)\t+\tNA\t+\t+\t\n CNS anomalies\t−\t+\t+ (3)\t+ (1), − (1)\t+ (1), − (1)\t− (3)\t−\t+\tNA\t+\t\nHead\t\n Head\t\t\t\t\t\t\t\t\t\t\t\n Microcephaly\t+\t+\t+ (1), − (2)\t+ (2)\t− (2)\t− (3)\t+\t+\t+\t+\t\n Eyes\t\t\t\t\t\t\t\t\t\t\t\n Arched eyebrows\t+\t+\t− (3)\t− (2)\t+ (1) − (1)\t− (3)\t−\t+\t+\t+\t\n Long eyelashes\t+\t−\t− (3)\t− (2)\t+ (2)\t− (3)\tNA\tNA\t+\t+\t\n Long palpebral fissures\t+\t+\t+ (3)\t+ (1), − (1)\t− (2)\t− (3)\t−\t+\tNA\t+\t\n Nose\t\t\t\t\t\t\t\t\t\t\t\n Prominent nasal bridge\t+\t+\t+ (3)\t− (2)\t− (2)\t− (3)\t−\t+\t+\t+\t\n Long philtrum\t+\t+\t+ (3)\t− (2)\t+ (2)\t− (3)\t+\t+\t+\t+\t\n Mouth/chin\t\t\t\t\t\t\t\t\t\t\t\n Very thin upper lip\t−\t+\t+ (3)\t− (2)\t+ (2)\t− (3)\t+\t+\t+\t+\t\n High arched palate\t+\t+\t− (3)\t− (2)\t− (2)\t+ (3)\t+\tNA\tNA\t+\t\n Retrognathia\t−\t+\t+ (3)\t− (2)\t− (2)\t− (3)\t−\tNA\t+\t−\t\n Ears\t\t\t\t\t\t\t\t\t\t\t\n Low set\t−\t−\t+ (3)\t− (2)\t− (2)\t− (3)\tNA\tNA\t+\t+\t\n Large\t−\t−\t− (3)\t+ (2)\t+ (2)\t− (3)\t+\t+\t+\t+\t\nCardiovascular system\t\n Congenital heart disease\tNA\t−\tPS, ASD (1)\nPS, ASD, VSD (1)\n− (1)\tNA (1), VSD (1)\tTOF/ASD (1)\nNA (1)\tNA (3)\tTOF\t−\tPS\tPDA\t\nRespiratory system\t\n Recurrent infections\t+\t−\t+ (3)\t− (2)\t− (2)\t− (3)\tNA\tNA\t+\t+\t\nGastrointestinal system\t\n Feeding difficulties\t+\t+\t+ (3)\t+ (2)\t+ (2)\t− (3)\t+\t+\t+\t+\t\n Chronic constipation\t+\t+\t− (3)\t− (2)\t− (2)\t− (3)\tNA\t+\tNA\t+\t\n Allergic colitis\tNA\tNA\tNA\tNA\tNA\tNA\tNA\tNA\tNA\t+\t\nSkeletal system\t\n Scoliosis\t+\t+\t+ (1), − (2)\t+ (1), − (1)\t+ (1), − (1)\t− (3)\t−\t−\t−\t+\t\n Sacral dimple\t+\t−\t−\t− (1), + (1)\t−\t−\t−\t−\tNA\t+\t\n Fingers/toes abnormalities\t+\t+\t+ (3)\t+ (1), − (1)\t+ (2)\t+ (2), − (1)\t+\t+\t+\t+\t\nEndocrine system\t\n Hypothyroidism\t+\t−\t− (3)\t+ (1), − (1)\t− (2)\t− (3)\tNA\tNA\tNA\t+\t\n Insulin resistance\tNA\tNA\tNA\tNA\tNA\tNA\tNA\tNA\tNA\t+\t\nImmune system\t\n Hypogammaglobulinemia\t−\t+\t− (3)\t− (2)\t− (2)\t− (3)\tNA\tNA\tNA\t+\t\nAbbreviations: ASD, atrial septal defect; PDA, patent ductus arteriosus; CNS, central nervous system; F, female; Fam, family; IP, index patient; M, male; NA, not applicable; PS, pulmonary stenosis; TOF, tetralogy of Fallot; VSD, ventricular septal defect; +, present; −, absent; (#), number of individuals.\n\nIt is important to highlight that hypothyroidism and IgG and IgA immunodeficiency have been reported previously in other cases.1 Our patient is the third case with hypothyroidism and the second with hypogammaglobulinemia (Table 1), underscoring the value of screening for these conditions. These findings could be explained by the fact that the OTUD6B gene is expressed in the thyroid and lymphocytes.7 Also, additional clinical manifestations that had not been previously reported were present in our proband, including allergic colitis and insulin resistance. Further studies must be conducted to confirm their relation with OTUD6B variants.\n\nOur patient’s clinical features were initially compatible with the diagnosis of Kabuki syndrome (OMIM 147920) and consistent with other reports.2,3 Other diagnoses, such as Rubinstein-Taybi syndrome (OMIM 180849) and DiGeorge syndrome (OMIM 188400), among others, had been suggested as differential diagnoses. Consequently, diagnosing cases with partially overlapping complex phenotypes warrants the use of broad genetic tests, such as exome sequencing.\n\nGiven the homozygous pathogenic variant identified in our case, the clinical manifestations were consistent with those of 6 other patients (Table 1; Fam 1, 2, 3, 8).1,3 The presence of craniofacial dysmorphism (ie, microcephaly in 5/7 patients, long palpebral fissures in 7/7 patients, and nose features in 7/7 patients), as well as recurrent respiratory infections (5/6 patients; 1 patient not reported), and chronic constipation (4/7 patients) are all clinical features that might be predominantly associated with this variant. Differences between these patients included the presence of congenital heart disease (3/6 patients), as well as the diagnosis of hypothyroidism (2/6 patients) and hypogammaglobulinemia (2/6 patients).\n\nThe broad clinical picture is caused by the genetic variant type. For example, variants that lead to the absence of protein are associated with more severe phenotypes, compared with protein conformation changes only (Table 1). The research literature has mainly reported homozygous cases, making it difficult to approach this differential diagnosis of compound heterozygous states given the lack of knowledge on its impact on loss of function, and to the expression of different allele combinations.\n\nKnowing the clinical impact of genetic variants on the organs and systems that could be affected guides the physician to intentionally review them. Therefore, an action plan can be established for the patient’s medical management and improvement in his quality of life.\n\nDetermining the most appropriate therapeutic approach in patients with this intellectual disability syndrome has represented a challenge in terms of patient management, particularly in seizure control.\n\nFurthermore, gastrointestinal and cardiologic manifestations, as well as motor and speech delays, can benefit from early treatment to ensure a better quality of life. Multiple standard treatments have been used but are associated with the development of adverse effects.\n\nThe presence of the c.433C>T variant in the homozygous state seems to severely affect the structure and function of the central nervous system.1,3 This could explain why our patient had difficult to control seizures, severe mental retardation, and an abnormal corpus callosum. OTUD6B regulates protein synthesis in non–small cell lung cancer cells, operating downstream from mTORC1. In the past few years, an increase in preclinical data has uncovered the molecular pathway of the mTOR, which appears to be crucial in many genetic and acquired epilepsy syndromes; it has been shown to integrate the intracellular signals required to control cell growth, nutrient metabolism, and protein translation.9,11 The mTOR complexes are essential in neurogenesis and in the establishment of neural circuits. This pathway regulates neural stem cell differentiation, neural progenitor migration, dendrite development, and neuron maturation.9\n\nDifferent animal models in which mTOR was hyperactivated showed that the inhibition of mTORC1 with rapamycin and other compounds, such as vigabatrin, valproic acid, and a ketogenic diet, resulted in the prevention, delay, and decrease in the number of seizures.11,12 Future studies must be conducted to evaluate whether the intervention of this pathway in patients with OTUD6B could further support the available therapeutic options.\n\nConclusion\nWe report the first Mexican case of the OTUD6B-related disorder, as well as the seventh patient (fourth family) worldwide, with the homozygous variant c.433C>T (p.Arg145*). The current challenge in these patients is their medical management. Our patient also had hypothyroidism and immunodeficiency, findings consistent with other reported cases. Moreover, allergic colitis and insulin resistance could be new expressions of the syndrome that need to be evaluated in future cases. Given our initial clinical diagnosis of Kabuki syndrome, due to the presence of craniofacial dysmorphism, limb abnormalities, and intellectual disability, and considering other authors’ initial clinical diagnoses (eg. Rubinstein-Taybi syndrome), we propose a genetic panel that includes the 3 syndromes, to shorten the diagnostic odyssey. Even if ES is the indicated approach in complex phenotypes, the interpretation of genetic variants using a broad test such as this may lead to difficulties in medical practice. Thus, a specific, targeted genetic test would be a preferable choice.\n\nWe would like to thank Dr Olaf Bodamer for his medical advice in this case.\n\nAuthors’ Note: Specific data are available on request.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval when reporting individual cases.\n\nInformed Consent: Written informed consent was obtained from parents for patient information to be published in this article. Parents provided permission and signed a consent form permitting full-face sharing in this article.\n\nORCID iDs: Maria Elena Romero-Ibarguengoitia \nhttps://orcid.org/0000-0002-2572-4043\n\nConsuelo Cantú-Reyna \nhttps://orcid.org/0000-0003-4432-9177\n\nHéctor Cruz-Camino \nhttps://orcid.org/0000-0002-2815-6619\n==== Refs\nReferences\n1 \nSantiago-Sim T Burrage LC Ebstein F , et al\nBiallelic variants in OTUD6B cause an intellectual disability syndrome associated with seizures and dysmorphic features\n. Am J Hum Genet . 2017 ;100 :676 -688\n.28343629 \n2 \nStraniero L Rimoldi V Soldà G , et al\nFirst replication of the involvement of OTUD6B in intellectual disability syndrome with seizures and dysmorphic features\n. Front Genet . 2018 ;9 :464 .30364145 \n3 \nSánchez-Soler MJ Serrano-Antón AT López-González V Juliana M Martínez B Guillén-Navarro E \nFirst Spanish case of syndromic intellectual disability with dysmorphic facies, seizures, and distal limb anomalies caused by balletic mutations in the OTUD6B gene [in Spanish]\n. An Pediatr (Barc) . 2020 ;92 :169 -171\n. doi:10.1016/j.anpedi.2019.03.010 31147255 \n4 \nAlkuraya FS \nPhenotypic expansion of OTUD6B-related syndrome\n. Am J Med Genet A . 2020 ;182 :1530 -1531\n. doi:10.1002/ajmg.a.61548 32181568 \n5 \nOTUD6B OTU deubiquitinase 6B [Homo sapiens (human)] . Updated August 18, 2020. Accessed August 27, 2020 \nhttps://www.ncbi.nlm.nih.gov/gene/51633\n6 \nXu Z Zheng Y Zhu Y Kong X Hu L \nEvidence for OTUD-6B participation in B lymphocytes cell cycle after cytokine stimulation\n. PLoS One . 2011 ;6 :e14514 . doi:10.1371/journal.pone.0014514 21267069 \n7 \nGTEx Portal . OTUD6B\n. Accessed December 18, 2019 \nhttps://gtexportal.org/home/gene/OTUD6B\n8 \nSobol A Askonas C Alani S , et al\nDeubiquitinase OTUD6B isoforms are important regulators of growth and proliferation\n. Mol Cancer Res . 2017 ;15 :117 -127\n.27864334 \n9 \nLiCausi F Hartman NW \nRole of mTOR complexes in neurogenesis\n. Int J Mol Sci . 2018 ;19 :1544 . doi:10.3390/ijms19051544 \n10 \nRichards S Aziz N Bale S , et al\nStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology\n. Genet Med . 2015 ;17 :405 -424\n. doi:10.1038/gim.2015.30 25741868 \n11 \nOstendorf AP Wong M \nmTOR inhibition in epilepsy: rationale and clinical perspectives\n. CNS Drugs . 2015 ;29 :91 -99\n.25633849 \n12 \nKoene LMC van Grondelle SE Onori MP , et al\nEffects of antiepileptic drugs in a new TSC/mTOR-dependent epilepsy mouse model\n. Ann Clin Transl Neurol . 2019 ;6 :1273 -1291\n. doi:10.1002/acn3.50829 31353861\n\n",
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"keywords": "OTUD6B; abnormalities; intellectual disability; seizures; whole-exome sequencing",
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"mesh_terms": "D000015:Abnormalities, Multiple; D002648:Child; D010450:Endopeptidases; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D008800:Mexico; D012640:Seizures; D000073359:Whole Exome Sequencing",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29789464;31147255;28343629;30364145;32181568;25633849;25741868;27864334;21267069;31353861",
"title": "Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case.",
"title_normalized": "comparison of genetic variants and manifestations of otud6b related disorder the first mexican case"
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{
"abstract": "We present the case of a patient, with history of myelodysplastic syndrome and recent bone marrow transplant, who developed fulminant liver failure secondary to herpes simplex virus (HSV) hepatitis. His presentation was unique, as findings of liver microabscesses on computed tomography scan have not been described previously in this patient population. Despite initial treatment with acyclovir, he continued to deteriorate, and later sensitivities found the HSV strain to be resistant to acyclovir. HSV hepatitis with secondary liver failure is rare and, without appropriate treatment, its mortality is >80%. Early suspicion and immediate therapy are the keys to improve patient survival.",
"affiliations": "Department of Critical Care, Division of Anesthesiology and Critical Care, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.;Department of Stem Cell Transplantation, Division of Internal Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.;Department of Critical Care, Division of Anesthesiology and Critical Care, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.;Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.;Department of Infectious Disease, Infection Control and Employee Health, Division of Internal Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.;Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.",
"authors": "Gutierrez|C|C|;Kebriaei|P|P|;Turner|K A|KA|;Yemelyanova|A|A|;Ariza-Heredia|E J|EJ|;Foo|W C|WC|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000998:Antiviral Agents; D017245:Foscarnet; D000637:Transaminases; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12556",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "18(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "acute liver failure; acyclovir; hepatitis; herpes simplex virus; liver microabscesses",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000212:Acyclovir; D000305:Adrenal Cortex Hormones; D000998:Antiviral Agents; D016026:Bone Marrow Transplantation; D024882:Drug Resistance, Viral; D017809:Fatal Outcome; D017245:Foscarnet; D006086:Graft vs Host Disease; D006525:Hepatitis, Viral, Human; D006801:Humans; D008099:Liver; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D000070659:Patient Comfort; D016133:Polymerase Chain Reaction; D018139:Simplexvirus; D000637:Transaminases; D014184:Transplantation, Homologous; D000077483:Valacyclovir; D014633:Valine",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "592-4",
"pmc": null,
"pmid": "27222930",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A unique presentation of acute liver failure from herpes simplex virus hepatitis.",
"title_normalized": "a unique presentation of acute liver failure from herpes simplex virus hepatitis"
} | [
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"abstract": "We present the case of a 32-year-old Indian male one-eyed individual with a history of unilateral panuveitis with HLA B 27 positive spondyloarthropathy on systemic immunosuppressant (Adalimumab). He developed recurrent inflammation in the same eye in a span of 2 years, later complicated with retinal vasculitis. On evaluation, he was diagnosed with tubercular uveitis and started on antitubercular treatment along with systemic steroids. Inview of Increased IOP due to steroid response, Inj. Secukinumab ( IL 17 A inhibitor) was started and significant improvement was noted.",
"affiliations": "Department of Uveitis and Ocular Immunology Services, Narayana Nethralaya, Bangalore, Karnataka, India.;Department of Clinical Immunology and Rheumatology, Bhagwan Mahavir Jain Hospital, Bangalore, Karnataka, India.;Department of Uveitis and Ocular Immunology Services, Narayana Nethralaya, Bangalore, Karnataka, India.;Department of Uveitis and Ocular Immunology Services, Narayana Nethralaya, Bangalore, Karnataka, India.;Department of Uveitis and Ocular Immunology Services, Narayana Nethralaya, Bangalore, Karnataka, India.;Department of Cataract, Narayana Nethralaya, Bangalore, Karnataka, India.",
"authors": "Mahendradas|Padmamalini|P|;Jain|Vikramraj K|VK|;Thomas|Sherina|S|;Kawali|Ankush|A|;Sanjay|Srinivasan|S|;Shetty|Bhujang K|BK|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C555450:secukinumab; D000068879:Adalimumab",
"country": "India",
"delete": false,
"doi": "10.4103/ijo.IJO_1081_20",
"fulltext": "\n==== Front\nIndian J Ophthalmol\nIndian J Ophthalmol\nIJO\nIndian Journal of Ophthalmology\n0301-4738 1998-3689 Wolters Kluwer - Medknow India \n\n33120695\nIJO-68-2569\n10.4103/ijo.IJO_1081_20\nCase Reports\nRole of secukinumab in ankylosing spondylitis with tubercular uveitis\nMahendradas Padmamalini Jain Vikramraj K 1 Thomas Sherina Kawali Ankush Sanjay Srinivasan Shetty Bhujang K 2 Department of Uveitis and Ocular Immunology Services, Narayana Nethralaya, Bangalore, Karnataka, India\n1 Department of Clinical Immunology and Rheumatology, Bhagwan Mahavir Jain Hospital, Bangalore, Karnataka, India\n2 Department of Cataract, Narayana Nethralaya, Bangalore, Karnataka, India\n\nCorrespondence to: Dr. Padmamalini Mahendradas, Narayana Nethralaya, 121/C, Chord Road, Rajajinagar, 1st ‘R’ Block, Bangalore - 560 010, Karnataka, India. E-mail: m.padmamalini@gmail.com\n11 2020 \n26 10 2020 \n68 11 2569 2572\n21 4 2020 01 9 2020 04 9 2020 Copyright: © 2020 Indian Journal of Ophthalmology2020This 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.We present the case of a 32-year-old Indian male one-eyed individual with a history of unilateral panuveitis with HLA B 27 positive spondyloarthropathy on systemic immunosuppressant (Adalimumab). He developed recurrent inflammation in the same eye in a span of 2 years, later complicated with retinal vasculitis. On evaluation, he was diagnosed with tubercular uveitis and started on antitubercular treatment along with systemic steroids. Inview of Increased IOP due to steroid response, Inj. Secukinumab ( IL 17 A inhibitor) was started and significant improvement was noted.\n\nIL 17A inhibitorSecukinumabspondyloarthropathytubercular uveitis\n==== Body\nThe management of ocular inflammatory diseases in the presence of active systemic infections or vice versa has always been a challenge especially with organisms like Mycobacterium tuberculosis. Incidence of reactivation of latent tuberculosis infection (LTBI) or active TB is high with most immunosuppressive agents. The role of Tumor Necrosis Factor (TNF) alpha in providing immunity to mycobacterial infections is well known.[12] Anti TNF therapy leads to decreased levels of interferon-gamma production and also reduced expression of Toll-like receptor 4 on dendritic cells.[3] In Rheumatoid arthritis, anti-TNF alpha inhibitors (especially Infliximab) among other biologics have been associated with increased risk of TB infection when compared to disease-modifying anti-rheumatic drugs.[4]\n\nIn Ankylosing spondylitis (AS), the first-line treatment is mainly with non-steroidal anti-inflammatory agents (NSAIDS) and in active cases despite treatment, anti-TNF alpha agents have proved to be very effective. The newer agent, IL17-A inhibitor, has proved to be useful for (a) TNF inhibitor-naive patients with active AS, and also for (b) those who have a poor response to (or, are intolerant) to TNF inhibitors.[5]\n\nSecukinumab (Cosentyx®; Novartis International AG, Basel, Switzerland) is a recombinant human monoclonal antibody that selectively targets IL17-A and spares the T- helper (Th1) pathway. This target specificity allows a better safety profile for secukinumab among other biologics by preserving Th1 based host immunity.\n\nCase Report\nA 34-year-old Indian male patient presented to us with complaints of blurred vision, redness and eyepain in the left eye (LE) of 2 weeks duration. A fire cracker injury to the right eye resulted in a complete loss of vision in that eye. His best-corrected visual acuity was no perception of light in the right eye (RE) and 20/20P, N6 in the LE. Right eye examination showed corneal edema with old keratic precipitates (KPs), elevated intraocular pressure, and glaucomatous optic atrophy [Fig. 1a]. LE examination showed fine KPs, cells 2+, flare 2+, posterior synechiae, and deposits on the crystalline lens [Fig. 1b]. Posterior segment examination showed vitritis ++, hyperemic disc, and chorioretinal scars in the inferotemporal retina [Fig. 2a] He was diagnosed with LE panuveitis evauated in detail for the possibility of sympathetic ophthalmia and it was ruled out. Fundus Fluorescein Angiography (FFA, Spectralis HRA, Heidelberg Engineering, Heidelberg, Germany) was done which showed mild disc and perivascular leak capillary nonperfusion (CNP) areas and staining of the chorioretinal scars in the inferotemporal quadrant in the LE [Fig. 2b and c]. His systemic investigations were normal (including Mantoux (negative) and Quantiferon TB gold test (Negative) with Normal Chest X Ray) except for a positive Human Leucocyte Antigen (HLA) B 27, hence referred to a rheumatologist. He was diagnosed with ankylosing spondylitis and started on immunosuppressive therapy along with continuation of topical medications and systemic steroids. Patient was asymptomatic for 2 years until he developed recurrence in the LE. At this point he was on Inj Adalimumab 40 mg taken once in 15 days for 7 months after complete evaluation in view of his systemic activity. On examination his RE was status quo, LE had a vision of 20/20, with fibrinous anterior chamber reaction, vitritis+ and retinal vasculitis in the superior quadrant [Fig. 3a]. FFA of LE revealed a delayed arm to retina time of 42 seconds, leakage and staining of retinal vessels in the superior quadrant and CNP areas in superotemporal quadrant with blocked fluorescence corresponds to retinal haemorrhages [Fig. 3b and c]. A diagnosis of LE panuveitis with retinal vasculitis was made and patient was investigated. He was found to be Quantiferon Tuberculosis test (QTB) positive, and was found to have, a“tree in bud” appearance on HRCT (high resolution computed tomography), but his sputum and BAL (Bronchioalveolar lavage) were negative for AFB (acid-fast bacilli). Systemic Methotrexate and Inj. Adalimumab therapy were stopped. He was started on topical prednisolone 1% eyedrops, ATT (anti Tubercular Therapy) with systemic prednisolone 1mg/kg, and targeted laser was given to the areas of CNP. Two days later patient worsened with an episode of lower respiratory tract infection, suspected pulmonary tuberculosis reactivation, and raised intraocular pressure of 30 mm Hg in the LE. Hence, topical prednisolone was changed to loteprednol etabonate 1%, systemic steroids were tapered to 20 mg OD, ATT was continued, injection Secukinumab 150 mg s/c (subcutaneous) once a week was added after 10 days of ATT and anti-glaucoma drops were started. Patient improved systemically and his ocular findings also improved gradually hence systemic and topical steroids were tapered and stopped [Fig. 4]. Patient completed 9 months course of ATT. He was given a total of 8 injections of s/c Secukinumab 150 mg weekly and later tapered to two weekly once followed by monthly schedule. At present patient's uveitis and ankylosing spondylitis is well under control with Secukinumab therapy.\n\nFigure 1 (a and b): Anterior segment photograph of the (a) right eye showing corneal edema, areas of sclera thinning with peripheral anterior synechiae and (b) left eye showing posterior synechiae and pigments on anterior lens capsule\n\nFigure 2 (a): Colour fundus photo of the left eye showing grade two media haze and mild hyperemia of the optic disc. (b and c): Fundus fluorescein angiography of the left eye showing (b) mild disc and perivascular leak (c) capillary non perfusion (CNP) areas in the inferotemporal quadrant and staining of the chorioretinal scars\n\nFigure 3 (a): Colour fundus photograph of the left eye showing retinal vasculitis with retinal haemorrhages. (b and c): Fundus fluorescein angiography of the left eye showing (b) leakage and staining of retinal vessels in the superior quadrant and (c) CNP areas in superotemporal quadrant\n\nFigure 4 Fundus photograph of the left eye showing healed vasculitis with laser scars in the superotemporal, temporal and inferotemporal quadrant\n\nDiscussion\nTNF alfa has an important role in the pathogenesis of uveal inflammation by recruiting leukocytes to the eye, chemokine production, promotion of leukocytes adhesion to vascular endothelium and it also promotes maturation of dendritic cells which acts as antigen-presenting cells and activate macrophages.[6] In the pathogenesis of TB, TNF alpha regulates granuloma formation and hence the ability to restrict bacterial growth.[7] So anti-TNF monoclonal antibodies (including infliximab, adalimumab, and certolizumab) pose a higher risk for reactivation of TB infection. Our patient was one eyed and he was doing well with Inj adalimumab. After two years of Methotrexate and 7 months of Adalimumab therapy for ankylosing spondylitis, he presented with panuveitis and retinal vasculitis, positive QTB gold test along with characteristic HRCT findings which according to the COTS nomenclature[8] fell under TB panuveitis. Hence he was started on ATT and systemic steroids. But since the patient was a strong steroid responder and also one eyed, steroids were tapered and Inj. Secukinumab was tried to control the disease activity.\n\nSecukinumab acts by the unique mechanism of selectively targeting IL-17A, a downstream product of Type 17 cells, and leaves the other functions of Th17 cells like release of IL-22 and TNF intact thus limiting the scope for off-target-related effects with secukinumab compared with other biologics.[9] Secukinumab has been found to have a superior safety profile in the long term treatment of Psoriasis and AS with no increased rate of adverse effects over time.[9] Our patient responded well to Inj Secukinumab along with systemic ATT.\n\nConclusion\nSecukinumab can be a useful and safer alternative to TNF alpha-blockers in spondyloarthopathies with suspected TB especially when steroids are contraindicated. The role of Secukinumab in the treatment of ocular TB is still unexplored but may prove to be a promising option as steroid-sparing agent.\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\nAcknowledgement\nWe acknowledge Dr. Kushagra Jain for providing the fundus images.\n==== Refs\n1 Winthrop KL Baxter R Liu L Varley CD Curtis JR Baddley JW Mycobacterial diseases and antitumour necrosis factor therapy in USA Ann Rheum Dis 2013 72 37 42 22523429 \n2 Minozzi S Bonovas S Lytras T Pecoraro V Gonzaález-Lorenzo M Bastiampillai AJ Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: A systematic review and meta-analysis Expert Opin Drug Saf 2016 15 Sup1 11 34 27924643 \n3 Netea MG Radstake T Joosten LA van der Meer JW Barrera P Kullberg BJ Salmonella septicemia in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: Association with decreased interferon-gamma production and Toll-like re- ceptor 4 expression Arthritis Rheum 2003 48 1853 7 12847679 \n4 Furst DE The risk of infections with biologic therapies for rheumatoid arthritis Semin Arthritis Rheum 2010 39 327 46 19117595 \n5 Blair HA Secukinumab: A review in ankylosing spondylitis Drugs 2019 79 433 43 30793255 \n6 Nakamura S Yamakawa T Sugita M Kijima M Ishioka M Tanaka S The role of tumor necrosis factor-alpha in the induction of experimental autoimmune uveoretinitis in mice Investig Ophthalmol Vis Sci 1994 35 3884 9 7928185 \n7 Ray JC Flynn JL Kirschner DE Synergy between individual TNF-dependent functions determines granuloma performance for controlling Mycobacterium tuberculosis infection J Immunol 2009 182 3706 17 19265149 \n8 Agrawal R Agarwal A Jabs DA Kee A Testi I Mahajan S Collaborative Ocular Tuberculosis Study (COTS) Group Standardization of nomenclature for ocular tuberculosis – results of collaborative ocular tuberculosis study (COTS) Workshop Ocul Immunol Inflamm 2019 10 1 11 \n9 Deodhar A Mease PJ McInnes IB Baraliakos X Reich K Blauvelt A Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: Integrated pooled clinical trial and post-marketing surveillance data Arthritis Res Ther 2019 21 111 31046809\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0301-4738",
"issue": "68(11)",
"journal": "Indian journal of ophthalmology",
"keywords": "IL 17A inhibitor; Secukinumab; spondyloarthropathy; tubercular uveitis",
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D006801:Humans; D008297:Male; D013167:Spondylitis, Ankylosing; D014605:Uveitis",
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"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": "12847679;7928185;27924643;30793255;19265149;22523429;19117595;31821096;31046809",
"title": "Role of secukinumab in ankylosing spondylitis with tubercular uveitis.",
"title_normalized": "role of secukinumab in ankylosing spondylitis with tubercular uveitis"
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"abstract": "Hidradenitis suppurativa and psoriasis are considered chronic inflammatory diseases suggesting the existence of common pathogenetic pathways. We present two cases of comorbid psoriasis and hidradenitis suppurativa, treated with certolizumab pegol and brodalumab due to failure of response to other conventional therapies. Monoclonal antibody therapies have revolutionized the treatment of chronic inflammatory disorders such as psoriasis and hidradenitis suppurativa. Given the good clinical response to anti-IL-17 and anti-tumor necrosis factor agents in patients undergoing psoriasis and hidradenitis treatment, investigations on this direction could represent the starting point in new therapeutic approach for revolutionary treatment in these difficult-to-treat diseases.",
"affiliations": "Tzaneio Hospital, Piraeus/Athens, Greece.;Andreas Sygros University Hospital, Athens, 161 21, Greece.;Tzaneio Hospital, Piraeus/Athens, Greece.;Andreas Sygros University Hospital, Athens, 161 21, Greece.",
"authors": "Tampouratzi|Eleftheria|E|;Kanni|Theodora|T|0000-0002-4537-1556;Katsantonis|John|J|;Douvali|Theodora|T|",
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"fulltext": "\n==== Front\nF1000Res\nF1000Res\nF1000Research\nF1000Research\n2046-1402 F1000 Research Limited London, UK \n\n10.12688/f1000research.21216.2\nClinical Practice Article\nArticles\nCase report: Treating a co-existence of hidradenitis suppurativa and psoriasis with different therapeutic approaches\n[version 2; peer review: 3 approved]\n\nTampouratzi Eleftheria ConceptualizationData CurationMethodologySupervisionValidationVisualizationWriting – Original Draft PreparationWriting – Review & Editing1 Kanni Theodora Writing – Original Draft Preparationhttps://orcid.org/0000-0002-4537-1556a2 Katsantonis John Writing – Original Draft Preparation1 Douvali Theodora Writing – Original Draft Preparation2 \n1 Tzaneio Hospital, Piraeus/Athens, Greece\n\n2 Andreas Sygros University Hospital, Athens, 161 21, Greece\na kannidora@med.uoa.grNo competing interests were disclosed.\n\n\n22 12 2020 \n2019 \n8 20029 12 2020 Copyright: © 2020 Tampouratzi E et al.2020This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hidradenitis suppurativa and psoriasis are considered chronic inflammatory diseases suggesting the existence of common pathogenetic pathways. We present two cases of comorbid psoriasis and hidradenitis suppurativa, treated with certolizumab pegol and brodalumab due to failure of response to other conventional therapies. Monoclonal antibody therapies have revolutionized the treatment of chronic inflammatory disorders such as psoriasis and hidradenitis suppurativa. Given the good clinical response to anti-IL-17 and anti-tumor necrosis factor agents in patients undergoing psoriasis and hidradenitis treatment, investigations on this direction could represent the starting point in new therapeutic approach for revolutionary treatment in these difficult-to-treat diseases.\n\nhidradenitis suppurativapsoriasiscertolizumabbrodalumabThe author(s) declared that no grants were involved in supporting this work.Revised Amendments from Version 1\nIn the revised version of our manuscript, we changed the title to “Treating co-existence of hidradenitis suppurativa and psoriasis”, instead of the term combination. Also, we provide severity assessment before and after treatment for psoriasis and hidradenitis, for both cases. The clinical improvement is estimated using the PASI (Psoriasis Area Severity Index) score, BSA (Body Surface Area), and IHS4 (International Hidradenitis Suppurativa Severity Scoring System) score, while the impact on the quality of life is estimated with the DLQI (Dermatology Life Quality Index) score.\n==== Body\nIntroduction\nHidradenitis suppurativa (HS) and psoriasis are considered chronic inflammatory diseases suggesting the existence of common pathogenetic links\n1–\n3. Patients with psoriasis and HS have elevated levels of tumor necrosis factor (TNF) and interleukin-17 (IL-17) in lesional and non lesional tissues, which has been the justification for selective targeting of these inflammatory pathways\n4–\n7. We present two cases of co-existence of psoriasis and HS treated with certolizumab pegol and brodalumab due to the peculiarities of treatment with other therapies.\n\nCase report\nThe first patient, a 27-year-old Caucasian woman, presented with extensive psoriasis vulgaris covering her head, trunk, lower limbs over a period of 5 years, with a recent PASI (Psoriasis Area Severity Index) score of 10.5 and 10% BSA (Body Surface Area) score. She, also, suffered from psoriatic arthritis with axial joint involvement (manifestations of hierolagonitis) over the previous 2 years and moderate HS of Hurley II stage disease on the axillae over the last year, with IHS4 (International Hidradenitis Suppurativa Severity Scoring System) score 10 (\nFigure 1a, b, c, d, e). Despite the limited extent of the lesions, the patient presented considerable pain, discomfort and substantial negative effect on quality of life. Patient’s DLQI (Dermatology Life Quality Index) score was, also very high, 21. The patient didn’t have a positive family history for the above diseases and the molecular control for HLA-B27 was negative. Previous treatments with topical corticosteroids and methotrexate for one year were not effective and treatment with apremilast for 8 months didn’t offer clinical improvement in both diseases. The patient underwent comprehensive laboratory investigations, including complete blood cell count, chemistry panel, tuberculosis (Quantiferon-TB Gold test), human immunodeficiency virus and hepatitis B and C screening and chest x-ray. Since all these examinations revealed values within normal limits and because of the patient’s desire for childbirth, she was treated with certolizumab pegol (CZP). The initial dose was 400mg, followed by 400mg every 2 weeks. Treatment with CZP significantly improved psoriasis and psoriatic arthritis at week 8 and HS at week 12. The PASI score after treatment was 1, BSA was 2%, whereas IHS4 score was 1. Except the clinical improvement, the DLQI score was impressively reduced to 2. (\nFigure 1f–i). She continues treatment 9 months after and at 3 months follow-up is fully controlled.\n\nFigure 1. Psoriatic and HS lesions of patient 1.\n(\na–\ne) Psoriatic and HS lesions of first patient before treatment with certolizumab pegol. (\nf–\nj) Psoriatic and HS lesions of first patient after treatment with certolizumab pegol.\n\nThe second patient, a 42-year-old Caucasian man, was referred to our hospital’s dermatological department with multiple, itchy, scaly, red-gray psoriatic plaques covering almost all his body: scalp, arms, trunk, thighs (\nFigure 2a–d) for the previous 6 months, over a history of 10 years psoriatic disease (recent PASI: 18.5, BSA: 45%). The patient, also, experienced concomitant psoriatic arthritis with peripheral joint involvement and dactylitis discomfort over the previous 10 years, and moderate HS of Hurley II stage disease appearing on the groin area in the previous year. The IHS4 score was 10. The above diseases had a negative impact factor on his quality of life with DLQI 25. The patient’s family history was positive: his mother and sister were also suffering from psoriasis. The patient had until recently received almost all the available therapies related to his diseases: cyclosporine for 2 years interrupted due to urea and creatinin increase (examinations restored after discontinuation), methotrexate and golimumab for 3 years with improvement only in psoriatic arthritis, adalimumab ustekinumab and secukinumab, with a partial response. After a complete laboratory examination, with results in normal limits, the patient started therapy with brodalumab. The initial dose was 210 mg at weeks 0, 1, 2 followed by 210 mg every 2 weeks. His psoriasis and psoriatic arthritis were highly improved at week 8 (\nFigure 2 e–h), as was HS at week 16. The PASI score after treatment was 1.5, the BSA was 8%, while IHS4 score was reduced to 3. He has continued treatment for 1 year; at 3 months follow-up he reported improvement in his quality of life and the DLQI score was 1.\n\nFigure 2. Psoriatic lesions of patient 2.\n(\na–\nd) Psoriatic lesions of second patient before treatment with brodalumab. (\ne–\nh) Psoriatic lesions of second patient after treatment with brodalumab.\n\nDiscussion\nMonoclonal antibody therapies have revolutionized the treatment of chronic inflammatory disorders such as psoriasis and HS. CZP is a TNF inhibitor that does not have a fragment crystallizable (Fc) region, which is normally present in a complete antibody and therefore it does not cause antibody-dependent cell-mediated cytotoxicity\n8–\n10. In contrast to other whole-antibody anti-TNFs, CZP crosses the placenta only by passive diffusion and could therefore be considered as the first-line choice of treatment for women who wish to become pregnant. Since CZP is an anti-TNF drug, therapies which have good clinical response in both psoriasis/psoriatic arthritis and HS, it was chosen as the treatment of choice in our case since it also has a safe profile for possible future pregnancy.\n\nBrodalumab is a monoclonal antibody against human IL-17 receptor A (IL-17RA). Given its efficacy in psoriasis and its mechanism of action in psoriatic arthritis and HS, due to the patient’s non response to all the available treatment options it was decided its use on the above combination diseases\n11–\n14.\n\nIt is well known that psoriasis and HS likely share immunopathogenetic pathways, including involvement of IL-17 and TNF. Given the good clinical response to anti-IL 17 and anti-TNF drugs in psoriasis and HS treatment, investigations into this direction could represent a starting point for a new therapeutic approach for revolutionary treatment of two difficult to treat diseases.\n\nData availability\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nConsent\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patients.\n\n10.5256/f1000research.30681.r76345\nReviewer response for version 2\nWu Kevin K. 1Referee \n1 University of California, Irvine, Irvine, CA, USA\n\nCompeting interests: No competing interests were disclosed.\n\n\n8 1 2021 \nCopyright: © 2021 Wu KK2021This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 2recommendationapproveAccept. No additional comments.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nNo\n\nIs the background of the cases’ history and progression described in sufficient detail?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the conclusion balanced and justified on the basis of the findings?\n\nYes\n\nReviewer Expertise:\n\nNA\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.30681.r76343\nReviewer response for version 2\nNikolakis Georgios 12Refereehttps://orcid.org/0000-0002-0920-9092 \n1 Department of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany\n\n2 European Hidradenitis Suppurativa Foundation, Dessau, Germany\n\nCompeting interests: No competing interests were disclosed.\n\n\n7 1 2021 \nCopyright: © 2021 Nikolakis G2021This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 2recommendationapproveIn this version of the manuscript Tampouratzi and colleagues have provided all validated scores and patient reported outcomes to strengthen the quality of their manuscript. I would like to congratulate them and have no further comments.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nNo\n\nIs the background of the cases’ history and progression described in sufficient detail?\n\nPartly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nPartly\n\nIs the conclusion balanced and justified on the basis of the findings?\n\nNo\n\nReviewer Expertise:\n\nHS, sebocytes, acne, melanoma, allergy\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.23356.r71707\nReviewer response for version 1\nWu Kevin K. 1Referee \n1 University of California, Irvine, Irvine, CA, USA\n\nCompeting interests: No competing interests were disclosed.\n\n\n28 9 2020 \nCopyright: © 2020 Wu KK2020This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapprove-with-reservationsThank you for these two interesting cases. One major thing missing from this paper are objective measurements of improvement after starting the respective therapies. Simply stating \"His psoriasis and psoriatic arthritis were highly improved at week 8 (\nFigure 2 e–h), as was HS at week 16\" or \"Treatment with CZP significantly improved psoriasis and psoriatic arthritis at week 8 and HS at week 12 (\nFigure 1f–i).\" does not give the reader an objective measurement of how much better the patient's disease process became following therapy. Did you measure PASI/IGA scores? Did the patients improve based on their Hurley or HISCR scores? This paper should only be accepted for indexing after including some essential, objective outcome measures. If these measures cannot be obtained, then this manuscript should be rejected for indexing.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nNo\n\nIs the background of the cases’ history and progression described in sufficient detail?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the conclusion balanced and justified on the basis of the findings?\n\nYes\n\nReviewer Expertise:\n\nPsoriasis, HS, atopic dermatitis, biologics, epidemiology.\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.\n\nKanni Theodora Andreas Sygros University Hospital, Greece\n \nCompeting interests: No competing interests were disclosed.\n\n\n8 12 2020 \nDear Dr. Wu,\n\n We revised our manuscript according to your comments.\n\n We provide severity assessment before and after treatment for both cases.\n\n The clinical improvement for psoriasis and hidradenitis is estimated using the PASI (Psoriasis Area Severity Index) score, BSA (Body Surface Area), and IHS4 (International Hidradenitis Suppurativa Severity Scoring System) score, while the impact on the quality of life is estimated with the DLQI (Dermatology Life Quality Index) score.\n\n10.5256/f1000research.23356.r57162\nReviewer response for version 1\nNikolakis Georgios 12Refereehttps://orcid.org/0000-0002-0920-9092 \n1 Department of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany\n\n2 European Hidradenitis Suppurativa Foundation, Dessau, Germany\n\nCompeting interests: Dr Kanni and I both work on collaborating groups on Hidradenitis suppurativa (Athens, Greece and Dessau Germany, respectively). We published together in 2016 in JID (Journal of Investigative Dermatology). This does not affect my current review, it was objective to the best of my knowledge.\n\n\n11 12 2019 \nCopyright: © 2019 Nikolakis G2019This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationrejectI have prepared a PDF file with most of the points I think need to be addressed in order to make this case acceptable for indexing - please find the file\nhere\n. For the second case we have really no proof, even a single photo, showing that brodalumab led to improvement of HS. Both Psoriasis and HS need to be assessed using both descriptive terms but also objective and validated scoring systems, to quantify the improvement.\n\n Moreover, the improvement of HS under certolizumab pegol is not clear for me, since I cannot tell that inflammatory lesions (nodules, abscesses or sinus tracts) have decreased after therapy.\n\n Since I believe that this case report can add to the current literature, opening ways for more anti-inflammatory treatments for HS, I think that updating the documentation accordingly and providing some proof for the improvement of HS will make the manuscript acceptable for indexing.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nNo\n\nIs the background of the cases’ history and progression described in sufficient detail?\n\nPartly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nPartly\n\nIs the conclusion balanced and justified on the basis of the findings?\n\nNo\n\nReviewer Expertise:\n\nHS, sebocytes, acne, melanoma, allergy\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.\n\nKanni Theodora Andreas Sygros University Hospital, Greece\n \nCompeting interests: No competing interests were disclosed.\n\n\n8 12 2020 \nDear Dr. Nikolakis,\n\n We revised our manuscript according to your comments.\n\n We provide severity assessment before and after treatment for both cases.\n\n The clinical improvement for psoriasis and hidradenitis is estimated using the PASI (Psoriasis Area Severity Index) score, BSA (Body Surface Area), and IHS4 (International Hidradenitis Suppurativa Severity Scoring System) score, while the impact on the quality of life is estimated with the DLQI (Dermatology Life Quality Index) score.\n\n Regarding your comment about the photographic documentation of HS improvement of the second patient, the patient denied taking photos. The location of his HS lesions is on the groin area and we did not have the patient’s consent for photographic documentation.\n\n10.5256/f1000research.23356.r57163\nReviewer response for version 1\nTzellos Thrasyvoulos 1Referee \n1 Department of Clinical Medicine, University of Tromsø, Tromsø, Norway\n\nCompeting interests: Advisory Board and primary investigator for UCB and Abbvie. Do not know about the authors. These conflicts of interest did not influence my review of this manuscript.\n\n\n10 12 2019 \nCopyright: © 2019 Tzellos T2019This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapproveI suggest changing the title to:\n\n \"Treating co-existence of hidradenitis suppurativa and psoriasis\"\n\n Introduction:\nPlease change \"We present two cases of comorbidity of psoriasis and HS” to ”We present two cases of co-existence of psoriasis and HS”.\n\n\n\n\n For case report 1:\nPlease provide a severity assessment for psoriasis.\n\nThe authors only refer to “extensive”. It would be important to report PASI or another measure of severity assessment. \n\n\n\n\n For case report 2:\nPlease provide a severity assessment for psoriasis as for case 1.\n\nAlso it reported negative impact on quality of life. Please provide a measure if available. For example VAS pain 6 or DLQI 10.\n\n\n\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the background of the cases’ history and progression described in sufficient detail?\n\nPartly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the conclusion balanced and justified on the basis of the findings?\n\nYes\n\nReviewer Expertise:\n\nHidradenitis suppurativa, atopic dermatitis, biologics, Evidence based medicine\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\nKanni Theodora Andreas Sygros University Hospital, Greece\n \nCompeting interests: No competing interests were disclosed.\n\n\n8 12 2020 \nDear Prof. Tzellos,\n\n We revised our manuscript according to your comments. All your comments were taken into account and please find below the answers:\nWe changed the title according to your suggestion.\n\nIn the introduction section, we changed the term comorbidity with the term co-existence.\n\nFinally, we provide severity assessment before and after treatment for both psoriasis and hidradenitis, as well as DLQI score for the impact on the quality of life.\n==== Refs\n1 \nPatel M Cohen JM Wriight NA :\nEpidemiology of concomitant psoriasis and hidradenitis suppurativa (HS): experience of a tertiary medical center.\n\nJ Am Acad Dermatol. \n2015 ;73 (4 ):701 –702\n.\n10.1016/j.jaad.2015.06.050 \n26369843 \n2 \nGiuseppe P Nicola P Valentina C :\nA Case of Moderate Hidradenitis Suppurativa and Psoriasis Treated with Secukinumab.\n\nAnn Dermatol. \n2018 ;30 (4 ):462 –464\n.\n10.5021/ad.2018.30.4.462 \n\n30065588 \n3 \nKridin K Shani M Schonmann Y :\nPsoriasis and Hidradenitis Suppurativa: A Large-scale Population-based Study.\n\nJ Am Dermatol. \n2018 ; pii: S0190-9622(18)32962-1.\n10.1016/j.jaad.2018.11.036 \n30502412 \n4 \nFrew JW Hawkes JE Krueger JG :\n A systematic review and critical evaluation of inflammatory cytokine associations in hidradenitis suppurativa [version 1; peer review: 2 approved, 1 approved with reservations].\n\nF1000Res. \n2018 ;7 :1930 .\n10.12688/f1000research.17267.1 \n\n30828428 \n5 \nFrew JW Hawkes JE Krueger JG :\nTopical, systemic and biologic therapies in hidradenitis suppurativa: pathogenic insights by examining therapeutic mechanisms.\n\nTher Adv Chronic Dis. \n2019 ;10 :2040622319830646 .\n10.1177/2040622319830646 \n\n30854183 \n6 \nKanni T Tzanetakou V Savva A :\nCompartmentalized Cytokine Responses in Hidradenitis Suppurativa.\n\nPLoS One. \n2015 ;10 (6 ):e0130522 .\n10.1371/journal.pone.0130522 \n\n26091259 \n7 \nLynde CW Poulin Y Vnder R :\nInterleukin 17A: toward a new understanding of psoriasis pathogenesis.\n\nJ Am Acad Dermatol. \n2014 ;71 (1 ):141 –150\n.\n10.1016/j.jaad.2013.12.036 \n24655820 \n8 \nPorter C Armstrong-Fisher S Kopotsa T :\nCertolizumab pegol does not bind the neonatal Fc receptor (FcRn): Consequences for FcRn-mediated\nin vitro transcytosis and\nex vivo human placental transfer.\n\nJ Reprod Immunol. \n2016 ;116 :7 –12\n.\n10.1016/j.jri.2016.04.284 \n27123565 \n9 \nDattola A Cannizzaro MV Mazzeo M :\nCertolizumab Pegol in the Treatment of Psoriasis and Psoriatic Arthritis: Preliminary Real-Life Data.\n\nDermatol Ther (Heidelb). \n2017 ;7 (4 ):485 –492\n.\n10.1007/s13555-017-0208-z \n\n29139035 \n10 \nChimenti MS Saraceno R Chiricozzi A :\nProfile of certolizumab and its potential in the treatment of psoriatic arthritis.\n\nDrug Des Devel Ther. \n2013 ;7 :339 –348\n.\n10.2147/DDDT.S31658 \n\n23620660 \n11 \nKimmel G Chima M Kim HJ :\nBrodalumab in the treatment of moderate to severe psoriasis in patients when previous anti-interleukin 17A therapies have failed.\n\nJ Am Acad Dermatol. \n2019 ;81 (3 ):857 –859\n.\n10.1016/j.jaad.2019.05.007 \n31078609 \n12 \nAttia A Abushouk AI Ahmed H :\nSafety and Efficacy of Brodalumab for Moderate-to-Severe Plaque Psoriasis: A Systematic Review and Meta-Analysis.\n\nClin Drug Investig. \n2017 ;37 (5 ):439 –51\n.\n10.1007/s40261-017-0500-9 \n28197901 \n13 \nTchero H Hrlin C Bekara F :\nHidradenitis Suppurativa: A Systematic Review and Meta-analysis of Therapeutic Interventions.\n\nIndian J Dermatol Venereol Leprol. \n2019 ;85 (3 ):248 –257\n.\n30924446 \n14 \nBilal J Riaz IB Kamal MU :\nA Systematic Review and Meta-analysis of Efficacy and Safety of Novel Interleukin Inhibitors in the Management of Psoriatic Arthritis.\n\nJ Clin Rheumatol. \n2018 ;24 (1 ):6 –13\n.\n10.1097/RHU.0000000000000583 \n28926467\n\n",
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"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000068582:Certolizumab Pegol; D005260:Female; D017497:Hidradenitis Suppurativa; D006801:Humans; D008297:Male; D011565:Psoriasis; D011788:Quality of Life; D012867:Skin",
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"title": "Case report: Treating a co-existence of hidradenitis suppurativa and psoriasis with different therapeutic approaches.",
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] |
{
"abstract": "A liver allograft recipient developed acute-type adult T-cell leukemia (ATL) during tacrolimus treatment, 2 years after undergoing transplantation for subacute fulminant hepatitis. Both donor and recipient were asymptomatic carriers of human T-cell lymphotropic virus type I (HTLV-I), but the ATL cells originated from the recipient. Tacrolimus treatment was discontinued, and combination chemotherapy was administered. The patient achieved complete remission, but the transplanted liver was acutely and chronically rejected. The patient did not respond to rescue therapy with tacrolimus, prednisolone, and mycophenolate mofetil and died of hepatic failure. Liver biopsies showed CD4+ ATL cell infiltration at the onset of ATL but not at the terminal stage. Moreover, Southern blotting revealed clonal integration of HTLV-I into the host genome of lymphoma cells at onset but not at the terminal stage. ATL after liver transplantation has not been previously described. The clinical course of the posttransplantational ATL was atypical, because it did not progress after the onset of rejection.",
"affiliations": "Department of Haematology, Kagoshima University Hospital, Kagoshima, Japan. suzuki2@m.kufm.kagoshima-u.ac.jp",
"authors": "Suzuki|Shinsuke|S|;Uozumi|Kimiharu|K|;Maeda|Masahiko|M|;Yamasuji|Yoshiko|Y|;Hashimoto|Shin-ichi|S|;Komorizono|Yasuji|Y|;Owatari|Satsuki|S|;Tokunaga|Masahito|M|;Haraguchi|Kouichi|K|;Arima|Naomichi|N|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1532/IJH97.05158",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "83(5)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D017809:Fatal Outcome; D006084:Graft Rejection; D006505:Hepatitis; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D014184:Transplantation, Homologous",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "429-32",
"pmc": null,
"pmid": "16787875",
"pubdate": "2006-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "9240905;11380402;2799926;7812011;14974943;8200004;8030652;9272134;9633895;15919464;7030473;8645854;11785849;15665110;16048490;11374406;3063441;1288292;14729650;11275994;8505941;6311121;1751370;7977487;8896433",
"title": "Adult T-cell leukemia in a liver transplant recipient that did not progress after onset of graft rejection.",
"title_normalized": "adult t cell leukemia in a liver transplant recipient that did not progress after onset of graft rejection"
} | [
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"abstract": "BACKGROUND\nCisplatin, mitomycin C and anthracyclines demonstrate high activity in BRCA1-deficient tumors. This study aimed to evaluate the efficacy of the triplet combination of these drugs in BRCA1-driven high-grade serous ovarian carcinomas (HGSOCs).\n\n\nMETHODS\nTen HGSOC patients with germ-line BRCA1 mutation received neoadjuvant chemotherapy (NACT) consisting of mitomycin C 10 mg/m2 (day 1), doxorubicin 30 mg/m2 (days 1 and 8) and cisplatin 80 mg/m2 (day 1), given every 4 weeks (MAP regimen). The comparator group included 16 women, who received standard NACT combination of paclitaxel 175 mg/m2 and carboplatin (6 AUC), given every 3 weeks (TCbP scheme).\n\n\nRESULTS\nNone of the patients treated by the MAP scheme demonstrated complete pathologic response in ovaries, while 4 women showed absence of tumor cells in surgically excised omental specimens. When chemotherapy response scores (CRS) were considered, poor responsiveness (CRS 1) was not observed in the MAP group, but was common for the TCbP regimen (6/16 (38 %) for ovaries and 5/16 (31 %) for omentum; p = 0.05 and 0.12, respectively). Median treatment-free interval (TFI) was not reached in women treated by the MAP, but was 9.5 months for the TCbP scheme (p = 0.1). The rate of the recurrence within 1 year after the completion of the treatment was 4/10 (40 %) for the MAP and 10/13 (77 %) for the TCbP (p = 0.1).\n\n\nCONCLUSIONS\nThe attempt to intensify NACT by administering combination of 3 drugs did not result in high rate of complete pathologic responses. However, there was a trend towards higher efficacy of the MAP regimen versus conventional TCbP scheme with regard to CRS and clinical outcomes.",
"affiliations": "N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.;N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.;N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.;N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.;N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.;N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.;N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.;N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.;N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.;N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia. evgeny@imyanitov.spb.ru.",
"authors": "Gorodnova|Tatiana V|TV|;Sokolenko|Anna P|AP|;Kotiv|Khristina B|KB|;Sokolova|Tatiana N|TN|;Ivantsov|Alexandr O|AO|;Guseynov|Konstantin D|KD|;Nekrasova|Ekaterina A|EA|;Smirnova|Olga A|OA|;Berlev|Igor V|IV|;Imyanitov|Evgeny N|EN|",
"chemical_list": null,
"country": "Poland",
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"doi": "10.1186/s13053-021-00173-2",
"fulltext": "\n==== Front\nHered Cancer Clin Pract\nHered Cancer Clin Pract\nHereditary Cancer in Clinical Practice\n1731-2302 1897-4287 BioMed Central London \n\n173\n10.1186/s13053-021-00173-2\nResearch\nNeoadjuvant therapy of BRCA1-driven ovarian cancer by combination of cisplatin, mitomycin C and doxorubicin\nGorodnova Tatiana V. 1 Sokolenko Anna P. 12 Kotiv Khristina B. 1 Sokolova Tatiana N. 1 Ivantsov Alexandr O. 12 Guseynov Konstantin D. 1 Nekrasova Ekaterina A. 1 Smirnova Olga A. 1 Berlev Igor V. 13 Imyanitov Evgeny N. evgeny@imyanitov.spb.ru 123 1 grid.465337.00000 0000 9341 0551N.N. Petrov Institute of Oncology, 197758 Saint-Petersburg, Russia \n2 St.-Petersburg Pediatric Medical University, 194100 Saint-Petersburg, Russia \n3 I.I. Mechnikov North-Western Medical University, 195067 St.-Petersburg, Russia \n3 2 2021 \n3 2 2021 \n2021 \n19 1415 1 2021 27 1 2021 © The Author(s) 2021Open 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\nCisplatin, mitomycin C and anthracyclines demonstrate high activity in BRCA1-deficient tumors. This study aimed to evaluate the efficacy of the triplet combination of these drugs in BRCA1-driven high-grade serous ovarian carcinomas (HGSOCs).\n\nMethods\nTen HGSOC patients with germ-line BRCA1 mutation received neoadjuvant chemotherapy (NACT) consisting of mitomycin C 10 mg/m2 (day 1), doxorubicin 30 mg/m2 (days 1 and 8) and cisplatin 80 mg/m2 (day 1), given every 4 weeks (MAP regimen). The comparator group included 16 women, who received standard NACT combination of paclitaxel 175 mg/m2 and carboplatin (6 AUC), given every 3 weeks (TCbP scheme).\n\nResults\nNone of the patients treated by the MAP scheme demonstrated complete pathologic response in ovaries, while 4 women showed absence of tumor cells in surgically excised omental specimens. When chemotherapy response scores (CRS) were considered, poor responsiveness (CRS 1) was not observed in the MAP group, but was common for the TCbP regimen (6/16 (38 %) for ovaries and 5/16 (31 %) for omentum; p = 0.05 and 0.12, respectively). Median treatment-free interval (TFI) was not reached in women treated by the MAP, but was 9.5 months for the TCbP scheme (p = 0.1). The rate of the recurrence within 1 year after the completion of the treatment was 4/10 (40 %) for the MAP and 10/13 (77 %) for the TCbP (p = 0.1).\n\nConclusions\nThe attempt to intensify NACT by administering combination of 3 drugs did not result in high rate of complete pathologic responses. However, there was a trend towards higher efficacy of the MAP regimen versus conventional TCbP scheme with regard to CRS and clinical outcomes.\n\nKeywords\nOvarian cancerBRCA1Neoadjuvant chemotherapyCisplatinMitomycin CDoxorubicinMinistry of Science and Higher Education of the Russian Federation075-15-2020-789issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nOvarian cancer (OC) is a common malignancy, which holds the leading position in the mortality caused by gynecological tumors [1]. The worldwide incidence of OC approaches approximately three hundred thousand new cases per year, with almost two-thirds of affected patients dying from this disease [2]. High-grade serous ovarian cancer (HGSOC) is the most frequent OC histological type. A significant portion of HGSOCs is attributed to germ-line mutations in BRCA1 or BRCA2 genes. BRCA1/2-driven ovarian tumors usually develop via inactivation of the remaining allele of the involved gene. Consequently, these cancers demonstrate a tumor-selective deficiency in DNA repair by homologous recombination and pronounced sensitivity to platinum compounds, PARP inhibitors and mitomycin C [3, 4].\n\nOvarian tumors often do not cause symptoms at early stages; therefore, most HGSOC patients are diagnosed with already inoperable disease. These women are often subjected to neoadjuvant chemotherapy (NACT), which is aimed to reduce tumor burden and allow surgical intervention [5]. BRCA1-associated ovarian malignancies demonstrate significantly better responses to the NACT as compared to sporadic neoplasms [6]. Although these patients usually undergo complete cytoreductive surgery followed by adjuvant therapy, most BRCA1-driven HGSOCs eventually relapse [7]. These relapses are attributed to the acquisition of the resistance of tumor clones to systemic therapy. The most known mechanism of acquired platinum resistance is the emergence of mutations, which restore the open reading frame in the BRCA1 gene [4]. This route is mainly applicable to heavily pretreated patients but appears to be less characteristic for the initial phases of OC therapy [8]. On the other hand, NACT often results in the selection of BRCA1-proficient cells, which exist in small amounts in chemonaive tumors and repopulate tumor mass during platinum exposure [9].\n\nIntensification of the therapy is a common approach aimed to prevent the emergence of resistant clones. We have previously reported promising results of applying cisplatin plus mitomycin C combination for the NACT of BRCA1-driven carcinomas. This therapy resulted in a significant reduction of the tumor burden in all analyzed patients and in complete pathologic responses observed in 2/12 (17 %) treated women [10]. We reasoned that combining this regimen with an additional drug may further improve the outcomes of NACT. Previous studies suggested that BRCA1-driven tumors are particularly sensitive to anthracyclines, while their responsiveness to taxanes is under the question [10, 11]. Consequently, we decided to add doxorubicin to cisplatin plus mitomycin C as a third drug. Here we present the results of the trial involving this 3-drug combination.\n\nMethods\nThe design of the study was discussed on the council involving medical oncologists, cancer gynecologists and hereditary cancer specialists. It was decided that the pilot trial would include 10 patients with initially inoperable BRCA1-driven HGSOC, and the main end-point will be the rate of pathologic complete responses. While all patients received the same neoadjuvant regimen (MAP: mitomycin C 10 mg/m2 (day 1), doxorubicin 30 mg/m2 (days 1 and 8), cisplatin 80 mg/m2 (day 1), given every 4 weeks), the physicians were permitted to administer the therapy of their choice after the surgery. This approach provided some flexibility given that the combination of carboplatin and paclitaxel (TCbP) is a standard option for the treatment of ovarian cancer [1] and that some post-NACT tumor samples have restored BRCA1 function and therefore may not be potentially responsive to platinum drugs [8, 9]. The recruitment of patients was performed from August 2017 to December 2018 based on the results of the PCR-based test for Slavic recurrent germ-line mutations [12, 13]. According to the study protocol, all tumor samples were subjected to the loss-of-heterozygosity (LOH) analysis before the NACT and after the surgery. LOH test was performed as described in [9]. All tumors were also analyzed for the TP53 somatic mutations, given that TP53 inactivation is a ubiquitous feature of BRCA1-driven carcinomas [14]. The study was approved by the local Ethics Committee. All patients included in the study provided informed consent.\n\nAlthough this study was not randomized, we considered for the comparison of treatment outcomes 16 consecutive patients with germ-line BRCA1 mutations, who were referred to the N.N. Petrov Institute of Oncology (St.-Petersburg, Russia) between February 2017 and December 2019 and were subjected to a standard NACT combination of paclitaxel 175 mg/m2 plus carboplatin (6 AUC), given every 3 weeks. Most of these patients were negative for PCR-detectable recurrent BRCA1 mutations; however, they were found to carry a germ-line pathogenic allele upon the analysis of the entire BRCA1 and BRCA2 coding sequence, i.e., after the start of NACT [13].\n\nAll women receiving MAP or TCbP were managed by the same surgical team. Tumor responses were evaluated according to RECIST criteria using computed tomography and magnetic resonance imaging. None of the patients treated by MAP or TCbP received bevacizumab. Three patients in the MAP arm but none in the TCbP group were subjected to the hyperthermic intraperitoneal chemotherapy (HIPEC) during surgery. None of the included patients described in this report received maintenance by PARP inhibitors after completion of the first-line therapy, as this indication was not approved in Russia at the time of the study.\n\nThe statistical analysis was performed using SPSS 13.0 software package. Age distribution and the duration of the follow-up were compared by the Mann-Whitney U-test. Median treatment-free interval (TFI) was evaluated using Kaplan-Meyer curves. Other comparisons were performed with the Fisher’s exact test.\n\nResults\nFive patients included in the study of the neoadjuvant combination of mitomycin C, cisplatin and doxorubicin had stage IIIC HGSOC and another 5 women were diagnosed with stage IV disease (Table 1). Partial response to this therapy was observed in all 10 cases considered. Seven women had toxicities of grades 1 or 2; 2 patients had toxicity grade 3 and 1 subject experienced grade IV thrombocytopenia. None of the HGSOCs showed a complete pathological response in the ovaries, and only one woman demonstrated chemotherapy response score (CRS) 3, according to Böhm et al. [15]. Omental tumor response, which is more predictive for the disease outcome than adnexal CRS [15], showed considerably better values: 4 women had no residual tumor cells in the omentum, 1 patient had CRS 3 and 5 cases demonstrated CRS 2. There were no instances of poor responsiveness to the therapy categorized as CRS 1. The median TFI and progression-free survival (PFS) were not reached.\nTable 1 BRCA1-mutated HGSOC patients receiving neoadjuvant therapy consisting of mitomycin C, doxorubicin and cisplatin\n\nID\tAge\tStage\tBRCA1 mutation\tSomatic BRCA1 status before NACT\tMAP cycles\n(NACT)\tSurgical debulking\tResponse by RECIST\tCRS (ovary / omentum)\tSomatic BRCA1 status after NACT\tACT\n(cycles)\tTFI, months\tPFS, months\tOS, months\tToxicities and grades\tTP53 mutation\t\nMAP1\t64\tIIIC\tc.5266dupC\tLOH\t3\tComplete + HIPEC\tPR (-44 %)\tCRS 3 / no tumor cells in omentum\tLOH\tMAP (2)\t25.4+\t32.2+\t32.2+\tAnemia 1; nephrotoxicity 1\tC135W\t\nMAP2\t35\tIVA (pleuritis)\tc.68_69delAG\tLOH\t3\tComplete + HIPEC\tPR (-73 %)\tCRS 2 / no tumor cells in omentum\tna\tMAP (1), AT (2)\t6.9\t14.4\t26.9\tAnemia 1\tR175H\t\nMAP3\t50\tIIIC\tc.4034delA\tLOH\t4\tComplete\tPR (-35 %)\tCRS 2 / CRS 2\tLOH\tMAP (3)\t23.6+\t31.6+\t31.6+\tAnemia 1\tY234H\t\nMAP4\t57\tIVB (lymph nodes)\tc.5266dupC\tLOH\t3\tComplete + HIPEC\tPR (-90 %)\tCRS 2 / CRS 3\tRetention of the wild-type allele\tAT (3)\t29.2+\t36.6+\t36.6+\tDiarrhea 1; emesis 1; gastritis 1; nausea 1; leukopenia 2; nephrotoxicity 2; thrombocytopenia 4\tR213X\t\nMAP5\t50\tIIIC\tc.5266dupC\tna\t3\tComplete\tPR (-33 %)\tCRS 2 / no tumor cells in omentum\tLOH\tMAP (3)\t22.2+\t29.5+\t29.5+\tAnemia 1; leukopenia 1; nausea 1; thrombocytopenia 1\tc.97-1G > A\t\nMAP6\t45\tIVB (spleen, lymph nodes)\tc.1961delA\tLOH\t4\tSuboptimal\tPR (-47 %)\tCRS 2 / CRS 2\tLOH\tTCbP (6)\t21+\t30.4+\t30.4+\tAnemia 1; nausea 1; thrombosis\tR213X\t\nMAP7\t56\tIVB (pleuritis, lymph nodes)\tc.5266dupC\tna\t3\tComplete\tPR (-47 %)\tCRS 2 / CRS 2\tLOH\tMAP (1)\t4.1\t8.3\t29.8+\tAnemia 2; nephrotoxicity 3\tc.314delG\t\nMAP8\t58\tIIIC\tc.4034delA\tLOH\t5\tComplete\tPR (-46 %)\tCRS 2 / CRS 2\tLOH\tTCbP (4)\t11.5\t20.7\t28.2+\tAnemia 1; neutropenia 2\tR248Q\t\nMAP9\t46\tIIIC\tc.4034delA\tLOH\t4\tComplete\tPR (-64 %)\tCRS 2 / CRS 2\tLOH\tMAP (2)\t3.1\t11.2\t15.8\tThrombocytopenia 2\tI255S\t\nMAP10\t40\tIVB (pleuritis, lymph nodes)\tc.5266dupC\tLOH\t4\tComplete\tPR (-36 %)\tna / no tumor cells in omentum\tna\tNone\t28.5+\t37.6+\t37.6+\tAnemia 1; hepatotoxicity 2; thrombocytopenia 2; nephrotoxicity 3\tM133R\t\nACT Adjuvant chemotherapy, AT Doxorubicin 60 mg/m2 and paclitaxel 175 mg/m2, every 3 weeks, CRS Chemotherapy response score, HIPEC hyperthermic intraperitoneal chemotherapy, LOH Loss of heterozygosity, na Not analyzed, MAP Mitomycin C 10 mg/m2 (day 1), doxorubicin 30 mg/m2 (days 1 and 8) and cisplatin 80 mg/m2 (day 1), given every 4 weeks, NACT Neoadjuvant chemotherapy, OS Overall survival, PFS Progression-free survival, PR Partial response, TCbP Paclitaxel 175 mg/m2 plus carboplatin (6 AUC), given every 3 weeks, TFI Treatment-free interval.\n\nNotes: Tumor responses presented in the table describe the status of patients observed after the completion of the NACT, i.e. straight before the surgery. Patient MAP10 was diagnosed with ovarian cancer upon surgery, which was performed in another hospital and was limited to the excision of ovaries. She was considered eligible for the NACT study, as she had a significant tumor burden and could not be subjected to primary debulking surgery; she received no adjuvant therapy, as no residual tumor cells was seen in the surgical material. Patient MAP4 demonstrated the restoration of heterozygosity in a post-NACT tumor sample, suggesting that the tumor may no longer be platinum-sensitive [8, 9]; based on this finding, combination of paclitaxel and doxorubicin was given after the surgery; similarly, this combination was incorporated in the adjuvant treatment for patient MAP2, where the molecular analysis of post-NACT tumor tissue failed to establish somatic BRCA1 status. Patients MAP6 and MAP8 received TCbP combination after the surgery due to preference of their primary physicians.\n\n\n\nSixteen patients receiving paclitaxel plus carboplatin had slightly more favorable stage distribution, as 12 subjects had HGSOC of stage IIIC and 4 patients demonstrated stage IV disease (Table 2). While all patients treated by MAP showed partial response, 4/16 (25 %) women subjected to the TCbP combination produced only the disease stabilization and there was one HGSOC with the progression on this therapy. There was a remarkable difference from MAP regimen with regard to pathological responses, as minimal response score was observed in 6/16 (38 %) cases for ovarian tumor masses and 5/16 (31 %) HGSOCs for omental metastases (p = 0.05 and 0.12, respectively). While the median follow-up for the TCbP group was shorter than for MAP patients, median TFI was already achieved and reached 9.5 months (Fig. 1). Thirteen patients had sufficient follow-up to evaluate 1-year outcomes; the recurrence rate at 1 year after the completion of the treatment was 10/13 (77 %) for the TCbP, while the same value was 4/10 (40 %) for the MAP regimen (p = 0.1).\nTable 2 Comparative characteristics of patients with BRCA1-mutated HGSOC receiving NACT combination of mitomycin C, doxorubicin and cisplatin versus women treated by paclitaxel plus carboplatin\n\nClinical characteristics\tMAP group (N = 10)\tTCbP group (N = 16)\tStatistical comparison\t\nMedian age of onset (range)\t50 (35–64)\t49 (37–72)\tNot significant\t\nPattern of BRCA1 mutations\tc.5266dupC (n = 5), c.4034delA (n = 3), c.68_69delAG (n = 1), c.1961delA (n = 1)\tc.5266dupC (n = 2), c.4034delA (n = 2), c.68_69delAG (n = 1), C61G (n = 1), c.1510delC (n = 1), Q563X (n = 1), c.2076dupT (n = 1), c.2983_2984delAA (n = 1), c.3247del5 (n = 1), c.3601_3602delGG (n = 1), c.3718_3719delCA (n = 1), Y1509X (n = 1), G1706E (n = 1), c.5152 + 1G > T (n = 1)\tp = 0.005 (founder vs. non-founder mutations; Fisher’s exact test)\t\nFIGO stage\t\n IIIC\t5 (50 %)\t12 (75 %)\tp = 0.23 (stage III vs. IV; Fisher’s exact test)\t\n IVA\t1 (10 %)\t2 (13 %)\t\n IVB\t4 (40 %)\t2 (13 %)\t\n NACT cycles (range)\t3–5\t3–8\t\t\nCytoreduction\t\n Optimal\t9 (90 %)\t14 (88 %)\tp = 1.0 (Fisher’s exact test)\t\n Suboptimal\t1 (10 %)\t1 (6 %)\t\n None\t0\t1 (6 %)\t\nResponse by RECIST\t\n CR\t0\t0\tp = 0.12 (objective response vs. lack of objective response; Fisher’s exact test)\t\n PR\t10 (100 %)\t11 (69 %)\t\n SD\t0\t4 (25 %)\t\n PD\t0\t1 (6 %)\t\nChemotherapy response score (CRS) in the ovaries\t\n CRS 1\t0\t6 (38 %)\tp = 0.05 (CRS 1 vs. other; Fisher’s exact test)\t\n CRS 2\t8 (80 %)\t9 (56 %)\t\n CRS 3\t1 (10 %)\t0\t\n Tissue not available for evaluation\t1 (10 %)\t1 (10 %)\t\nChemotherapy response score (CRS) in the omentum\t\n CRS 1\t0\t5 (31 %)\tp = 0.12 (CRS 1 vs. other; Fisher’s exact test)\t\n CRS 2\t5 (40 %)\t8 (50 %)\t\n CRS 3\t1 (10 %)\t0\t\n No tumor cells\t4 (40 %)\t2 (13 %)\t\n Tissue not available for evaluation\t0\t1 (6 %)\t\n ACT cycles (range)\t1–6\t1–6\t\t\n Median follow-up, months (range)\t30.1 (15.8–36.6)\t23.4 (10.7–45.2)\tp = 0.28 (Mann-Whitney Test)\t\n Median treatment-free interval (95 % CI)\tNot reached\t9.5 (7.8–11.2)\tp = 0.109 (Log Rank [Mantel-Cox])\t\n Recurrence within one year after completion of treatment\t4 (40 %)\t10/13a (77 %)\tp = 0.1 (Fisher’s exact test)\t\nACT adjuvant chemotherapy, CRS chemotherapy response score, MAP mitomycin C 10 mg/m2 (day 1), doxorubicin 30 mg/m2 (days 1 and 8), cisplatin 80 mg/m2 (day 1), given every 4 weeks, NACT neoadjuvant chemotherapy, TCbP paclitaxel 175 mg/m2 plus carboplatin (6 AUC), given every 3 weeks\n\na13 out of 16 patients had sufficient follow-up for the estimation of 1-year recurrence rate\n\nFig. 1 Treatment-free interval for patients treated with the combination of mitomycin C, cisplatin and doxorubicin and for women treated by the paclitaxel plus carboplatin doublet\n\n\n\nDiscussion\nOur previous study involving 12 BRCA1-mutated HGSOCs treated with the combination of cisplatin and mitomycin C revealed complete pathologic responses in 2 out of 12 patients [10]. We anticipated that the addition of doxorubicin to this combination may increase the rate of elimination of all tumor cells detectable in surgically excised tissues. The obtained data are sufficient to state that the applied triplet does not significantly increase the rate of complete pathologic responses as compared to the previously applied combination of two drugs.\n\nAt the same time, short-term results of MAP therapy look encouraging. In addition to a reasonably good rate of objective responses, half of the included cases demonstrated complete or nearly-complete absence of tumor cells in the omentum. Omental response score is the main predictor of the long-term outcomes of NACT, so it is a valuable marker allowing robust evaluation of various chemotherapy regimens [15].\n\nPrevious studies suggested that the TCbP regimen may be less efficient in BRCA1-mutated HGSOCs as compared to other NACT schemes [10]. These data sets compared prospective and retrospective patients treated by different surgeons. The quality of surgical debulking is critical for the outcome of HGSOC treatment, therefore these comparisons are prone to biases. Within the present study, we analyzed groups of patients who were managed at the same time interval by the same group of surgeons. However, the MAP and TCbP groups of patients were not balanced with regard to the pattern of mutations. The selection of patients for the MAP therapy involved rapid PCR tests for recurrent Slavic mutations [13]. The TCbP HGSOC group is significantly enriched by subjects with “rare” BRCA1 pathogenic alleles, which were detected by the next-generation sequencing analysis after the start of NACT. There are some data suggesting that distinct BRCA1 and BRCA2 mutations may exert distinct sensitivity to platinum compounds and PARP inhibitors [4]. Although we acknowledge differences in the pattern of BRCA1 mutations as a limitation of the study, it should be noted that all published trials on PARP inhibitors did not consider the type of mutation as a confounding factor [4, 16].\n\nThe landscape of the treatment BRCA1/2-mutated HGSOC is rapidly evolving. In particular, PARP inhibitors have been recently included in the standards for the first-line maintenance therapy, as they significantly delay the time to tumor recurrence [16]. None of the patients considered in this report received PARP inhibitors because they were not locally approved for early lines of HGSOC treatment at the time of the study. Consequently, it is unclear whether the differences observed between distinct NACT regimens will be maintained upon the incorporation of PARP-targeted drugs.\n\nConclusions\nIn summary, this study suggests that BRCA1-associated HGSOCs may require distinct therapeutic NACT regimens as compared to conventional TCbP doublet. If this is the case, the fast turn-around time for BRCA1/2 testing could become a critical factor for appropriate treatment decisions. Recent data indicate that BRCA1/2-associated HGSOCs do not show inferior outcomes when treated by NACT before the surgery, while primary surgical intervention is clearly the best approach in sporadic ovarian tumors [7, 17, 18]. These findings are likely to increase the acceptance of NACT for BRCA1/2 germline mutation carriers and, therefore, stimulate large neoadjuvant clinical trials for this category of HGSOC patients.\n\nAbbreviations\nCRSChemotherapy response score\n\nHGSOCHigh-grade serous ovarian cancer\n\nLOHLoss of heterozygosity\n\nMAPMitomycin C, anthracycline, platinum\n\nNACTNeoadjuvant chemotherapy\n\nOCOvarian cancer\n\nPFSProgression-free survival\n\nTCbPTaxanes and carboplatin\n\nTFITreatment-free interval\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthors’ contributions\nTG, KK, IB, KG, EN and OS managed study patients and analyzed clinical data; TS performed the molecular analysis; AI carried out morphological analysis; AS integrated and analyzed the obtained data and contributed to the manuscript preparation; EI designed the study and wrote the first draft of the manuscript. All authors have read and approved the final version of the manuscript.\n\nFunding\nThis work has been supported by the Ministry of Science and Higher Education of the Russian Federation (grant № 075-15-2020-789).\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThe study was performed in full accordance with ethics guidelines. A written informed consent from study participants was obtained.\n\nConsent for publication\nAll living patients provided the consent for publication.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Lheureux S Gourley C Vergote I Oza AM Epithelial ovarian cancer Lancet 2019 393 1240 53 10.1016/S0140-6736(18)32552-2 30910306 \n2. Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 68 394 424 10.3322/caac.21492 30207593 \n3. Iyevleva AG Imyanitov EN Cytotoxic and targeted therapy for hereditary cancers Hered Cancer Clin Pract 2016 14 17 10.1186/s13053-016-0057-2 27555886 \n4. Le Page C Amuzu S Rahimi K Gotlieb W Ragoussis J Tonin PN Lessons learned from understanding chemotherapy resistance in epithelial tubo-ovarian carcinoma from BRCA1and BRCA2mutation carriers Semin Cancer Biol. 2020 19 S1044-579X(20)30177-2 \n5. Leary A Cowan R Chi D Kehoe S Nankivell M Primary surgery or neoadjuvant chemotherapy in advanced ovarian cancer: The debate continues Am Soc Clin Oncol Educ Book. 2016 35 153 62 10.14694/EDBK_160624 27249696 \n6. Gorodnova TV Sokolenko AP Ivantsov AO Iyevleva AG Suspitsin EN Aleksakhina SN High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation Cancer Lett 2015 369 363 7 10.1016/j.canlet.2015.08.028 26342406 \n7. Gorodnova T Sokolenko A Ni V Ivantsov A Kotiv K Petrik S BRCA1-associated and sporadic ovarian carcinomas: outcomes of primary cytoreductive surgery or neoadjuvant chemotherapy Int J Gynecol Cancer 2019 29 779 86 10.1136/ijgc-2018-000175 30839285 \n8. Sokolenko AP Bizin IV Preobrazhenskaya EV Gorodnova TV Ivantsov AO Iyevleva AG Molecular profiles of BRCA1-associated ovarian cancer treated by platinum-based therapy: Analysis of primary, residual and relapsed tumors Int J Cancer 2020 146 1879 88 10.1002/ijc.32776 31693165 \n9. Sokolenko AP Savonevich EL Ivantsov AO Raskin GA Kuligina ES Gorodnova TV Rapid selection of BRCA1-proficient tumor cells during neoadjuvant therapy for ovarian cancer in BRCA1 mutation carriers Cancer Lett 2017 397 127 32 10.1016/j.canlet.2017.03.036 28377179 \n10. Gorodnova TV Kotiv KB Ivantsov AO Mikheyeva ON Mikhailiuk GI Lisyanskaya AS Efficacy of neoadjuvant therapy with cisplatin plus mitomycin C in BRCA1-mutated ovarian cancer Int J Gynecol Cancer 2018 28 1498 506 10.1097/IGC.0000000000001352 30247247 \n11. Byrski T Gronwald J Huzarski T Grzybowska E Budryk M Stawicka M Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy J Clin Oncol 2010 28 375 9 10.1200/JCO.2008.20.7019 20008645 \n12. Cybulski C Kluźniak W Huzarski T Wokołorczyk D Kashyap A Rusak B The spectrum of mutations predisposing to familial breast cancer in Poland Int J Cancer 2019 145 3311 20 10.1002/ijc.32492 31173646 \n13. Sokolenko AP Sokolova TN Ni VI Preobrazhenskaya EV Iyevleva AG Aleksakhina SN Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients Breast Cancer Res Treat 2020 184 229 35 10.1007/s10549-020-05827-8 32776218 \n14. Holstege H Joosse SA van Oostrom CT Nederlof PM de Vries A Jonkers J High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer Cancer Res 2009 69 3625 33 10.1158/0008-5472.CAN-08-3426 19336573 \n15. Böhm S Faruqi A Said I Lockley M Brockbank E Jeyarajah A Chemotherapy response score: Development and validation of a system to quantify histopathologic response to neoadjuvant chemotherapy in tubo-ovarian high-grade serous carcinoma J Clin Oncol 2015 33 2457 63 10.1200/JCO.2014.60.5212 26124480 \n16. Madariaga A Lheureux S Oza AM Tailoring ovarian cancer treatment: Implications of BRCA1/2 mutations Cancers (Basel) 2019 11 416 10.3390/cancers11030416 \n17. Petrillo M Marchetti C De Leo R Musella A Capoluongo E Paris I BRCA mutational status, initial disease presentation, and clinical outcome in high-grade serous advanced ovarian cancer: a multicenter study Am J Obstet Gynecol 2017 217 334.e1-e9 10.1016/j.ajog.2017.05.036 28549976 \n18. Ponzone R BRCA1/2 status and chemotherapy response score to tailor ovarian cancer surgery Crit Rev Oncol Hematol 2020 157 103128 10.1016/j.critrevonc.2020.103128 33137578\n\n",
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"title": "Neoadjuvant therapy of BRCA1-driven ovarian cancer by combination of cisplatin, mitomycin C and doxorubicin.",
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"abstract": "A variety of behavioral interventions have been shown to improve symptoms of non-rapid eye movement parasomnias. Prior reports have typically examined outcomes of a single behavioral intervention. However, non-rapid eye movement parasomnias may benefit from a multipronged treatment approach similar to that used in the behavioral treatment of other sleep disorders. Through a series of 3 case reports, we demonstrate the utility of a case-conceptualization based, integrative approach to behavioral treatment of adult non-rapid eye movement parasomnias. For all patients (2 with disorders of arousal and 1 with sleep-related eating disorder), symptoms were satisfactorily reduced after 3-6 sessions. Treatment was tailored to each individual, but common elements included education, hypnosis, and identifying and reducing priming factors (eg, stress, insufficient sleep) and precipitating factors (eg, noise or touch from bed partners).",
"affiliations": "Department of Neurology, Center for Circadian and Sleep Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Department of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah.",
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"abstract": "METHODS\nTwo female patients aged over 80 years developed central nervous symptoms after drinking large amounts of water (more than 3 l per day).\n\n\nMETHODS\nBoth had a hypoosmolar hyponatremia that was induced by concomitant treatment with hydrochlorothiazid (HCT) in the one case and in the other case relied on a distal tubular damage due to reflux nephropathy.\n\n\nMETHODS\nHyponatremia was corrected after withdrawal of HCT and fluid restriction and central nervous symptoms disappeared rapidly.\n\n\nCONCLUSIONS\nDistal tubular urinary dilution can be disturbed by HCT and parenchymal renal disease and can result in symptomatic hyponatremia after drinking large amounts of water.",
"affiliations": "Medizinische Klinik, Universitätsklinikum Tübingen.;Medizinische Klinik, Universitätsklinikum Tübingen.;Medizinische Klinik, Universitätsklinikum Tübingen.;Urologische Klinik, Universitätsklinikum Tübingen.",
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{
"abstract": "BACKGROUND\nAtypical hemolytic uremic syndrome (aHUS) is a rare disease with a high recurrence rate after kidney transplantation. In most cases, aHUS are caused by genetic mutations of components of the complement alternative pathway. In this single-center series, we present our data of 12 consecutive patients with aHUS and the outcome after kidney transplantation.\n\n\nMETHODS\nIn this 10-year retrospective study, we identified 12 patients with aHUS who were managed in our center since 2003. We reviewed clinical data, including genetic testing, posttransplant course and response to therapy including the prophylactic use of eculizumab.\n\n\nRESULTS\nOverall, eight patients are women. Six of our patients have at least one genetic mutation causing aHUS, including 4 with complement factor H mutations. Nine patients had at least one previous kidney transplant that failed secondary to recurrent aHUS (75% of our patients). Three patients were treated with eculizumab and plasmapheresis for recurrent aHUS after kidney transplantation; two of them responded to the therapy. Four patients received prophylactic eculizumab; three of them received 6 months and one has been on life long therapy. No signs of recurrence have been observed in these 4 patients so far.\n\n\nCONCLUSIONS\nGenetic mutations of the complement alternative pathway were confirmed in half of our patients, most of those mutations are in CHF. We demonstrate that treatment or prophylaxis with eculizumab was effective in reversing or preventing aHUS whether or not genetic complement mutations were identified.",
"affiliations": "1 Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD. 2 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD. 3 Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD. 4 Address correspondence to: Nada Alachkar, M.D., Johns Hopkins University School of Medicine, 600 Wolfe Street. Brady 502, Baltimore, MD 21287.",
"authors": "Matar|Dany|D|;Naqvi|Fizza|F|;Racusen|Lorraine C|LC|;Carter-Monroe|Naima|N|;Montgomery|Robert A|RA|;Alachkar|Nada|N|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D017242:Complement Factor H; C481642:eculizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000000200",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "98(11)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D065766:Atypical Hemolytic Uremic Syndrome; D002648:Child; D002675:Child, Preschool; D017242:Complement Factor H; D003170:Complement Pathway, Alternative; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010956:Plasmapheresis; D011183:Postoperative Complications; D012008:Recurrence; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"pages": "1205-12",
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"pubdate": "2014-12-15",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Atypical hemolytic uremic syndrome recurrence after kidney transplantation.",
"title_normalized": "atypical hemolytic uremic syndrome recurrence after kidney transplantation"
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"literaturereference": "MATAR D, NAQVI F, RACUSEN LC, CARTER-MONROE N, ALACHKAR N, MONTGOMERY RA.. ATYPICAL HEMOLYTIC UREMIC SYNDROME RECURRENCE AFTER KIDNEY TRANSPLANTATION. TRANSPLANTATION. 2014;98 (11):1205-1212",
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{
"abstract": "OBJECTIVE\nDespite morbidities and fatalities, nationwide epidemiologic data for severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), are not widely available. We aimed to investigate SCAR epidemiology over the last two decades in Korea.\n\n\nMETHODS\nWe analyzed individual case safety reports (ICSRs) of SCARs in the Korea Adverse Event Reporting System from 1988 to 2013. Administered drugs, demographic profiles, and causality assessment according to the World Health Organization-Uppsala Monitoring Center system were analyzed.\n\n\nRESULTS\nA total of 755 SCAR cases (508 SJS/TEN, 247 DRESS) were reported. The number of SCAR ICSRs has been increasing with increasing ICSRs for overall adverse drug events. Since 2010, the number of SCAR ICSRs has increased up to 100 cases/year. Allopurinol was the most common causative drug (SJS/TEN: 10.2%; DRESS: 11.3%; SCAR ICSRs: 10.6%), followed by carbamazepine (SJS/TEN: 8.7%; DRESS: 9.7%; SCAR ICSRs: 8.6%). Regarding drug groups, antiepileptics (19.5%) and antibiotics for systemic use (12.7%) were common causative drug groups. Twenty SCAR-related deaths were recorded. Antibacterials were the most common causes of deaths (8 cases), followed by antiepileptics (5 cases). The potential risk of SCARs was not specified in the drug information leaflet for 40.2% of drugs causing SJS/TEN and 82.5% causing DRESS syndrome in Korea.\n\n\nCONCLUSIONS\nThe number of SCAR ICSRs has increased rapidly with recent active pharmacovigilance programs in Korea. Allopurinol and antiepileptics are the most common individual and categorical causative agents, respectively.",
"affiliations": "Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.;Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.;Regional Pharmacovigilance Center, Seoul National University Hospital, Seoul, Korea.;Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.;Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.;College of Pharmacy, Seoul National University, Seoul, Korea.;Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.",
"authors": "Kang|Min Gyu|MG|https://orcid.org/0000-0002-3239-4492;Sohn|Kyung Hee|KH|https://orcid.org/0000-0001-8407-8080;Kang|Dong Yoon|DY|https://orcid.org/0000-0003-4283-2633;Park|Han Ki|HK|https://orcid.org/0000-0002-5460-9917;Yang|Min Suk|MS|https://orcid.org/0000-0002-9861-0530;Lee|Ju Yeun|JY|https://orcid.org/0000-0002-2261-7330;Kang|Hye Ryun|HR|https://orcid.org/0000-0002-2317-4201",
"chemical_list": "D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D002220:Carbamazepine; D000493:Allopurinol",
"country": "Korea (South)",
"delete": false,
"doi": "10.3349/ymj.2019.60.2.208",
"fulltext": "\n==== Front\nYonsei Med JYonsei Med. JYMJYonsei Medical Journal0513-57961976-2437Yonsei University College of Medicine 10.3349/ymj.2019.60.2.208Original ArticleAllergyAnalysis of Individual Case Safety Reports of Severe Cutaneous Adverse Reactions in Korea https://orcid.org/0000-0002-3239-4492Kang Min-Gyu 123https://orcid.org/0000-0001-8407-8080Sohn Kyung-Hee 14https://orcid.org/0000-0003-4283-2633Kang Dong-Yoon 56https://orcid.org/0000-0002-5460-9917Park Han-Ki 17https://orcid.org/0000-0002-9861-0530Yang Min-Suk 18https://orcid.org/0000-0002-2261-7330Lee Ju-Yeun 9https://orcid.org/0000-0002-2317-4201Kang Hye-Ryun 156101 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.2 Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea.3 Regional Pharmacovigilance Center, Chungbuk National University Hospital, Cheongju, Korea.4 Department of Internal Medicine, Kyung-Hee University Hospital, Seoul, Korea.5 Regional Pharmacovigilance Center, Seoul National University Hospital, Seoul, Korea.6 Drug Safety Monitoring Center, Seoul National University Hospital, Seoul, Korea.7 Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea.8 Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea.9 College of Pharmacy, Seoul National University, Seoul, Korea.10 Division of Allergy and Clinical Immunology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.Corresponding author: Hye-Ryun Kang, MD, PhD, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Tel: 82-2-2072-0820, Fax: 82-2-742-3291, helenmed@snu.ac.kr01 2 2019 17 1 2019 60 2 208 215 19 9 2018 21 12 2018 29 12 2018 © Copyright: Yonsei University College of Medicine 20192019Yonsei University College of MedicineThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://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.Purpose\nDespite morbidities and fatalities, nationwide epidemiologic data for severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), are not widely available. We aimed to investigate SCAR epidemiology over the last two decades in Korea.\n\nMaterials and Methods\nWe analyzed individual case safety reports (ICSRs) of SCARs in the Korea Adverse Event Reporting System from 1988 to 2013. Administered drugs, demographic profiles, and causality assessment according to the World Health Organization-Uppsala Monitoring Center system were analyzed.\n\nResults\nA total of 755 SCAR cases (508 SJS/TEN, 247 DRESS) were reported. The number of SCAR ICSRs has been increasing with increasing ICSRs for overall adverse drug events. Since 2010, the number of SCAR ICSRs has increased up to 100 cases/year. Allopurinol was the most common causative drug (SJS/TEN: 10.2%; DRESS: 11.3%; SCAR ICSRs: 10.6%), followed by carbamazepine (SJS/TEN: 8.7%; DRESS: 9.7%; SCAR ICSRs: 8.6%). Regarding drug groups, antiepileptics (19.5%) and antibiotics for systemic use (12.7%) were common causative drug groups. Twenty SCAR-related deaths were recorded. Antibacterials were the most common causes of deaths (8 cases), followed by antiepileptics (5 cases). The potential risk of SCARs was not specified in the drug information leaflet for 40.2% of drugs causing SJS/TEN and 82.5% causing DRESS syndrome in Korea.\n\nConclusion\nThe number of SCAR ICSRs has increased rapidly with recent active pharmacovigilance programs in Korea. Allopurinol and antiepileptics are the most common individual and categorical causative agents, respectively.\n\nPharmacovigilanceStevens-Johnson syndrometoxic epidermal necrolysisdrug hypersensitivity syndromeMinistry of Food and Drug Safetyhttps://doi.org/10.13039/501100003569\n==== Body\nINTRODUCTION\nAn adverse drug reaction (ADR) is defined as an unintended harmful reaction to a drug.1 With advances in medicine, people are taking more medications, and adverse drug events (ADEs) are rapidly increasing. Lazzarou, et al.2 reported that ADRs are the fourth leading cause of death in the US, after heart disease, cancer, and stroke. According to the Global Burden of Disease report of 2013, the number of worldwide ADR-related deaths was 142000 in 2013, a 1.5-fold increase over that reported in 1990.3 Thus, ADR is an important medical issue related to patient safety and a heavy socioeconomic burden.\n\nCutaneous ADR is the most common type of ADR and can be caused by many widely used medications.4 Despite cutaneous ADRs being usually self-limited, some ADEs can manifest as severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS) syndrome. Although early diagnosis of SCARs is crucial, it is difficult to differentiate SCARs at initial presentation from other disease conditions with cutaneous manifestations. Therefore, the mortality due to SCARs is considerably high (20–25%), and morbidities causing lasting disabilities are also relatively common.5\n\nThe epidemiology of SCARs seems to be different between countries. SCAR development is known to be significantly influenced by both genetic background and the pattern of drug usage. Previous studies have reported that the epidemiology of SCARs in Korean people seem different from that in Europeans, as well as the Han Chinese in East Asia.67 However, to date, there has been no nationwide epidemiologic study of SCARs in Korea.\n\nIn this study, we aimed to investigate the epidemiology and common causative drugs of SCARs by reviewing individual case safety reports (ICSRs) of the Korea Adverse Event Reporting System (KAERS) since its introduction in 1988.\n\nMATERIALS AND METHODS\nKAERS\nThe KAERS is an ADE reporting system developed by the Korea Institute of Drug Safety and Risk Management (KIDS), an official agency for managing drug safety. It contains ICSRs of any suspected ADEs voluntarily reported by healthcare personnel, consumers, and manufacturers. Each ICSR contains the following information: 1) demographic profile of the patient with the suspected ADE, 2) phenotype coded according to World Health Organization Adverse Reactions Terminology (WHO-ART 092 version), seriousness, and outcome, 3) causative drug or drugs and/or co-administered drugs coded according to the Anatomical Therapeutic Chemical (ATC) classification system and the dose/route/frequency/duration of these medications, and 4) causality assessment performed by specialists of each regional pharmacovigilance center according to the WHO-Uppsala Monitoring Center (UMC) criteria.\n\nSelection of SCAR ICSRs\nThis study was approved by the Review Board of Korea Institute of Drug Safety and Risk Management. We extracted ICSRs from 1988 to 2013 that were in line with WHO-ART codes from the KIDS-KAERS database (KIDS-KD): 1) SJS, WHO-ART code “0042/001/0014/0100”; 2) TEN, WHO-ART code “0013/005/0014/0100”; and 3) DRESS syndrome, WHO-ART code “2309/002/1810/.” ICSRs of drug hypersensitivity syndrome (WHO-ART code “2309/001/1810/”), which was formerly usually used to describe DRESS-like symptoms, were also extracted. Two allergy specialists with experience in pharmacovigilance independently reviewed the detailed information in each ICSR of suspected SCARs and rechecked the causality assessment and culprit drugs (Fig. 1). Among the ICSRs of suspected SCARs extracted from the KIDS-KD, only the ICSRs in which two allergy specialists assessed the causality as “possible,” “probable,” or “certain” were included for analysis. Some ICSRs coded for drug hypersensitivity syndrome were re-categorized into ICSRs for DRESS syndrome if they matched the diagnostic criteria for DRESS syndrome. For the assessment of causative drugs, we included ICSRs in which a single drug was listed as the causative drug or in which multiple drugs were listed but co-administration was usually regarded as standard therapy, such as anti-tuberculosis treatments. We did not consider ICSRs of SCARs in which all the co-administered drugs were listed as causative drugs or there was no detailed information to assess the culprit drug based on the history of ICSRs. To minimize the possibility of duplication or overestimation of SCAR ICSRs, reports from pharmaceutical companies based on literature reviews or consumer protection agencies lacking drug information or causality assessments were excluded from analysis.\n\nRESULTS\nSummary of SCAR ICSRs\nFrom 1988 to 2013, a total of 478519 ADEs were spontaneously included in the KAERS. Of those, 755 cases (0.16%) were of SCARs, comprising 508 cases of SJS/TEN (67.3%) and 247 cases of DRESS syndrome (32.7%). Since the reporting of the first SCAR case in 1991, an increasing tendency has been observed for SCAR ICSRs (Fig. 2). Since 2010, more than 100 SCAR ICSRs have been submitted annually. Despite the increasing tendency of SCAR ICSRs, the proportion of SCAR ICSRs among all ICSRs did not increase (0.19% in 2010, 0.25% in 2011, 0.17% in 2012, and 0.11% in 2013).\n\nThe clinical characteristics of SCAR ICSRs are described in Table 1. The mean age of patients with SCARs was 50.3±20.7 years (mean±SD), of which 28.4% were older adults (age: 65 years or more) and 8.2% were children/adolescents (age: 18 years or less). Male patients accounted for 48.7% of the total ICSRs. The mean age and proportion of the older adult patients with SJS/TEN were not significantly different from those with DRESS syndrome (53.1±17.8 years vs. 48.8±22.0 years and 29.7% vs. 27.7%, respectively). Further, the proportion of childhood/adolescent patients was significantly higher in the SJS/TEN group than in the DRESS group (11.1% vs. 2.6%, respectively, p<0.01).\n\nThe most common drug administration route was oral (72.3%), followed by intravenous injection (25.8%), subcutaneous injection (1.0%), and eye-drop instillation (0.9%). The drug administration route was not different between the DRESS and SJS/TEN groups (p>0.05). The median time for symptom latency (from drug administration to symptom onset) was 19 days, with a mean±SD of 24.6±21.5 days. The median time for symptom latency was longer in the DRESS group than in the SJS/TEN group, by a median of 11 days (31.2±26.0 days vs. 20.4±17.0 days, p<0.05).\n\nCausative drugs\nThe most common causative drug in the SCAR ICSRs was allopurinol (10.6%), the proportion of which was the highest in both the DRESS and SJS/TEN groups (Table 2), followed by carbamazepine (8.6%), lamotrigine (4.4%), methazolamide (2.1%), valproic acid (2.1%), vancomycin (1.6%), dapsone (1.5%), paracetamol (1.3%), amoxicillin and/or enzyme inhibitor (1.2%), piperacillin and/or enzyme inhibitor (1.2%), and sulfamethoxazole and trimethoprim (1.2%). Table 2 shows detailed information for causative drugs listed in SCAR ICSRs.\n\nAccording to the ATC subgroups, antiepileptics (ATC code: N03A) were the most common causative drugs (19.5% of total SCAR ICSRs), followed by antibacterials (ATC code: J01A, 12.7%), anti-gout preparations (ATC code: M04A, 10.6%), and non-steroidal anti-inflammatory drugs (NSAIDs, ATC code: M01A, 4.7%).\n\nAmong antiepileptics, carboxamide derivatives (ATC code N03AF, 9.7% of total SCAR ICSRs) including carbamazepine and oxcarbazepine were the most common SCAR-causing drugs, followed by other antiepileptics including lamotrigine (ATC code N03AX, 6.2%), fatty acid derivatives including valproic acid (ATC code: N03AG, 2.1%), and hydantoin derivatives including phenytoin (ATC code: N03AB, 1.1%). Among antibacterials, cephalosporin (ATC code: J01DB, J01DC, J01DD, and J01DE) was the most common SCAR-causing antibacterial (3.6% of total SCAR ICSRs), followed by beta-lactam antibacterials; penicillins (ATC code: J01C, 2.8%) including ampicillin, amoxicillin, and piperacillin; other antibacterials including glycopeptide antibacterials (ATC code: J01X, 1.7%); quinolone antibacterials (ATC code: J01M, 1.5%); and sulfonamides and trimethoprim (ATC code: J01E, 1.2%). Among NSAIDs (ATC code: M01A, 4.4%), propionic acid derivatives (ATC code: M01AE) including ibuprofen and dexibuprofen were the most common SCAR-causing NSAIDs (2.0%), followed by acetic acid derivatives and related substances including diclofenac or aceclofenac (ATC code: M01AB, 0.8%), coxibs (ATC code: M01AH, 0.5%), and fenamates (ATC code: M01AG, 0.5%). Fig. 3 shows the detailed proportions of SCAR-causing drugs according to the pharmacologic main group (level 2) or pharmacologic/therapeutic subgroup (level 3) per the WHO's ATC classification system.\n\nDrug labeling information\nWe reviewed the drug labeling information provided by the Korea Pharmaceutical Information Center (http://www.health.kr) to examine whether the potential to cause SCARs was specified in the drug labeling information (Table 2). The labeling information of 59.8% of the 61 SJS/TEN-causing drugs specified the potential risk for SJS/TEN. In almost all SJS/TEN cases (90.2%), SJS/TEN was caused by drugs whose potential to cause the condition was specified in the drug labeling information. With regard to DRESS, the labeling information of only 14 of 80 (17.5%) causative drugs specified the potential risk for DRESS. Approximately 60% of DRESS cases were attributable to drugs whose labeling information did not specify the potential to cause DRESS. Among antitubercular drugs, which were the culprit drugs in 12 DRESS cases, the drug label for only ethambutol mentioned its potential to cause DRESS syndrome. The potential risk for the development of DRESS was not specified in the leaflets of other anti-tuberculosis drugs, such as rifampin, isoniazid, and pyrazinamide.\n\nMortality review\nSCAR-related deaths were reported in 2.6% SCAR ICSRs (20 out of 755 SCAR ICSRs) (Table 3). With regard to DRESS syndrome, the drug-associated mortality rate was 1.2%, with voriconazole, phenytoin, and oxcarbazepine each accounting for one death. The mortality rate in the SJS/TEN group was 3.3%, with two cases attributable to allopurinol, eight to anti-infectives, two to antiepileptics, two to antitubercular drugs, and one case each to fenofibrate, methazolamide, and anti-leukemia drugs. Among the cases in which death occurred, death in two DRESS syndrome cases (voriconazole and phenytoin) and three SJS/TEN cases (cefazedone, doxycycline, and fenofibrate) was attributable to drugs whose potential to cause SCARs was not indicated on the drug label.\n\nDISCUSSION\nIn this study, we investigated SCAR ICSRs submitted to the KAERS since 1989. Recently, the tendency for SCAR ICSRs has increased, with more than 100 SCAR ICSRs spontaneously submitted annually. Allopurinol and carbamazepine were the most common SCAR-causing drugs. Antiepileptics and antibacterials were the most common SCAR-inducing drug groups. The mortality rates in SCAR ICSRs in Korea were considerably lower (2.6%) than those reported in other countries. The potential risk for SCAR development was not sufficiently specified in the drug labeling information, especially for DRESS syndrome (82.5% of drugs in the DRESS group and 17.5% of drugs in the SJS/TEN group).\n\nSince SCARs are rare, their epidemiology has not been sufficiently studied in Korea. Few studies have been published on the epidemiologic nature and causative drugs of SCARs in Korea. Furthermore, these studies were conducted in a single hospital or a limited number of hospitals, making it difficult to draw nationwide assumptions regarding SCAR development. Recently, a multicenter study based on the Korean Pharmacovigilance Research Network database reported that there were 100 SCAR cases from July 2009 to December 2010.8 Yang, et al.9 evaluated the nationwide claims database in Korea and reported that the incidence of SJS ranged from 3.96 to 5.03 per million and that of TEN ranged from 0.94 to 1.45 per million from 2010 to 2013. In our study, 755 SCAR cases were reported since ADE spontaneous reporting began in Korea. The number of ICSRs of SCARs has been increasing in Korea. More than 100 SCAR cases have been spontaneously reported every year since 2010. A total of 193 cases was spontaneously reported to KAERS in 2013. It remains unclear whether the increasing trend of SCAR ICSRs resulted from an actual increase in the development of SCARs in Korea. Although SCAR ICSRs are steadily increasing, the proportion of SCAR ICSRs among ICSRs of overall adverse events is declining. Thus, the increasing SCAR ICSRs seem to be the result of active pharmacovigilance by regional pharmacovigilance centers rather than being truly an increase in SCAR ICSRs.\n\nAlthough allopurinol-induced and carbamazepine-induced SCARs are both common in Korea and in other countries,10 the epidemiology of SCARs in Korea might be somewhat different from that in other countries.11 Allopurinol-induced SCARs are common in Korea and Taiwan. The HLA-B*58:01 genotype is a well-known risk factor for allopurinol-induced SCARs in the Han Chinese in Taiwan (OR 580.3).12 The allele frequency of HLA-B*58:01 is 12.2% in Koreans13 and 9–11% in the Han Chinese,12 such that HLA-B*58:01 screening proved to be effective to prevent allopurinol-induced SCARs in Korea14 and Taiwan.15 However, the allele frequency of HLA-B*58:01 is lower in Japanese (1–2%)16 and Caucasians (1–6%).17 Carbamazepine-induced SCAR is also common in Korea and Taiwan. In the Han Chinese, the incidence of carbamazepine-induced SCARs was more than 10-fold higher than that in other ethnic groups.18 The HLA-B*15:02 haplotype is clearly associated with carbamazepine-induced SCARs (OR 2504.0).19 However, the HLA-B15:02 allele frequency was show to be quite low (0.41%) in the Korean population, compared to that in Han Chinese (10–15%).1920 Instead, HLA-A3101 is highly associated with carbamazepine-induced SJS in Korean population.6 Abacavir, which is an anti-retroviral drug used to treat HIV/AIDS, is known to frequently elicit hypersensitivity reactions in individuals of European descent.21 However, abacavir-induced SCAR ICSRs have not been reported in Korea. Methazolamide was one of the common SCAR-causing drugs in our study. HLA-B*59:01 is a known risk factor for methazolamide-induced SCARs. The HLA-B*59:01 allele is present in 1–2% of Korean population, but in <0.5% of Chinese population, and is extremely rare in Caucasian individuals.22 To date, methazolamide-related SCARs have been reported only in Koreans, Japanese, and Chinese.\n\nThe mortality rate in SCAR ICSRs in our study was much lower than rates in other studies.21232425 Mortality due to SJS and TEN has been previously reported to be 1–13% and 30–50%, respectively. In our study, the mortality rates in SJS ICSRs and TEN ICSRs were 2.9% (12 cases among 408 SJS ICSRs) and 5% (5 cases among 100 TEN ISCRs), respectively. The mortality rates in DRESS ICSRs were also quite low in our study (1.2%), compared to those in other studies (approximately 10%).2627 It is difficult to generalize whether the mortality rate associated with SCARs in Korea is lower than rates in other countries. We retrospectively reviewed the SCAR ICSRs in the KIDS-KD. Sekula, et al.24 reported that a considerable number of SCAR-related deaths occurred after successful treatment and following hospital discharge. If the outcomes in SCAR ICSRs are not properly followed up, SCAR-related mortality might be underestimated. However, Yang, et al.9 analyzed Korean national health insurance data and reported that the mortality associated with TEN was approximately 15%, which was still lower than that in other countries.\n\nThe labeling information of many drugs in our study did not contain relevant warnings for the possibility of SCAR development. Information about the potential risk for DRESS syndrome was not mentioned in the labeling information for approximately two-thirds of the DRESS-causing drugs in our study. Although approximately 5% of all DRESS syndrome cases were attributable to dapsone and lamotrigine, the relevant labeling information for DRESS syndrome was not included for either drug. Among the 10 common DRESS syndrome-inducing drugs, the risk for DRESS syndrome was mentioned in the labeling information for only five drugs. Considering the severity of SCARs, it will be necessary to mention the potential risk of SCAR development in the labeling information during post-marketing surveillance.\n\nThis study has some limitations. First, it was based on the ICSRs from the KIDS-KD, which is based on a spontaneous ADE reporting system. Therefore, the numbers may be underestimated due to underreporting. Second, the information in the ICSRs might not be sufficient to fully evaluate the complex epidemiologic nature of SCARs. Important epidemiologic factors were sometimes omitted in the ICSRs. Notably, multiple drugs taken at the time of symptom onset were registered as causative agents in cases in which the SCAR-inducing drug could not be determined. To overcome these limitations, the SCAR Special Interest Group was formed and a web-based SCAR registry was established in Korea. The SCAR registry enrolled patients with SCARs and gathered detailed epidemiologic information on baseline characteristics and various SCAR-associated phenotypes, in addition to collecting blood samples for the evaluation of genetic factors, such as HLA haplotype.\n\nWe investigated the epidemiologic characteristics and causative drugs of SCARs in Korea using a nationwide ICSR database. Allopurinol was the most common SCAR-inducing individual drug in both the DRESS and SJS/TEN groups. Antiepileptics were the most common SCAR-causing drug group, followed by antibacterials and NSAIDs. We found that, despite the seriousness of SCARs, the potential of a drug to cause SCARs was not mentioned in the labeling information for more than half of the culprit agents studied.\n\nACKNOWLEDGEMENTS\nThis research was supported by a grant from the Ministry of Food and Drug Safety to the regional pharmacovigilance center in 2017.\n\n\nConceptualization: Min-Gyu Kang, Han-Ki Park, Hye-Ryun Kang.\n\nData curation: Min-Gyu Kang, Han-Ki Park.\n\nFormal analysis: Min-Gyu Kang, Han-Ki Park.\n\nFunding acquisition: Min-Gyu Kang, Hye-Ryun Kang.\n\nInvestigation: Min-Gyu Kang, Hani-Ki Park, Hye-Ryun Kang.\n\nMethodology: Min-Gyu Kang, Dong-Yoon Kang, Min-Seok Yang, Kyung-Hee Sohn.\n\nProject administration: Min-Gyu Kang.\n\nResources: Min-Gyu Kang, Han-Ki Park.\n\nSoftware: Min-Gyu Kang.\n\nSupervision: Min-Seok Yang, Hye-Ryun Kang, Ju-Yeun Lee.\n\nValidation: Min-Gyu Kang, Kyung-Hee Sohn, Ju-Yeun Lee.\n\nVisualization: Min-Gyu Kang.\n\nWriting—original draft: Min-Gyu Kang, Hye-Ryun Kang.\n\nWriting—review & editing: Min-Gyu Kang, Dong-Yoon Kang, Min-Seok Yang, Ju-Yeun Lee, Han-Ki Park, Kyung-Hee Sohn, Hye-Ryun Kang.\n\n\n\n\nThe authors have no potential conflicts of interest to disclose.\n\nFig. 1 Scheme of the selection process for ICSRs of SCARs in the KIDS-KD. ICSRs, individual case safety reports; SCARs, severe cutaneous adverse reactions; KIDS-KD, Korea Institute of Drug Safety and Risk Management-Korea Adverse Event Reporting System database; ADE, adverse drug event; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; DRESS syndrome, drug reaction with eosinophilia and systemic symptoms syndrome; DHS, drug hypersensitivity syndrome; WHO-ART, World Health Organization Adverse Reactions Terminology.\nFig. 2 Trends in annual numbers of ICSRs of SCARs in KAERS. ICSRs, individual case safety reports; SCARS, severe cutaneous adverse reactions; KAERS, Korea Adverse Event Reporting System; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; DRESS syndrome, drug reaction with eosinophilia and systemic symptoms syndrome.\nFig. 3 Proportion of causative drugs for SCARs categorized by the main therapeutic group (second level) per ATC classification. (A) Total, (B) SJS/TEN, (C) DRESS syndrome. SCARs, severe cutaneous adverse reactions; ATC, anatomical therapeutic chemical; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; DRESS syndrome, drug reaction with eosinophilia and systemic symptom syndrome. ATC code: B01 (antithrombotic agents), H02 (corticosteroids for systemic use), J01 (antibacterials for systemic use), J04 (antimycobacterials), L01 (antineoplastic agents), M01 (anti-inflammatory and antirheumatic products), M04 (anti-gout preparations), N02 (analgesics), N03 (antiepileptics), S01 (ophthalmologicals), and undetermined (cases in which two or more drugs were simultaneously reported as a causative agent so that the culprit drug could not be identified).\nTable 1 Baseline Characteristics in Individual Case Safety Reports of SCARs\n\tTotal\tDRESS syndrome\tSJS/TEN\t\nNumber of self-reports\t755\t247\t508\t\nAge (mean±SD, yr)\t50.3±20.7\t53.1±17.8\t48.8±22.0\t\n Elderly (≥65 yrs) (%)\t28.4\t29.7\t27.7\t\n Children/adolescents (≤18 yrs) (%)\t8.2\t2.6\t11.1\t\nMale sex (%)\t48.7\t49.2\t48.5\t\nNumber of causative drugs (mean±SD)\t1.6±1.2\t1.5±0.9\t1.6±1.2\t\nLatent period [median (mean±SD), days]\t19 (24.6±21.5)\t27 (31.2±26.0)\t16 (20.4±17.0)\t\nRoute of administration (%)\t\t\t\t\n Oral\t72.3\t70.6\t72.8\t\n Intravenous injection\t25.8\t27.5\t25.3\t\n Others (subcutaneous or eye-drop instillation)\t1.9\t1.8\t2.0\t\nSD, standard deviation; SCARs, severe cutaneous adverse reactions; DRESS syndrome, drug reaction with eosinophilia and systemic symptoms syndrome; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.\n\nTable 2 Common SCAR-Causing Drugs and Drug Labeling Information\nSCARs\tn\tDRESS syndrome\tn\tSJS/TEN\tn\t\nTotal\t755\tTotal\t247\tTotal\t508\t\nAllopurinol\t80\tAllopurinol\t28\tAllopurinol\t52\t\nCarbamazepine\t65\tCarbamazepine\t24\tCarbamazepine\t41\t\nLamotrigine\t33\tDapsone*\t9\tLamotrigine\t25\t\nMethazolamide\t16\tLamotrigine*\t8\tMethazolamide\t16\t\nValproic acid\t16\tOxcarbazepine\t8\tValproic acid\t10\t\nVancomycin\t12\tVancomycin\t7\tParacetamol\t9\t\nDapsone\t11\tPiperacillin and enzyme inhibitor*\t7\tAmoxicillin and enzyme inhibitor\t8\t\nParacetamol\t10\tCefotaxime*\t6\tTMP/SMX\t7\t\nAmoxicillin and enzyme inhibitor\t9\tValproic acid\t6\tIbuprofen\t6\t\nPiperacillin and enzyme inhibitor\t9\tCiprofloxacin*\t4\tCeftriaxone\t5\t\nTMP/SMX\t9\tPhenytoin*\t4\tIloprost*\t5\t\nOxcarbazepine\t8\tRifampicin*\t3\tVancomycin\t5\t\nPhenytoin\t8\tOthers\t56\tAcetylsalicylic acid\t4\t\nCeftriaxone\t7\tUndetermined\t77\tCelecoxib\t4\t\nIbuprofen\t7\t\t\tDoxycycline*\t4\t\nCefotaxime\t6\t\t\tMefenamic acid\t4\t\nCiprofloxacin\t6\t\t\tPhenytoin\t4\t\nAcetylsalicylic acid\t5\t\t\tAmoxicillin and enzyme inhibitor\t3\t\nIloprost\t5\t\t\tClarithromycin\t3\t\nCelecoxib\t4\t\t\tDiclofenac\t3\t\nDiclofenac\t4\t\t\tDorzolamide\t3\t\nDoxycycline\t4\t\t\tEnalapril\t3\t\nMefenamic acid\t4\t\t\tGabapentin\t3\t\nPropionic acid derivatives\t4\t\t\tMethotrexate\t3\t\nSulfasalazine\t4\t\t\tPropionic acid derivatives\t3\t\nClarithromycin\t3\t\t\tTramadol\t3\t\nDorzolamide\t3\t\t\tZonisamide\t3\t\nEnalapril\t3\t\t\tOthers\t105\t\nFenofibrate\t3\t\t\tUndetermined\t164\t\nGabapentin\t3\t\t\t\t\t\nLevetiracetam\t3\t\t\t\t\t\nMethotrexate\t3\t\t\t\t\t\nMoxifloxacin\t3\t\t\t\t\t\nRifampicin\t3\t\t\t\t\t\nRivaroxaban\t3\t\t\t\t\t\nSunitinib\t3\t\t\t\t\t\nTopiramate\t3\t\t\t\t\t\nTramadol\t3\t\t\t\t\t\nZonisamide\t3\t\t\t\t\t\nOthers\t127\t\t\t\t\t\nUndetermined\t241\t\t\t\t\t\nSCARs, severe cutaneous adverse reactions; DRESS syndrome, drug reactions with eosinophilia and systemic symptoms syndrome; SJS/TEN, Stevens-Johnsons syndrome/Toxic epidermal necrolysis.\n\nOthers: drugs for which less than three cases were reported. Undetermined: cases in which two or more drugs were simultaneously reported as a causative agent so that the culprit drug could not be identified. TMP/SMX: trimethoprim and sulfamethoxazole.\n\n*Drugs for which the labeling information did not include the risk of SCARs.\n\nTable 3 Summary of Cases of SCAR-Related Deaths and Drug Labeling Information for SCARs\nDiagnosis\tCausative drug\tATC code\tNumber\t\nDRESS syndrome\tVoriconazole*\tJ\t1\t\nOxcarbazepine\tN\t1\t\nPhenytoin*\tN\t1\t\nSJS/TEN\tFenofibrate*\tC\t1\t\nCefazedone*\tJ\t1\t\nCefoperazone/cefuroxime/amikacin\tJ\t1\t\nDoxycycline*\tJ\t1\t\nIsoniazid\tJ\t1\t\nLevofloxacin/ethambutol/ rifampicin/isoniazid\tJ\t1\t\nLevofloxacin/meropenem\tJ\t1\t\nTigecycline\tJ\t2\t\nVancomycin/teicoplanin/ceftriaxone\tJ\t1\t\nMethotrexate\tL\t1\t\nVincristine/rituximab/prednisolone/doxorubicin/L cyclophosphamide\tL\t1\t\nAllopurinol\tM\t2\t\nCarbamazepine\tN\t1\t\nValproic acid\tN\t1\t\nMethazolamide\tS\t1\t\nSCARs, severe cutaneous adverse reactions; DRESS syndrome, drug reactions with eosinophilia and systemic symptom syndrome; SJS/TEN, Stevens-Johnsons syndrome/toxic epidermal necrolysis; ATC, anatomical therapeutic chemical.\n\n*Drugs for which the labeling information did not include the risk of SCARs.\n==== Refs\n1 International drug monitoring: the role of national centres Report of a WHO meeting World Health Organ Tech Rep Ser 1972 498 1 25 4625548 \n2 Lazarou J Pomeranz BH Corey PN Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies JAMA 1998 279 1200 1205 9555760 \n3 GBD 2013 Mortality and Causes of Death Collaborators Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 Lancet 2015 385 117 171 25530442 \n4 Swanson L Colven RM Approach to the patient with a suspected cutaneous adverse drug reaction Med Clin North Am 2015 99 1337 1348 26476256 \n5 Yang MS Kang MG Jung JW Song WJ Kang HR Cho SH Clinical features and prognostic factors in severe cutaneous drug reactions Int Arch Allergy Immunol 2013 162 346 354 24193402 \n6 Kim SH Lee KW Song WJ Kim SH Jee YK Lee SM Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans Epilepsy Res 2011 97 190 197 21917426 \n7 Kang HR Jee YK Kim YS Lee CH Jung JW Kim SH Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans Pharmacogenet Genomics 2011 21 303 307 21301380 \n8 Kim MY Yang MS Kang HR Cho SH Min KU Analysis of drugs causing severe cutaneous adverse reactions, based on the Korean Database of spontaneously reported adverse drug reactions Korean J Med 2014 86 710 721 \n9 Yang MS Lee JY Kim J Kim GW Kim BK Kim JY Incidence of Stevens-Johnson Syndrome and toxic epidermal necrolysis: a nationwide population-based study using National Health Insurance Database in Korea PLoS One 2016 11 e0165933 27835661 \n10 Park HJ Kim YJ Kim DH Kim J Park KH Park JW HLA allele frequencies in 5802 Koreans: varied allele types associated with SJS/TEN according to culprit drugs Yonsei Med J 2016 57 118 126 26632391 \n11 Jung JW Kim JY Park IW Choi BW Kang HR Genetic markers of severe cutaneous adverse reactions Korean J Intern Med 2018 33 867 875 29921043 \n12 Hung SI Chung WH Liou LB Chu CC Lin M Huang HP HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol Proc Natl Acad Sci U S A 2005 102 4134 4139 15743917 \n13 Lee KW Oh DH Lee C Yang SY Allelic and haplotypic diversity of HLA-A, -B, -C, -DRB1, and -DQB1 genes in the Korean population Tissue Antigens 2005 65 437 447 15853898 \n14 Jung JW Kim DK Park HW Oh KH Joo KW Kim YS An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing Genet Med 2015 17 807 814 25634024 \n15 Ko TM Tsai CY Chen SY Chen KS Yu KH Chu CS Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study BMJ 2015 351 h4848 26399967 \n16 Niihara H Kaneko S Ito T Sugamori T Takahashi N Kohno K HLA-B*58:01 strongly associates with allopurinol-induced adverse drug reactions in a Japanese sample population J Dermatol Sci 2013 71 150 152 23669020 \n17 Lonjou C Borot N Sekula P Ledger N Thomas L Halevy S A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs Pharmacogenet Genomics 2008 18 99 107 18192896 \n18 Chen P Lin JJ Lu CS Ong CT Hsieh PF Yang CC Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan N Engl J Med 2011 364 1126 1133 21428768 \n19 Hung SI Chung WH Jee SH Chen WC Chang YT Lee WR Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions Pharmacogenet Genomics 2006 16 297 306 16538176 \n20 Lee KW Jeon H Park JY HLA-B*15 diversity in the Korean population Tissue Antigens 2000 56 428 435 11144290 \n21 Mockenhaupt M Viboud C Dunant A Naldi L Halevy S Bouwes Bavinck JN Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study J Invest Dermatol 2008 128 35 44 17805350 \n22 Shu C Shu D Tie D Yu M Zhang R Wang T Toxic epidermal necrolysis induced by methazolamide in a Chinese-Korean man carrying HLA-B*59:01 Int J Dermatol 2015 54 1242 1245 25970075 \n23 Schöpf E Stühmer A Rzany B Victor N Zentgraf R Kapp JF Toxic epidermal necrolysis and Stevens-Johnson syndrome. An epidemiologic study from West Germany Arch Dermatol 1991 127 839 842 2036029 \n24 Sekula P Dunant A Mockenhaupt M Naldi L Bouwes Bavinck JN Halevy S Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis J Invest Dermatol 2013 133 1197 1204 23389396 \n25 Sekula P Liss Y Davidovici B Dunant A Roujeau JC Kardaun S Evaluation of SCORTEN on a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis included in the RegiSCAR study J Burn Care Res 2011 32 237 245 21228709 \n26 Eshki M Allanore L Musette P Milpied B Grange A Guillaume JC Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure Arch Dermatol 2009 145 67 72 19153346 \n27 Chiou CC Yang LC Hung SI Chang YC Kuo TT Ho HC Clinicopathological features and prognosis of drug rash with eosinophilia and systemic symptoms: a study of 30 cases in Taiwan J Eur Acad Dermatol Venereol 2008 22 1044 1049 18627428\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0513-5796",
"issue": "60(2)",
"journal": "Yonsei medical journal",
"keywords": "Pharmacovigilance; Stevens-Johnson syndrome; drug hypersensitivity syndrome; toxic epidermal necrolysis",
"medline_ta": "Yonsei Med J",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000493:Allopurinol; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D002220:Carbamazepine; D004348:Drug Labeling; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D056910:Republic of Korea; D012871:Skin Diseases; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "0414003",
"other_id": null,
"pages": "208-215",
"pmc": null,
"pmid": "30666843",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": "11144290;15743917;15853898;16538176;17805350;18192896;18627428;19153346;2036029;21228709;21301380;21428768;21917426;23389396;23669020;24193402;25530442;25634024;25970075;26399967;26476256;26632391;27835661;29921043;4625548;9555760",
"title": "Analysis of Individual Case Safety Reports of Severe Cutaneous Adverse Reactions in Korea.",
"title_normalized": "analysis of individual case safety reports of severe cutaneous adverse reactions in korea"
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{
"abstract": "BACKGROUND\nTo analyze the characteristics of the patients with diagnosis of spontaneous retroperitoneal hematoma associated with anticoagulation therapy and antiplatet therapy.\n\n\nMETHODS\nFrom January 2006 to March 2013, 9 patients (6 from Haseki Training and Research Hospital - Urology Department and 3 from Istanbul Medical Faculty - Gynecology and Obstetric Department) were included in the study. Patients charts including sex, age, comorbidities, main complaint, and medication intake were examined. Also initial hemoglobin level, initial International Normalized Ratio level, red blood cells and fresh frozen plasma units transfused were evaluated.\n\n\nRESULTS\nMedian age was 60 year-old. Abdominal pain and flank pain were common symptoms. Eight patients were taking only anticoagulation therapy, 2 only antiplatet therapy and 1 both anticoagulation and antiplatet therapy. Median initial hemoglobin value was 9,0 g/dL and median International Normalized Ratio level was 3.2 Patients were evaluated by abdominal ultrasonography or abdominal computer tomography. Seven patients were treated conservatively. Only one patient died because of septic shock with a mortality ratio of 11%.\n\n\nCONCLUSIONS\nDespite benefits of anticoagulation and antiplatet theraphy these agents have serious side-affects as retroperitoneal hemorrhage in elderly patients taking multi-drug medication.",
"affiliations": "Haseki Research and Training Hospital, Department of Urology, Istanbul. simsek76@yahoo.com.",
"authors": "Simsek|Abdulmuttalip|A|;Ozgor|Faruk|F|;Yuksel|Bahar|B|;Bastu|Ercan|E|;Akbulut|Mehmet Fatih|MF|;Kucuktopcu|Onur|O|;Sarilar|Omer|O|;Berberoglu|Ahmet Yalcin|AY|;Gurbuz|Zafer Gokhan|ZG|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors",
"country": "Italy",
"delete": false,
"doi": "10.4081/aiua.2014.4.266",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-3562",
"issue": "86(4)",
"journal": "Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica",
"keywords": null,
"medline_ta": "Arch Ital Urol Androl",
"mesh_terms": "D000328:Adult; D000368:Aged; D000925:Anticoagulants; D005260:Female; D006406:Hematoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D012187:Retroperitoneal Space",
"nlm_unique_id": "9308247",
"other_id": null,
"pages": "266-9",
"pmc": null,
"pmid": "25641448",
"pubdate": "2014-12-30",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Spontaneous retroperitoneal hematoma associated with anticoagulation therapy and antiplatet therapy: two centers experiences.",
"title_normalized": "spontaneous retroperitoneal hematoma associated with anticoagulation therapy and antiplatet therapy two centers experiences"
} | [
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"abstract": "The incidence of breast carcinoma following prophylactic mastectomy is probably less than 2%. We present a 43-year-old female to male transsexual who developed breast cancer 1 year after bilateral nipple- sparing subcutaneous mastectomy as part of female to male gender reassignment surgery. In addition to gender reassignment surgery, total abdominal hysterectomy with bilateral salpingo-oophorectomy (to avoid the patient from entering menopause and to eliminate any subsequent risk of iatrogenic endometrial carcinoma), colpocleisys, metoidioplasty, phalloplasty, urethroplasty together with scrotoplasty/placement of testicular prosthesis and perineoplasty were also performed. Before the sex change surgery, the following diagnostic procedures were performed: breast ultrasound and mammography (which were normal), lung radiography (also normal) together with abdominal ultrasound examination, biochemical analysis of the blood and hormonal status.According to medical literature, in the last 50 years only three papers have been published with four cases of breast cancer in transsexual female to male patients. All hormonal pathways included in this complex hormonal and surgical procedure of transgender surgery have important implications for women undergoing prophylactic mastectomy because of a high risk of possible breast cancer.",
"affiliations": "Faculty of Medicine, University of Belgrade, Dr,Subotica 8, 11000, Belgrade, Serbia. nikolicdrdejan@gmail.com",
"authors": "Nikolic|Dejan V|DV|;Djordjevic|Miroslav L|ML|;Granic|Miroslav|M|;Nikolic|Aleksandra T|AT|;Stanimirovic|Violeta V|VV|;Zdravkovic|Darko|D|;Jelic|Svetlana|S|",
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"fulltext": "\n==== Front\nWorld J Surg OncolWorld J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central 1477-7819-10-2802327326910.1186/1477-7819-10-280Case ReportImportance of revealing a rare case of breast cancer in a female to male transsexual after bilateral mastectomy Nikolic Dejan V 125nikolicdrdejan@gmail.comDjordjevic Miroslav L 1djordjevic@uromiros.comGranic Miroslav 12nacelnik@bkosa.edu.rsNikolic Aleksandra T 13nikolicdrsasa@gmail.comStanimirovic Violeta V 4violeta.stanimirovic@gmail.comZdravkovic Darko 12majadare@eunet.rsJelic Svetlana 12svetlana.jelic011@gmail.com1 Faculty of Medicine, University of Belgrade, Dr.Subotica 8, 11000, Belgrade, Serbia2 University Medical Center “Bezanijska kosa”, Bezanijska kosa bb, 10080, Belgrade, Serbia3 Dedinje Cardiovascular Institute, Heroja Milana Tepica 1a, 11000, Belgrade, Serbia4 Medicines and Medical Devices Agency of Serbia, Vojvode Stepe 458, 11221, Belgrade, Serbia5 Department of Oncosurgery, Clinic for Oncology, University Medical Center “Bezanijska kosa”, 11080, Belgrade, Serbia2012 28 12 2012 10 280 280 28 7 2012 26 11 2012 Copyright ©2012 Nikolic et al.; licensee BioMed Central Ltd.2012Nikolic et al.; licensee BioMed Central Ltd.This 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.The incidence of breast carcinoma following prophylactic mastectomy is probably less than 2%. We present a 43-year-old female to male transsexual who developed breast cancer 1 year after bilateral nipple- sparing subcutaneous mastectomy as part of female to male gender reassignment surgery. In addition to gender reassignment surgery, total abdominal hysterectomy with bilateral salpingo-oophorectomy (to avoid the patient from entering menopause and to eliminate any subsequent risk of iatrogenic endometrial carcinoma), colpocleisys, metoidioplasty, phalloplasty, urethroplasty together with scrotoplasty/placement of testicular prosthesis and perineoplasty were also performed. Before the sex change surgery, the following diagnostic procedures were performed: breast ultrasound and mammography (which were normal), lung radiography (also normal) together with abdominal ultrasound examination, biochemical analysis of the blood and hormonal status.\n\nAccording to medical literature, in the last 50 years only three papers have been published with four cases of breast cancer in transsexual female to male patients. All hormonal pathways included in this complex hormonal and surgical procedure of transgender surgery have important implications for women undergoing prophylactic mastectomy because of a high risk of possible breast cancer.\n\nFemale to male surgeryMastectomyBreast cancer\n==== Body\nBackground\nThe incidence of breast carcinoma after prophylactic mastectomy is probably less than 2% [1]. Several studies such as those by Pennisi and Capozzi [2] and by Woods [3] have been conducted, where only few patients, from more than 1,000 patients included in the study (prophylactic subcutaneous mastectomy), developed breast cancer after years of follow-up (incidence rate 0.6%). However, one of the major concerns about nipple sparing mastectomy is the persistent risk of breast cancer development when this is used for prophylaxis, with much controversy about the safety of these procedures from an oncological point of view [4,5]. At present there are no randomized studies on the effects of long-term testosterone use on breast cancer risk. In a 20-year follow-up study of 110 female to male transsexuals in Serbia, there were none with breast carcinoma [6].\n\nCase presentation\nA female to male transsexual, who underwent complex sex reassignment surgery after bilateral subcutaneous nipple sparing mastectomy (weight of removed breast tissue: left breast tissue, 275 g; right breast tissue, 295 g), presented 1 year after surgery with a painless left areoral mass. Samples of the left and right breast tissues sent for pathological analysis following subcutaneous mastectomy were benign.\n\nThe patient was 42 years old at the time the breast cancer was discovered, and 41 years old at the time of transgender surgery. The patient started testosterone therapy 18 months prior to sex reassignment (250 mg intramuscularly every 2 weeks). After the sex reassignment surgery, he received 250mg testosterone every 17 days for the next 12 months. At the time of sex change surgery, the patient was premenopausal.\n\nThe patient did not have any relatives with a history of any type of cancer. Family history of breast cancer and ovarian cancer in first-degree or second-degree relatives was thus negative, with no prior breast biopsies in clinical history, and therefore he was not a high-risk patient for breast cancer. BRCA1 and BRCA2 testing were not performed.\n\nA routine chest X-ray image revealed an areolar mass on the left-hand side with N2 axillary node status, as well as lung metastases. Metastases in both lungs were confirmed by multislice spiral computed tomography. The classification, according to the American Joint Committee on Cancer, was T2N2M1, stage IV. Liver function tests and tumor markers (Ca 15–3) were normal.\n\nHormone profile studies confirmed satisfactory androgen replacement (normal testosterone with luteinizing hormone and follicle-stimulating hormone suppression.\n\nA neoadjuvant therapy (fluorouracil, adriamycin and cyclophosphamide) 3-week protocol was administered to the patient, for six cycles. Owing to shrinkage of the tumor mass, radical mastectomy together with axillary dissection was performed after neoadjuvant therapy was finished. Trastuzumab (6 mg/kg intravenous infusion over 30 to 90 minutes every 3 weeks) was administered to the patient in combination with paclitaxel (80 mg/m2 every week) as adjuvant chemotherapy. Both drugs were administered to the patient after six cycles of fluorouracil, adriamycin and cyclophosphamide and radical breast surgery.\n\nResults\nHistological examination of the breast tumor showed invasive ductal carcinoma of breast tissue and metastasis of invasive ductal carcinoma in the lymph nodes of the left axilla (12+/13),while the lymph nodes of the right axilla were negative for metastasis. Estrogen and progesterone receptors were negative although the Her 2/neu receptor was positive (60% of the tumor cells were 3+). Receptors for Ki-67 (50%) were positive. Androgen receptors (ARs) in breast cancer were also positive (2%).\n\nAssessment of the tumor response following neoadjuvant therapy was good, with shrinkage of the primary tumor in the left breast from 63mm×54mm×50mm to 40mm×40mm×40mm.\n\nFor evaluation, a scintigraphy was performed along with four multislice spiral computed tomography scans (performed quarterly). No liver or bone metastases were revealed. Prior to neoadjuvant therapy, lung metastases were present in both the left and right lungs, with a maximum diameter of 11mm. Following neoadjuvant therapy these metastases were found to be smaller, with a maximum diameter of 9mm. After radical mastectomy and axillary dissection and 2 months after the start of treatment with trastuzumab and paclitaxel, only one metastasis with a diameter of 5mm was observed in the right lung on multislice spiral computed tomography of the thorax and abdomen. There were no metastases on other parts of the body.\n\nDiscussion\nThe incidence of breast carcinoma after prophylactic mastectomy is probably less than 2% [1]. Several studies such as those by Pennisi and Capozzi [2] and by Woods [3] have been conducted, where only a few patients, from more than 1,000 patients included in the study (prophylactic subcutaneous mastectomy), developed breast cancer after years of follow-up (incidence rate 0.6%). However, one of the major concerns about nipple sparing mastectomy is the persistent risk of breast cancer development when this is used for prophylaxis, with much controversy about the safety of these procedures from an oncological point of view [4,5]. At present there are no randomized studies on the effects of long-term testosterone use on breast cancer risk. In a 20-year follow-up study of 110 female to male transsexuals in Serbia, there were none with breast carcinoma [6].\n\nOur presenting case of breast cancer and lung metastases in a female to male transsexual exposed to exogenous androgens is very rare and has not previously been described. Direct effects of androgens on inducing breast cell proliferation and cancer via the AR are biologically impossible. In our patient, androgen-positive receptors were found in only 2% of breast tumor cells. In vitro studies have shown an inhibitory effect of androgens on breast cell proliferation and growth [7]. Negative findings for estrogen and progesterone receptors open the question of whether there is any hormonal dependence, or genetically determined carcinogenesis, irrespective of testosterone therapy.\n\nThe role of elevated androgen levels and the AR expression in male breast cancer as well as in female breast cancer is still unclear [8,9].\n\nBased on a few early articles by Grattarola [10], the androgen excess theory states that urinary androgen excretion and intratumoral estrogen receptor status confirm the existence of hormone-dependent disease and predict the clinical outcome from ovariectomy in patients with metastatic breast cancer.\n\nPositive AR immunostaining was found in approximately 70% of invasive female breast carcinomas and in a significant number of triple-negative tumors [11].\n\nA recent study of case records for 1,849 patients with breast cancer revealed that positive AR immunostaining was inversely correlated with clinical stage, histological grade and mitotical score. Positive AR immunostaining was therefore associated with less aggressive tumors [12].\n\nStandard therapy with antiestrogens and antiaromatase drugs is effective against increased estrogen production but quite ineffective against androgen excess. Additional therapy in these cases might be needed as well as determination of the origin (ovarian or adrenal) of the androgen excess in the particular patient. Ovariectomy (surgical, radiological or medical) would be indicated if the excess originates from the ovaries, while sulfatase inhibitors would be indicated in patients with adrenal source of androgen excess [9].\n\nThe Surveillance, Epidemiology and End Results cancer registry,which includes more than 2,000 male patients, has highlighted the fact that 93.7% of male breast cancers were ductal or unclassified, while 2.6% were papillary, 1.8% were mucinous and only 1.5% were lobular [13]. Breast cancers in men are significantly more likely to express hormone receptors than cancers in the female breast [8,13]. As much as 81% of male breast cancers express the progesterone receptor, and even 90% of them express the estrogen receptor. Knowing this, adjuvant hormonal therapy (including progestins, androgens, steroids, aminoglutethamide, estrogens, letrozole) has an important role in the treatment of these patients. However, literature data report AR expression in 34 to 95% of male breast cancer with no clear association with its prognosis [8]. Mutations in the AR gene have been reported in male patients with breast cancer [14], but again no causal association could be demonstrated.\n\nIt would be even more difficult to hypothesize on the role of androgen excess and the AR expression in the evolution of breast cancer in female to male transsexual patients due to the small number of such cases reported in literature. However, for those clinicians who deal with these patients, it is important to bear in mind all of the complex relationships between AR expression in breast cancer and other steroid receptors and growth factors.\n\nThere are certain dilemmas that must be addressed. In spite of the fact that the excised glandular tissue was pathologically benign, were the diagnostic procedures performed before sex reassignment surgery in our case insufficiently precise or insufficiently reliable, so that breast cancer had not been revealed in time, or was androgen supplementation the trigger for activation of invasive ductal carcinoma of the breast and potential high-speed malignancy of breast cancer, resulting in metastases in both lungs within a very short time?\n\nAccording to medical literature, in the last 50 years there have been only three papers with four cases of breast cancer in transsexual female to male patients [15-17]. The first case, a 33-year-old female to male transsexual who developed breast cancer 10 years after cosmetic bilateral subcutaneous mastectomy and nipple reimplantation, was described in an article in Breast[15]. The following two patients mentioned in Clinical Breast were breast cancers diagnosed in two female to male transsexuals who had been treated with a supraphysiological doses of testosterone [16]. In addition, Gooren reported a single case of breast cancer in a female to male transsexual receiving testosterone hormone replacement therapy [17].\n\nOne should point out that the regularly performed bilateral removal of breast tissue including the nipple–areola complex, axillary tail and pectoral fascia was probably insufficient, and that breast cancer occurred in the residual breast tissue of the transsexual patient. However, it is very hard to speculate whether the patient could have developed breast cancer after oophorectomy with androgen supplementation if a total mastectomy had been performed.\n\nAs well as demonstrating the complex and poorly understood hormonal influences involved in the etiology of breast cancer, our patient’s management raised some important clinical issues. In this study the potential causative role of androgen replacement in breast malignancy, and the benefits, risks and safety of such treatment in breast cancer survivors, were discussed. The protection afforded to high-risk women undergoing prophylactic mastectomy is reviewed and the optimal hormonal management of this case was considered.\n\nConclusion\nThis rare and very interesting case demonstrates that, in spite of the involvement of different types of specialists, such as surgeons, oncosurgeons, gynecologists and endocrinologists, very complex procedures of sex reassignment surgery can sometimes result in possible malignant disease escaping medical control.\n\nRevealing and publishing cases such as this serves to raise awareness among doctors when starting the requested sex change process in these surgically and endocrinologically very complicated patients. The case also shows a need for change in clinical practice, to include magnetic resonance imaging prior to prophylactic mastectomy as a significantly more sensitive method for revealing invasive breast tumors [18].\n\nAbbreviations\nAR: Androgen receptor.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nND: Participated in preoperative and postoperative surgical and chemotherapy following of the patient, carried out the molecular genetic studies, writing the manuscript, participated in the sequence alignment, corrected the manuscript in final draft. DM: Did the transgender surgery, writing the manuscript, participated in the sequence alignment, corrected the manuscript in final draft. GM: Did the removal of the cancer of the breast, carried out the molecular genetic studies, participated in the sequence alignment. NA: Did the checkups of the patient, carried out the molecular genetic studies, writing the manuscript, participated in the sequence alignment, corrected the manuscript in final draft. SV: Made major instructions according to the chemotherapy, carried out the molecular genetic studies, writing the manuscript, participated in the sequence alignment, corrected the manuscript in final draft. ZD: Followed the patient in preoperative and postoperative period, writing the manuscript, participated in the sequence alignment, corrected the manuscript in final draft. JS: carried out the molecular genetic studies, writing the manuscript, participated in the sequence alignment, corrected the manuscript in final draft. All authors read and approved the final manuscript.\n==== Refs\nWillemsen HW Kaas R Peterse JH Rutgers EJ Breast carcinoma in residual breast tissue after prophylactic bilateral subcutaneous mastectomy Eur J SurgOncol 1998 24 331 332 \nPennisi VR Capozzi A Subcutaneous mastectromydata:a final statistical analysis of 1500 patients Aesthetic Plast Surgery 1989 13 15 21 10.1007/BF01570320 \nWoods JE Breast reconstruction: a current state of the art Mayo ClinProc 1986 61 579 585 10.1016/S0025-6196(12)62008-4 \nGarcia-Etienne CA Borgen PI Update on the indication of the nipple sparing mastectomy J Support Oncol 2006 4 225 230 16724644 \nChung AP Sacchini V Nipple-sparing mastectomy: where are we now? SurgOncol 2008 17 261 266 \nVujović S Popović S Milošević-Sbutega G Đorđević M Gooren LJG Transsexualism in Serbia: a twenty-year follow-up study J Sex Med 2009 6 1018 1023 10.1111/j.1743-6109.2008.00799.x 18331254 \nTraish AM Feeley RJ Guay AT Testosterone therapy in women with gynecological and sexual disorders: a triumph of clinical endocrinology from 1938 to 2008 J Sex Med 2009 6 334 351 19138368 \nGiordano SH A review of the diagnosis and mangement of male breast cancer Oncologist 2005 10 471 479 10.1634/theoncologist.10-7-471 16079314 \nSecreto G Zumoff B Role of androgen excess in the development of estrogen receptor-positive and estrogene receptor-negative breast cancer Anticancer Res 2012 32 3223 3228 22843896 \nPreda F Pizzocaro G Oriana S Riboldi G Severini A Di Fronzo G Secreto G Grattarola R Correlation between clinical response to bilateral oophorectomy, estrogen receptors and urinary androgen excretion in 49 patients with advanced breast cancer Tumori 1979 65 3 325 330 462582 \nMrklic I Pogorelic Z Capkun V Tomic S Expression of androgen receptors in triple negative breast carcinomas ActaHistochem 2012 Epub ahead of print 10.1016/j.acthis.2012.09.006 \nQi JP Yang YL Zhu H Wang J Jia Y Liu N Song YJ Zan LK Zhang X Zhou M Gu YH Liu T Hicks DG Tang P Expression of the androgen receptor and its correlation with molecular subtypes in 980 Chinese breast cancer patients Breast Cancer 2012 6 1 8 22259247 \nGiordano SH Cohen DS Buzdar AU Perkins G Hortobagyi GN Breast carcinoma in men: a population-based study Cancer 2004 101 51 57 10.1002/cncr.20312 15221988 \nSyrjakoski K Hyytinen ER Kuukasjarvi T Auvinen A Kallioniemi OP Kainu T Koivisto PA Androgen receptor gene alterations in Finnish male breast cancer Breast Cancer Res Treat 2003 77 167 170 10.1023/A:1021369508561 12602915 \nBurcombe RJ Makris A Pittam M Finer N Breast cancer after bilateral subcutaneous mastectomy in a female-to-male trans-sexual Breast 2003 12 290 293 10.1016/S0960-9776(03)00033-X 14659317 \nShao T Grossbard ML Klein P Breast cancer in female-to-male transsexuals: two cases with a review of physiology and management Clin Breast Cancer 2011 11 417 419 10.1016/j.clbc.2011.06.006 21831723 \nMueller A Gooren LJ Hormone-related tumors in transsexuals receiving treatment with cross-sex hormones Eur J Endocrinol 2008 159 197 202 10.1530/EJE-08-0289 18567667 \nHagen AI Kvistad KA Maehle L Holmen MM Aase H Styr B Vabo A Apold J Skaane P Moller P Sensitivity of MRI versus conventional screening in the diagnosis of BRCA-associated breast cancer in a national prospective series Breast 2007 16 367 374 10.1016/j.breast.2007.01.006 17317184\n\n",
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"transmissiondate": "20201103"
}
] |
{
"abstract": "Orf is a viral skin infection due to a poxvirus. It manifests as a nodule of the hands that heals spontaneously within 3-4 weeks, but may be persisting and difficult to treat in immunocompromised patients. Very few cases have been reported in transplant patients; therefore, management is not established. We report a renal transplant recipient with a rapidly growing orf which regressed after application of imiquimod and a reduction in immunosuppression without damage on his renal function. This case suggests that a rapidly growing orf in transplant patients behaves as an opportunistic infection and therefore minimization should be considered along with a topical treatment.",
"affiliations": "Department of Dermatology, Edouard Herriot Hospital Group, Hospices Civils de Lyon, Lyon, France.",
"authors": "Zaharia|Daniela|D|;Kanitakis|Jean|J|;Pouteil-Noble|Claire|C|;Euvrard|Sylvie|S|",
"chemical_list": "D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D007166:Immunosuppressive Agents; D000077271:Imiquimod",
"country": "England",
"delete": false,
"doi": "10.1111/j.1432-2277.2010.01147.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "23(10)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Transpl Int",
"mesh_terms": "D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000818:Animals; D004474:Ecthyma, Contagious; D005385:Fingers; D006229:Hand Dermatoses; D006801:Humans; D000077271:Imiquimod; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D012756:Sheep; D016896:Treatment Outcome",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "e62-4",
"pmc": null,
"pmid": "20681978",
"pubdate": "2010-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rapidly growing orf in a renal transplant recipient: favourable outcome with reduction of immunosuppression and imiquimod.",
"title_normalized": "rapidly growing orf in a renal transplant recipient favourable outcome with reduction of immunosuppression and imiquimod"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-01303",
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},
{
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"activesubstancename": "PREDNISOLONE"
},
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}
],
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"reaction": [
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
}
],
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},
"primarysource": {
"literaturereference": "Zaharia D, Kanitakis J, Pouteil-Noble C, Euvrard S.. Rapidly growing orf in a renal transplant recipient: favourable outcome with reduction of immunosuppression and imiquimod. Tansplant Int. 2010;23:62-64",
"literaturereference_normalized": "rapidly growing orf in a renal transplant recipient favourable outcome with reduction of immunosuppression and imiquimod",
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},
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"receiptdate": "20211225",
"receivedate": "20211225",
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},
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},
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"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
}
] |
{
"abstract": "In relation to the articles published in this journal by Valdivielso-Cortázar and Relea-Pérez, we have recently operated a patient who presented a digestive hemorrhage in immediate postoperative period due to Dieulafoy´s lesion at the mechanical gastrojejunal anastomosis.",
"affiliations": "Servicio de Cirugía General, Hospital Gutiérrez Ortega. Valdepeñas. Ciudad Real, España.;Cirugía General y del Aparato Digestivo, Hospital Gutierrez Ortega.;Cirugía General y del Aparato Digestivo, Carranza.",
"authors": "Menéndez Sánchez|Pablo|P|;León Salinas|Carlos|C|;García|Alberto|A|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.17235/reed.2018.5442/2017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-0108",
"issue": "110(5)",
"journal": "Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva",
"keywords": null,
"medline_ta": "Rev Esp Enferm Dig",
"mesh_terms": "D000368:Aged; D001158:Arteries; D004379:Duodenal Neoplasms; D017809:Fatal Outcome; D005743:Gastrectomy; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D018358:Neuroendocrine Tumors; D019106:Postoperative Hemorrhage; D013272:Stomach Diseases; D054079:Vascular Malformations",
"nlm_unique_id": "9007566",
"other_id": null,
"pages": "336-337",
"pmc": null,
"pmid": "29527906",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Consequences of a Dieulafoy's lesion in gastric surgery.",
"title_normalized": "consequences of a dieulafoy s lesion in gastric surgery"
} | [
{
"companynumb": "ES-BAYER-2018-127766",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "021317",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "TABLET",
"drugdosagetext": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "ACETYLSALICYLIC ACID (} 100 MG)"
}
],
"patientagegroup": "6",
"patientonsetage": "69",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Haematemesis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Gastrointestinal haemorrhage",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Gastrointestinal ulcer",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Haemodynamic instability",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MENENDEZ?SANCHEZ P, LEON?SALINAS C, GARCYA?CARRANZA A. CONSEQUENCES OF A DIEULAFOY^S LESION IN GASTRIC SURGERY. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS. 2018?110:5:336",
"literaturereference_normalized": "consequences of a dieulafoy s lesion in gastric surgery",
"qualification": "3",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20180709",
"receivedate": "20180709",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15121555,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20181010"
}
] |
{
"abstract": "In this article, we present a case of recurrent laryngeal nerve palsy not caused by nerve injury but due to local anesthetic infiltration that was applied prior to central venous catheterization. A 47-year-old female patient was admitted to emergency room with fatigue and nausea and was diagnosed with acute renal failure. Right jugular venous catheterization was performed for emergency hemodialysis with Seldinger technique using middle approach. Within minutes and immediately after the procedure the patient complained of hoarseness and shortness of breath, and she had stridor in her physical exam. Awake flexible fibreoptic laryngoscopy revealed unilateral right-sided vocal cord paralysis with no edema. The patient was asked to remain nil per os and observed in ER with nasal oxygen. At the 3rd hour of follow-up without any other intervention, her symptoms resolved. Due to its proximity to the internal jugular vein injury to the recurrent laryngeal nerve while attempting to insert a central venous line can occur, particularly with difficult and repeated attempts. Local anesthesia led temporary ipsilateral vocal cord paralysis in patients undergoing carotid endarterectomy is described in literature. We think temporary vocal cord palsy in our case was due to local anesthetic infiltration rather than nerve injury, since it resolved spontaneously within only hours. Expectant treatment is a good choice ensuring the patient's airway is safe. Emergency physicians should be aware of this rare complication and its right management.",
"affiliations": "Atatürk Training and Research Hospital, Department of Emergency Medicine, Turkey. Electronic address: gulpamukcu@gmail.com.;Atatürk Training and Research Hospital, Department of Emergency Medicine, Turkey.;Yıldırım Beyazıt University, Faculty of Medicine, Department of Emergency Medicine, Turkey.;Yıldırım Beyazıt University, Faculty of Medicine, Department of Emergency Medicine, Turkey.;Yıldırım Beyazıt University, Faculty of Medicine, Department of Emergency Medicine, Turkey.",
"authors": "Pamukçu Günaydın|Gül|G|;Gürü|Selahattin|S|;Aslan Taş|Elif|E|;Tanrıverdi|Fatih|F|;Kurtoğlu Çelik|Gülhan|G|",
"chemical_list": "D000779:Anesthetics, Local",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2017.08.037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "35(11)",
"journal": "The American journal of emergency medicine",
"keywords": "Central venous catheterization; Local anesthesia; Vocal cord paralysis",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D058186:Acute Kidney Injury; D000779:Anesthetics, Local; D002405:Catheterization, Central Venous; D005260:Female; D006801:Humans; D007828:Laryngoscopy; D008875:Middle Aged; D020127:Recovery of Function; D006435:Renal Dialysis; D014826:Vocal Cord Paralysis",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1790.e1-1790.e2",
"pmc": null,
"pmid": "28822609",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transient vocal cord paralysis following central venous hemodialysis catheter insertion.",
"title_normalized": "transient vocal cord paralysis following central venous hemodialysis catheter insertion"
} | [
{
"companynumb": "TR-GLENMARK PHARMACEUTICALS-2017GMK029964",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "206498",
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"drugcumulativedosagenumb": null,
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"drugdosagetext": "5 ML, USING A 22-GAUGE NEEDLE FOR LOCAL INFILTRATION ANESTHESIA",
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},
{
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},
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"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "UNK USING A 22-GAUGE NEEDLE FOR LOCAL INFILTRATION ANESTHESIA",
"drugenddate": null,
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"drugindication": "LOCAL ANAESTHESIA",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "EPINEPHRINE."
}
],
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"patientonsetage": "47",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Vocal cord paralysis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Paralysis recurrent laryngeal nerve",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PAMUK?U GUNAYDIN G, GURU S, ASLAN TAS E, TANRIVERDI F,KURTOGLU ?ELIK G.. TRANSIENT VOCAL CORD PARALYSIS FOLLOWING CENTRAL VENOUS HEMODIALYSIS CATHETER INSERTION. AMERICAN JOURNAL OF EMERGENCY MEDICINE. 2017;35(11):1790 E1-1790.E2",
"literaturereference_normalized": "transient vocal cord paralysis following central venous hemodialysis catheter insertion",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20171208",
"receivedate": "20171208",
"receiver": {
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"receivertype": "6"
},
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180321"
},
{
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"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE BITARTRATE\\LIDOCAINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "050",
"drugauthorizationnumb": "006488",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "LOCAL ANAESTHESIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "012",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LIDOCAINE/EPINEPHRINE (MANUFACTURER UNKNOWN)"
}
],
"patientagegroup": null,
"patientonsetage": "47",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Vocal cord paralysis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PAMUKCU G,GURU S,ASLAN T,TANRIVERDI F,KURTOGLU C. TRANSIENT VOCAL CORD PARALYSIS FOLLOWING CENTRAL VENOUS HEMODIALYSIS CATHETER INSERTION. AM-J-EMERG-MED 2017;.",
"literaturereference_normalized": "transient vocal cord paralysis following central venous hemodialysis catheter insertion",
"qualification": "3",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20171206",
"receivedate": "20171206",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14255218,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180321"
}
] |
{
"abstract": "Thrombotic thrombocytopenic purpura (TTP) is a life-threatening multisystem disease secondary to platelet aggregation. We present a patient who developed profound thrombocytopenia and anemia 8 days following initiation of therapy with clopidogrel after stent placement for carotid artery dissection. She did not have a disintegrin and metalloproteinase with thrombospondin domain 13 (ADAMTS 13) deficiency. Management included steroids and therapeutic plasma exchange. Clopidogrel has rarely been associated with TTP. Unlike other causes of acquired TTP, the diagnosis of early clopidogrel-associated TTP is largely clinical given the infrequent reduction in ADAMTS 13 activity.",
"affiliations": "Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York, United States.;Stony Brook University School of Medicine, Stony Brook, New York, United States.;Stony Brook University School of Medicine, Stony Brook, New York, United States.;Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York, United States.;Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York, United States.",
"authors": "Rubano|Jerry A|JA|;Chen|Kwan|K|;Sullivan|Brianne|B|;Vosswinkel|James A|JA|;Jawa|Randeep S|RS|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0035-1566127",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2193-6358",
"issue": "76(2)",
"journal": "Journal of neurological surgery reports",
"keywords": "TTP; carotid; clopidogrel; stent; thrombocytopenia",
"medline_ta": "J Neurol Surg Rep",
"mesh_terms": null,
"nlm_unique_id": "101601540",
"other_id": null,
"pages": "e287-90",
"pmc": null,
"pmid": "26623244",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports",
"references": "21493140;19180126;21889701;21875913;10852999;8369663;17868804;22624596;19286127;24553344;25213289;23111862;18721506",
"title": "Clopidogrel-Associated Thrombotic Thrombocytopenic Purpura following Endovascular Treatment of Spontaneous Carotid Artery Dissection.",
"title_normalized": "clopidogrel associated thrombotic thrombocytopenic purpura following endovascular treatment of spontaneous carotid artery dissection"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/15/0054999",
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"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "076273",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
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"drugindication": "ANTIPLATELET THERAPY",
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"drugrecurreadministration": "3",
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"medicinalproduct": "CLOPIDOGREL BISULFATE."
},
{
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"activesubstance": {
"activesubstancename": "ASPIRIN"
},
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{
"abstract": "OBJECTIVE\nTo present a novel case of immune retinopathy associated with nivolumab therapy for non-small cell lung cancer.\n\n\nMETHODS\nRetrospective chart review.\n\n\nRESULTS\nA 64-year-old woman presented with photoreceptor injury evidenced by hypoautofluorescent and hyperautofluorescent patches on fundus autofluorescence, loss of the ellipsoid zone on optical coherence tomography, and dysfunction of the rods and cones on electroretinogram. She had a history of Stage IV lung adenocarcinoma, treated with nivolumab, a checkpoint inhibitor. Serology testing was negative for paraneoplastic antibody panel, antirecoverin and antienolase antibodies, but positive for antiretinal antibodies against 30-kDa (carbonic anhydrase II), 35-kDa (GADPH), 38-kDA, 58-kDa (PKM2), and 112-kDa proteins. Cessation of the medication and high-dose oral steroids resulted in resolution of her symptoms and stability of ocular findings.\n\n\nCONCLUSIONS\nThe checkpoint inhibitors, including nivolumab, have significant ocular side effects. All patients receiving nivolumab should undergo a baseline comprehensive eye examination and should be counseled to seek medical attention immediately if visual changes occur.",
"affiliations": "West Coast Retina Medical Group, San Francisco, California; and.;West Coast Retina Medical Group, San Francisco, California; and.;West Coast Retina Medical Group, San Francisco, California; and.;West Coast Retina Medical Group, San Francisco, California; and.;West Coast Retina Medical Group, San Francisco, California; and.",
"authors": "Reddy|Manisha|M|;Chen|Judy J|JJ|;Kalevar|Ananda|A|;Terribilini|Ryan|R|;Agarwal|Anita|A|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors; D000077594:Nivolumab",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000675",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "14(2)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D002289:Carcinoma, Non-Small-Cell Lung; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008175:Lung Neoplasms; D008875:Middle Aged; D000077594:Nivolumab; D012164:Retinal Diseases; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "120-126",
"pmc": null,
"pmid": "29176534",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "IMMUNE RETINOPATHY ASSOCIATED WITH NIVOLUMAB ADMINISTRATION FOR METASTATIC NON-SMALL CELL LUNG CANCER.",
"title_normalized": "immune retinopathy associated with nivolumab administration for metastatic non small cell lung cancer"
} | [
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}
],
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{
"abstract": "Mycoplasma edwardii (M. edwardii) is an anthropozoonotic microorganism found in the upper respiratory and urogenital tracts of dogs. M. edwardii was one of the microbes isolated from peritoneal fluid of a 10-year-old child diagnosed with polymicrobial peritonitis following a puncture of dialysis tubing by a pet dog. Other unique pathogens representative of canine oral microflora isolated from this patient on peritoneal dialysis were Kingella denitrificans, Actinomycetes species and Capnocytophaga cynodegmi.",
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"authors": "Lalan|Shwetal P|SP|;Warady|Bradley A|BA|;Blowey|Douglas|D|;Waites|Ken B|KB|;Selvarangan|Rangaraj|R|",
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"doi": "10.5414/CN107976",
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"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000818:Animals; D002648:Child; D004285:Dogs; D004868:Equipment Failure; D005260:Female; D006801:Humans; D009174:Mycoplasma; D009175:Mycoplasma Infections; D010530:Peritoneal Dialysis; D010538:Peritonitis",
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"pmid": "24040782",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Mycoplasma edwardii peritonitis in a patient on maintenance peritoneal dialysis.",
"title_normalized": "mycoplasma edwardii peritonitis in a patient on maintenance peritoneal dialysis"
} | [
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}
],
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"literaturereference": "LALAN SP, WARADY BA, BLOWEY D, WAITES KB, SELVARANGAN R.. MYCOPLASMA EDWARDII PERITONITIS IN A PATIENT ON MAINTENANCE PERITONEAL DIALYSIS. DOI 10.5414/CN107976. CLINICAL NEPHROLOGY. 2015?83(1):45-48",
"literaturereference_normalized": "mycoplasma edwardii peritonitis in a patient on maintenance peritoneal dialysis",
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},
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},
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},
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] |
{
"abstract": "There have been reports of neurolytic transversus abdominis plane (TAP) block using different agents such as alcohol or phenol for the treatment of chronic abdominal pain caused by malignant abdominal wall invasion. However, to date, there have been no reports on neurolytic abdominal wall blocks for pain with non-cancer-related origin in cancer patients.\n\n\n\nWe performed subcostal TAP neurolysis using ethanol in a patient with esophageal cancer with constant pain at the site of gastrostomy. After neurolysis, the patient's overall pain decreased, with the exception of pain in the medial part of the gastrostomy site. We performed additional rectus sheath neurolysis using ethanol for the treatment of continuous pain at the medial site, and the effect of neurolysis has persisted for over 4 months.\n\n\n\nAlcohol-based TAP neurolysis and rectus sheath neurolysis provide effective pain control in a cancer patient with chronic treatment-related pain involving the abdominal wall.",
"affiliations": "Department of Anesthesiology and Pain Medicine, National Cancer Center, Goyang, Korea.;Department of Anesthesiology and Pain Medicine, National Cancer Center, Goyang, Korea.;Department of Anesthesiology and Pain Medicine, National Cancer Center, Goyang, Korea.;Department of Anesthesiology and Pain Medicine, National Cancer Center, Goyang, Korea.;Department of Anesthesiology and Pain Medicine, National Cancer Center, Goyang, Korea.",
"authors": "Lee|Ki Hoon|KH|;Kim|Dae Hyun|DH|;Kim|Yang Hyun|YH|;Ro|Soo Han|SH|;Lee|Jun|J|",
"chemical_list": "D000431:Ethanol",
"country": "Korea (South)",
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"doi": "10.4097/kja.19041",
"fulltext": "\n==== Front\nKorean J Anesthesiol\nKorean J Anesthesiol\nKJA\nKorean Journal of Anesthesiology\n2005-6419 2005-7563 Korean Society of Anesthesiologists \n\n31048655\n10.4097/kja.19041\nkja-19041\nCase Report\nNeurolytic abdominal wall blocks with alcohol for intractable gastrostomy site pain in a cancer patient -a case report-\nNeurolytic abdominal wall blockshttp://orcid.org/0000-0002-1259-6329Lee Ki Hoon http://orcid.org/0000-0002-4144-1182Kim Dae Hyun http://orcid.org/0000-0003-1146-0865Kim Yang Hyun http://orcid.org/0000-0001-9594-4132Ro Soo Han http://orcid.org/0000-0003-0123-3095Lee Jun \nDepartment of Anesthesiology and Pain Medicine, National Cancer Center, Goyang, Korea\nCorresponding author: Dae Hyun Kim, M.D., Ph.D. Department of Anesthesiology and Pain Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel: +82-31-920-1699 Fax: +82-31-920-1463 Email: dhkim@ncc.re.kr\n6 2020 \n30 4 2019 \n73 3 247 251\n1 2 2019 12 4 2019 30 4 2019 Copyright © The Korean Society of Anesthesiologists, 20202020This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nThere have been reports of neurolytic transversus abdominis plane (TAP) block using different agents such as alcohol or phenol for the treatment of chronic abdominal pain caused by malignant abdominal wall invasion. However, to date, there have been no reports on neurolytic abdominal wall blocks for pain with non-cancer-related origin in cancer patients.\n\nCase\nWe performed subcostal TAP neurolysis using ethanol in a patient with esophageal cancer with constant pain at the site of gastrostomy. After neurolysis, the patient’s overall pain decreased, with the exception of pain in the medial part of the gastrostomy site. We performed additional rectus sheath neurolysis using ethanol for the treatment of continuous pain at the medial site, and the effect of neurolysis has persisted for over 4 months.\n\nConclusions\nAlcohol-based TAP neurolysis and rectus sheath neurolysis provide effective pain control in a cancer patient with chronic treatment-related pain involving the abdominal wall.\n\nAbdominal wall painCancer painNeurolytic peripheral blockRectus sheath blockRegional anesthesiaTransversus abdominis plane block\n==== Body\nRegional anesthesia techniques for the abdominal wall, such as rectus sheath block and transversus abdominis plane (TAP) block, are components of multimodal anesthesia that are utilized in various types of surgeries, including different abdominal surgeries with accompanying laparotomy (including major abdominal surgeries), hernia repair, and cesarean delivery.\n\nIn this perioperative setting, abdominal wall block techniques are known to improve the quality of analgesia and reduce postoperative opioid consumption [1]. More specifically, the recent use of ultrasonography in these block techniques allows accurate localization of the needle tip and real-time confirmation of drug spread, which consequently reduces side effects and increases efficacy [2]. In addition, there are cases of long-term analgesia provision via catheter placement, which is being utilized following abdominal surgery.\n\nMeanwhile, there have been attempts to utilize these regional anesthetic techniques applied to the abdominal wall for chronic pain control. There have been reports of cases in which symptoms were successfully relieved via nerve block using local anesthetics as shown in a previous case series [3] that attempted TAP block using local anesthetics for the management of postoperative abdominal pain. Furthermore, there have been cases of attempted neurolysis for longer term treatment efficacy. Previous cases [4,5] have attempted TAP neurolysis using alcohol for the management of pain due to advanced cancer involving the abdominal wall, and another similar case [6] reported the use of phenol for TAP neurolysis. However, there has not been a case report describing neurolysis performed on the rectus sheath, and cases of alcohol-based neurolysis on the abdominal wall plane for management of non-cancer pain in cancer patient.\n\nIn this case report, we describe the case of a patient with persistent, intractable pain at the gastrostomy site despite long-term opioid use. We attempted alcohol-based TAP neurolysis and rectus sheath neurolysis, which successfully provided pain control without further opioid usage.\n\nThe patient provided written consent for the publication of this case.\n\nCase Report\nA 70-year-old male patient visited our pain clinic in December 2017 with gastrostomy site pain that started after percutaneous radiological gastrostomy was performed in May 2017.\n\nThe patient did not have any previous medical history, except for esophageal cancer located 26–32 cm inferior to the upper incisors. He received concurrent chemotherapy for a month in January 2017 but exhibited worsening of dysphagia and a consequent tendency of aspiration. For proper feeding, he underwent percutaneous radiological gastrostomy in May 2017.\n\nAlthough he experienced constant pain near the gastrostomy site immediately after the procedure, oncologist continued the use of the percutaneous endoscopic gastrostomy (PEG) tube due to the persistent tendency of aspiration. In June 2017, the patient was treated with a fentanyl patch 75 µg/h and short-acting fentanyl buccal Tab 400 µg for pain management and required hospitalization due to features of delirium suspected to originate from opioid treatment.\n\nWhen he visited our pain clinic in December 2017, he was being fed via the PEG tube. There were no abnormal findings on the abdominal computed tomography images, and physical examination did not indicate infection of the gastrostomy site. The patient also underwent PEG tube exchange under image guidance to ensure proper positioning of the tube, prior to visiting our pain clinic.\n\nThe pain was localized to the gastrostomy site and nearby abdominal wall located left and inferior to the xiphoid process. In addition, the pain was dull, with no signs of tenderness or local inflammation (Fig. 1). The patient was given a combination of acetaminophen 325 mg and tramadol HCl 37.5 mg 4 times a day for pain management. Although the pain control was effective (numerical rating scale [NRS] score of 5/10) for ~2 h after drug intake, the patient sometimes experienced severe pain with an NRS score of 9/10.\n\nIn addition to the oral administration of acetaminophen and tramadol, we locally applied a lidocaine patch and lidocaine 2.5% and prilocaine 2.5% cream to the site, but this was not effective. The use of 10% lidocaine spray was effective for ~20 min after the use, and therefore was utilized together with other drugs.\n\nNevertheless, there was no persistent improvement in pain. In January 2018, we attempted left-sided subcostal TAP block using 0.8% mepivacaine 4 cm3, and triamcinolone 10 mg and additional local anesthetics infiltration at the gastrostomy site using 1% lidocaine 4 cm3, under ultrasonography guidance. Immediately after the procedure, the pain near the gastrostomy tube was alleviated by ≥ 50% but quickly became aggravated again. After 2 weeks, we performed additional left-sided subcostal TAP block and lidocaine local infiltration at the gastrostomy site. Previous procedures were repeated. However, substantial pain relief was unclear after the procedure, and we were forced to provide oral administration of acetaminophen 325 mg plus tramadol HCl 37.5 mg 3 times a day and short-acting oxycodone HCl 5 mg in case of severe pain. However, the pain control was not effective, and the patient visited the emergency center several times due to pain.\n\nSubsequently, the patient’s dysphagia symptoms improved and the PEG tube was removed in May 2018. However, the patient continued to experience persistent abdominal wall pain near the gastrostomy site. This dull pain had an atypical tendency to worsen at night (NRS score of 9/10). As the pain relief from traditional medications (i.e., oxycodone HCl or acetaminophen 325 mg plus tramadol HCl 37.5 mg) was not effective, we considered additional opioid usage.\n\nWe explained to the patient that appropriate intake of the prescribed medication for pain control and dose titration are crucial. However, the patient strongly refused to use further opioid due to fear of using strong opioids—he reported a history of severe delirium caused by opioid usage (including high-dose fentanyl patch) prior to visiting our pain clinic, as well as side effects (i.e., constipation and drowsiness) after oral opioid usage after admission to our pain clinic. The patient continued to suffer from gastrostomy site pain and had difficulties in rehabilitation and daily activities (i.e., deep breathing and supraglottic swallowing) due to pain.\n\nThe effectiveness of oral medications, such as opioids, and of topical treatments, such as lidocaine patch, cream, and spray, was inappropriate. Whereas TAP block and local infiltration of lidocaine provided short-term pain relief by ≥ 50% without any side effects.\n\nTherefore, we decided to perform left-sided TAP prognostic block and subsequent neurolytic block. We explained possible side effects (i.e., neuritis, deafferentation pain, or abdominal muscle weakness) and unclear long-term outcomes. The patient still wanted to undergo neurolytic TAP block.\n\nWe performed left-sided subcostal TAP using 0.5% bupivacaine 5 cm3 under ultrasonography guidance. The patient exhibited temporary pain relief (~5 h after procedure) and the pain worsened again, indicating positive outcome of prognostic block.\n\nIn June 2018 (7 days after), we performed left-sided subcostal TAP neurolysis. We identified the abdominal muscle layer and rectus sheath under ultrasonography guidance and injected 0.8% mepivacaine 3 cm3 using a 26-G spinal needle. We confirmed concordant pain relief after 5 min and injected 6 cm3 of 100% ethanol with the spinal needle (Fig. 2A). The total ethanol concentration for neurolysis was assumed to be 66%.\n\nThe patient did not experience any side effects except slight discomfort at the injection site immediately after alcohol injection and started to experience pain relief. The patient barely experienced any pain (NRS 0/10) immediately after neurolysis. On the outpatient visit 1 week later, he still experienced mild pain (NRS 3/10) near the medial tip of the gastrostomy site but had no pain in other sites. Pain relief was continuously observed until the 2-month outpatient follow-up, and we discontinued the use of opioids and utilized pregabalin 75 mg for abdominal pain control. However, 3 months after neurolysis, the patient started to experience abdominal pain at the medial tip of gastrostomy site (NRS 6/10), and we were forced to increase the pregabalin dose and use short-acting opioids such as oxycodone HCl.\n\nThe patient refused to use opioid again due to constipation and wanted other treatment option. We performed left-sided rectus sheath block using 0.5% bupivacaine 5 cm3 under ultrasonography guidance, and a positive outcome (pain relief) was observed.\n\nOn the 3rd month after the first neurolysis procedure, we performed rectus sheath neurolysis by injecting 0.8% mepivacaine 3 cm3 and then injecting 100% ethanol 7 cm3 (Fig. 2B). The total ethanol concentration for neurolysis was assumed to be 70%.\n\nThe patient did not experience discomfort during the procedure and started to experience pain relief. Pain at the medial tip of the gastrostomy site substantially reduced from NRS 6/10 to 2/10. Currently, he is under 4-month follow-up, with pregabalin 150 mg 2 times a day and no opioid usage.\n\nDiscussion\nSubcostal TAP block acts on the fascial plane between the internal oblique and transversus abdominis, which contain the nerves from T7 to T10, to establish sensory block of the abdominal wall. Rectus sheath block acts on the terminal branches of the 7–11th intercostal nerves, which penetrate the posterior wall of the rectus abdominis muscle. Therefore, it provides better coverage of sense organs near the midline of abdomen relative to TAP block [7]. Based on the location of the pain in different patients, an appropriate method should be utilized to ensure analgesia of the whole abdomen (Fig. 3).\n\nThus, depending on the location of the pain, rectus sheath neurolysis can be considered a treatment option for intractable pain management, along with TAP neurolysis.\n\nTAP neurolysis cases reported thus far have been focused on pain management in patients with cancerous invasion of the abdominal wall. On the other hand, we report the case of a cancer patient who received intervention for the management of treatment-associated pain.\n\nThe patient in this case report suffered from atypical pain due to gastrostomy performed as a supportive part of cancer treatment, not because of abdominal wall invasion by the cancer.\n\nPain at the gastrostomy site often occurs acutely, and multiple causes including leakage, local infection, gastric mucosa irritation caused by tube malposition, peritoneum irritation, and pain caused by progression of the primary cancer have been reported [8].\n\nFor the patient in our case report, we assessed for potential malposition and local infection at the time of PEG tube exchange. However, the patient experienced persistent, atypical pain even after tube removal.\n\nFrom the characteristics of the pain, we hypothesized that the patient was suffering from somatic and/or neuropathic pain of unknown etiology rather than from visceral pain. We attempted to provide pain relief using various medications including opioids and topical agents. However, despite the clear side effects of opioids, appropriate pain control was not achieved. More specifically, the patient was undergoing rehabilitation of supraglottic swallowing due to symptoms of dysphagia and aspiration tendency. The abdominal pain was hindering deep breathing.\n\nTherefore, in order to prolong the effectiveness of TAP block using local anesthetics, we attempted neurolysis using alcohol, one of the agents used for peripheral nerve neurolysis, and successfully provided effective pain control and opioid sparing for ~4 months after the initial neurolysis.\n\nIn a previously reported case, TAP neurolysis using 33% ethanol was performed in a hospice patient with periumbilical pain due to abdominal wall mass associated with metastatic colon cancer, and although the pain decreased from NRS 7/10 to 0/10 over 2 days, the patient died on the 5th postoperative day because of cancer progression [5].\n\nIn another case series, TAP neurolysis using 33%–70% ethanol achieved pain reduction ≥ 50% over 17 days to 3 months in cases of abdominal pain due to colon cancer involving abdominal wall or neuroendocrine tumor involving abdominal wall [4].\n\nA case report of TAP neurolysis using phenol for pain extending from the umbilicus to the pubis due to epithelioid sarcoma involving the abdominal wall reported pain reduction from NRS 5/10 to 0/10 over a maximum of 3 weeks [6].\n\nThe previously reported cases used neurolysis to relieve pain due to cancer directly involving the abdominal wall. Whereas in our case, we used neurolysis to treat pain of non-cancerous origin, and pain reduction was achieved for up to 4 months.\n\nIn this case report, we utilized alcohol as a neurolytic agent. For TAP neurolysis, there are reports of the use of either alcohol or phenol, but no previous study has compared the effectiveness of the two agents. A previous study that performed splanchnic nerve neurolysis for abdominal pain control has demonstrated that there is no difference in effect of phenol and alcohol [9], but additional studies are required for neurolysis of the abdominal wall.\n\nAs of now, the neurolytic agent should be selected considering multiple factors, including the following: painful stimulation at the time of alcohol injection, possibility of neuritis, and the surgeon’s convenience based on characteristics (i.e., viscosity of phenol).\n\nIn conclusion, although additional studies for the selection of the neurolytic agent and procedure indication/efficacy are needed, we demonstrated that alcohol-based TAP neurolysis and rectus sheath neurolysis provide effective pain control and opioid sparing in a cancer patient with chronic treatment-related pain involving the abdominal wall.\n\nConflicts of Interest\n\nNo potential conflict of interest relevant to this article was reported.\n\nAuthor Contributions\n\nKi Hoon Lee (Writing – original draft)\n\nDae Hyun Kim (Supervision; Writing – review & editing)\n\nYang Hyun Kim (Writing – review & editing)\n\nSoo Han Ro (Writing – review & editing)\n\nJun Lee (Writing – review & editing)\n\nFig. 1. Patient’s gastrostomy site. Black oval: The patient’s initial painful area.\n\nFig. 2. (A) Transversus abdominis plane neurolysis ultrasonography image. EO: external oblique muscle, IO: internal oblique muscle. (B) Rectus sheath neurolysis ultrasonography image.\n\nFig. 3. Comparison of sensory block areas between left-sided subcostal transversus abdominis plane (TAP) block and bilateral rectus sheath block. Black oval: rectus sheath block, White oval: left subcostal TAP block.\n==== Refs\nReferences\n1 Johns N O’Neill S Ventham NT Barron F Brady RR Daniel T Clinical effectiveness of transversus abdominis plane (TAP) block in abdominal surgery: a systematic review and meta-analysis Colorectal Dis 2012 14 e635 42 22632762 \n2 Marhofer P Greher M Kapral S Ultrasound guidance in regional anaesthesia Br J Anaesth 2005 94 7 17 15277302 \n3 Baciarello M Migliavacca G Marchesini M Valente A Allegri M Fanelli G Transversus abdominis plane block for the diagnosis and treatment of chronic abdominal wall pain following surgery: a case series Pain Pract 2018 18 109 17 28294508 \n4 Hung JC Azam N Puttaniah V Malhotra V Gulati A Neurolytic transversus abdominal plane block with alcohol for long-term malignancy related pain control Pain Physician 2014 17 E755 60 25415790 \n5 Sakamoto B Kuber S Gwirtz K Elsahy A Stennis M Neurolytic transversus abdominis plane block in the palliative treatment of intractable abdominal wall pain J Clin Anesth 2012 24 58 61 22284321 \n6 Gebhardt R Wu K Transversus abdominis plane neurolysis with phenol in abdominal wall cancer pain palliation Pain Physician 2013 16 E325 30 23703432 \n7 Yarwood J Berrill A Nerve blocks of the anterior abdominal wall Continuing Educ Anaesth Crit Care Pain 2010 10 182 6 \n8 Bannister M Percutaneous gastrostomy tube site pain as a manifestation of liver metastases Eur Ann Otorhinolaryngol 2015 132 363 4 \n9 Dhanalakshmi K Engle MP Yu J Feng L Diane M The effectiveness of alcohol versus phenol based splanchnic nerve neurolysis for the treatment of intra-abdominal cancer pain Pain Physician 2016 19 281 92 27228515\n\n",
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"mesh_terms": "D000009:Abdominal Muscles; D034861:Abdominal Wall; D000368:Aged; D004938:Esophageal Neoplasms; D000431:Ethanol; D005774:Gastrostomy; D006801:Humans; D008297:Male; D009407:Nerve Block; D010148:Pain, Intractable",
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"abstract": "The choice of a regimen in metastatic pancreatic cancer patients following progression on 1st line therapy is empiric and outcomes are unsatisfactory. This phase II study was performed to evaluate the efficacy of therapy selected by immunohistochemistry (IHC) in these patients following progression after one or more therapies.\nEligible patients underwent a percutaneous biopsy of a metastatic lesion and treatment selection was determined by IHC. The study required 35 evaluable patients (power of 86%) for detecting a true 1-year survival rate of >20%.\nA tumor biopsy was performed in 48 of 49 accrued patients. Study therapy was not given (n=13) either due to insufficient tumor on biopsy (n=8) or due to worsening cancer related symptoms after biopsy (n=5). The demographics of evaluable patients (n=35) are male/female (59%/41%), with age range 34-78 years (median 63 years). Patients had 1-6 prior regimens (median of 2). The most common IHC targets were topoisomerase 1 or 2, thymidylate synthase, excision repair cross-complementation group 1 protein (ERCC1), and osteonectin secreted protein acidic and rich in cysteine (SPARC). Commercially available treatment regimens prescribed included FOLFIRI, FOLFOX, irinotecan, and doxorubicin. The response (RECIST) was 9%, the median survival was 5.6 months (94% CI, 3.8-8.2), and the 1-year survival was 20% (95% CI, 7-33%).\nIn all patients, IHC assays resulted in identification of at least two targets for therapy and a non-cross resistant regimen could be prescribed for therapy with evidence of some benefit. An IHC based treatment strategy is feasible and needs validation in larger studies.",
"affiliations": "Honor Health Research Institute, Scottsdale, AZ, USA.;Honor Health Research Institute, Scottsdale, AZ, USA.;Translational Genomics Research Institute, Phoenix, AZ, USA.;Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Honor Health Research Institute, Scottsdale, AZ, USA.;Translational Genomics Research Institute, Phoenix, AZ, USA.;Human Therapeutics Division, Intrexon Corporation, Germantown, MD, USA.;Cancer Research And Biostatistics(CRAB), Seattle, WA, USA.;Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Honor Health Research Institute, Scottsdale, AZ, USA.;Translational Genomics Research Institute, Phoenix, AZ, USA.;Translational Genomics Research Institute, Phoenix, AZ, USA.;Caris Life Sciences, Phoenix, AZ, USA.;Caris Life Sciences, Phoenix, AZ, USA.;Beth Israel Deaconess Medical Center, Boston, MA, USA.;Honor Health Research Institute, Scottsdale, AZ, USA.;Mayo Clinic Cancer Center, Phoenix, AZ, USA.",
"authors": "Ramanathan|Ramesh K|RK|;Weiss|Glen J|GJ|;Posner|Richard G|RG|;Rajeshkumar|N V|NV|;Jameson|Gayle|G|;Aziz|Meraj|M|;Hoering|Antje|A|;Bolejack|Vanessa|V|;Maitra|Anirban|A|;Fulk|Monica|M|;Stites|Edward C|EC|;Hlavacek|William S|WS|;Gatalica|Zoran|Z|;Xiu|Joanne|J|;Hidalgo|Manuel|M|;Von Hoff|Daniel D|DD|;Barrett|Michael T|MT|",
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"keywords": "Array comparative genomic hybridization (aCGH); immunohistochemistry (IHC); molecular profiling (MP); pancreatic cancer; phase II clinical trial",
"medline_ta": "J Gastrointest Oncol",
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"title": "A phase 2 trial of personalized cytotoxic therapy based on tumor immunohistochemistry in previously treated metastatic pancreatic cancer patients.",
"title_normalized": "a phase 2 trial of personalized cytotoxic therapy based on tumor immunohistochemistry in previously treated metastatic pancreatic cancer patients"
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"abstract": "BACKGROUND\nWe report the case of a patient presenting with orofacial tardive dyskinesia (TD), following administration of a first-generation antipsychotic (Loxapine).\n\n\nMETHODS\nFour weeks of repeated sessions of mindfulness-based cognitive therapy (MBCT) and mindfulness-based stress reduction (MBSR) protocols were administered, with TD hetero-quantified before and during each session via the Abnormal Involuntary Movement Scale (AIMS).\n\n\nRESULTS\nThe dyskinesia ameliorated quantitatively and qualitatively (1) during each session, and (2) at resting conditions in the long term. During some sessions, after which patients' compliance was auto-evaluated as maximal, complete arrest of the TD was observed. Hypothesis and Conclusion: We suggest mindfulness meditation as a novel adjunctive therapeutic approach for tardive dyskinesia, and invite for further clinical and neurological investigations.",
"affiliations": "Department of Psychiatry, Pitié-Salpêtrière Hospital, DMU Neuroscience, Sorbonne University, Assistance Publique-Hôpitaux de Paris (AP-HP), 75651 Paris, France.;Department of Psychiatry, Pitié-Salpêtrière Hospital, DMU Neuroscience, Sorbonne University, Assistance Publique-Hôpitaux de Paris (AP-HP), 75651 Paris, France.;Paris Brain Institute-Institut du Cerveau (ICM), Sorbonne University/CNRS/INSERM, UMR 7225/UMRS 1127, 75651 Paris, France.;Department of Psychiatry, Pitié-Salpêtrière Hospital, DMU Neuroscience, Sorbonne University, Assistance Publique-Hôpitaux de Paris (AP-HP), 75651 Paris, France.;Department of Psychiatry, Pitié-Salpêtrière Hospital, DMU Neuroscience, Sorbonne University, Assistance Publique-Hôpitaux de Paris (AP-HP), 75651 Paris, France.;Department of Psychiatry, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 94270 Paris, France.;Department of Psychiatry, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 94270 Paris, France.;Department of Psychiatry, Pitié-Salpêtrière Hospital, DMU Neuroscience, Sorbonne University, Assistance Publique-Hôpitaux de Paris (AP-HP), 75651 Paris, France.",
"authors": "Santoro|Maria Angela|MA|;English|Isolde|I|;Sezer|Idil|I|;Amagat|Mickael|M|;Ly|Frank|F|;Chaneac|Edouard|E|;Cailliez|Patricia|P|;Bottemanne|Hugo|H|0000-0003-2958-0849",
"chemical_list": null,
"country": "Italy",
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"doi": "10.3390/neurolint13030043",
"fulltext": "\n==== Front\nNeurol Int\nNeurol Int\nneurolint\nNeurology International\n2035-8385\n2035-8377\nMDPI\n\n34564288\n10.3390/neurolint13030043\nneurolint-13-00043\nCase Report\nImprovement of Tardive Dyskinesia during Mindfulness Meditation\nSantoro Maria Angela 1\nEnglish Isolde 1\nSezer Idil 2\nAmagat Mickael 1\nLy Frank 1\nChaneac Edouard 3\nCailliez Patricia 3\nhttps://orcid.org/0000-0003-2958-0849\nBottemanne Hugo 124*\nComi Cristoforo Academic Editor\n1 Department of Psychiatry, Pitié-Salpêtrière Hospital, DMU Neuroscience, Sorbonne University, Assistance Publique-Hôpitaux de Paris (AP-HP), 75651 Paris, France; Maria.angela.santoro@aphp.fr (M.A.S.); Isolde.english@gmail.com (I.E.); Mickael.amagat@aphp.fr (M.A.); Frank.ly@aphp.fr (F.L.)\n2 Paris Brain Institute-Institut du Cerveau (ICM), Sorbonne University/CNRS/INSERM, UMR 7225/UMRS 1127, 75651 Paris, France; Idil.sezer@aphp.fr\n3 Department of Psychiatry, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 94270 Paris, France; Edouard.chaneac@aphp.fr (E.C.); Patricia.cailliez@aphp.fr (P.C.)\n4 Department of Philosophy, SND Research Unit, Sorbonne University, UMR 8011, 75005 Paris, France\n* Correspondence: hugo.bottemanne@gmail.com\n30 8 2021\n9 2021\n13 3 439444\n30 4 2021\n05 8 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nBackground: We report the case of a patient presenting with orofacial tardive dyskinesia (TD), following administration of a first-generation antipsychotic (Loxapine). Intervention: Four weeks of repeated sessions of mindfulness-based cognitive therapy (MBCT) and mindfulness-based stress reduction (MBSR) protocols were administered, with TD hetero-quantified before and during each session via the Abnormal Involuntary Movement Scale (AIMS). Results: The dyskinesia ameliorated quantitatively and qualitatively (1) during each session, and (2) at resting conditions in the long term. During some sessions, after which patients’ compliance was auto-evaluated as maximal, complete arrest of the TD was observed. Hypothesis and Conclusion: We suggest mindfulness meditation as a novel adjunctive therapeutic approach for tardive dyskinesia, and invite for further clinical and neurological investigations.\n\ndystonia\ndyskinesia\nmindfulness-based cognitive therapy\nmindfulness meditation\nmovement disorder\npsychiatry\n==== Body\npmc1. Introduction\n\nMillions of people in the world are, nowadays, treated at an increasing rate with antipsychotics. This is known to be among the causative factors eliciting tardive dyskinesia in a subset of patients ranging from 20% to 50% [1,2]. Tardive dyskinesia is defined by the DSM5 as a disorder of movement emerging after short- or long-term usage of medications, persisting at least 1 month after discontinuation of drug usage. It is a syndrome characterized by a series of unstoppable, stereotyped movements, more frequently of the orofacial muscles, which dramatically impairs patients’ quality of life [3]. Although we don’t exactly know yet the neurological mechanisms implied, some evidence suggests that super sensitivity of D2 receptor, caused by chronic D2 receptor blockade [4] in the motor striatum (particularly by first-generation antipsychotics), as well as other genetic and environmental factors (age, polypharmacotherapy, etc.), might be involved [5].\n\nTreatment of this syndrome remains challenging without strong evidence of efficacy nor consensus among current approaches. Conventional drug strategies such as cholinergic drugs, gamma-aminobutyric acid agonists (baclofen, progabide) or calcium channel blockers are generally ineffective against dyskinesia [6]. Cholinergic drugs such as deanol, lecithin and meclofenoxate can even cause side effects. In addition, the prescription of anticholinergic drugs (such as procyclidine or isocarboxacid) to reduce the side effects of motor symptoms is probably a factor in the aggravation of dyskinesia. There is evidence from animal experiments that anticholinergic drugs could cause tardive dyskinesia [7]. Recently, some interest has arisen around neuropsychological interventions such as mindfulness meditation because of its inexpensiveness and the general benefits elicited in the psychiatric patients’ population; these practices have already been shown to improve symptomatology in dystonia [8] and may also have a role in iatrogenic dyskinesia, particularly that which is L-dopa induced [9]. These new non-drug approaches are well tolerated by patients, do not cause serious adverse effects and could have a place in therapeutic strategies against dyskinesia induced by neuroleptics [9].\n\nWe report here the case of a radical improvement obtained via mindfulness meditation, in a patient suffering from tardive dyskinesia after first-generation antipsychotic treatment, and we discuss possible mechanisms associated with this enhancement.\n\n2. Case Report\n\nWe report the case of a sixty-year-old male patient suffering from severe recurrent anxio-depressive disorder with hypochondriac dominant features, who, after the introduction of Loxapine, developed some major tardive dyskinesia (TD) involving the lips, jaw and perioral muscles.\n\nThe patient’s first major depressive episode was diagnosed in his thirties: an outpatient treatment starting with Fluoxetine 20 mg/per day was proposed but the patient was lost at follow-up. He was hospitalized in his mid-forties for scenarized suicidal thoughts in the context of a major depressive episode with major hypochondriac features; diagnosis of a recurrent major depressive disorder was established. Fluoxetine, which he was still taking, was substituted with Paroxetine 40 mg/per day and then with Sertraline at 200 mg/per day, which, together with the beginning of cognitive behavioural therapy, proved its efficacy and allowed for patient dismission and outpatient follow-up.\n\nTwo further hospitalizations were required in the last two years for pharmacological therapy adjustment because of an upsurge in hypochondriac anxio-depressive symptomatology. During the second-to-last hospitalization, the patient’s symptomatology required the beginning of an antipsychotic therapy with an anxiolytic and ideolytic aim, started with Loxapine 150 to 300 mg/per day. The patient did not show signs of extrapyramidal or poor motor tolerance during the administration of Loxapine. The patient presented hypochondriac delusions, congruent with mood, motivating the prescription of Risperidone 2 mg/per day. Sertraline was gradually substituted by Venlafaxine up to 300 mg/day and lithium introduced at 800 mg/day, corresponding to a serum lithemia of 0.7 mmol/L. The clinical improvement made it possible to stop Loxapine after two months of treatment. The patient was dismissed for anxio-depressive symptomatology regression, and addressed to our unit in order to build up to a societal reinsertion project.\n\nHe began to present facial tardive dyskinetic movements 3 months after stopping treatment, involving the lips, jaw and perioral muscles, only disappearing during patient sleep. A first assessment of patient’s dyskinesia using the Abnormal Involuntary Movement Scale (AIMS) [10] gave us a Total Score (TS) of 12 (sum of AIMS items 1 to 7) and an Overall Severity Index (OSI) of 3 (AIMS item 8), causing a level of awareness and distress (A&D) considered by the patient themself of 4 (AIMS item 10). Following the patient’s daily progressions, it was noticed that his general stress level reflected quantitatively and qualitatively on the dyskinesia. For this reason, mindfulness-based interventions, such as mindfulness-based cognitive therapy (MBCT), and mindfulness-based stress reduction (MBSR) strategies were employed. As a matter of fact, MBCT and MBSR are already known to reduce the levels of stress hormones [11], to also reduce anxiety [12] and to improve mood symptoms [13]. TD was hetero-quantified through the AIMS before and during any meditation session by a trained operator, in an observational manner.\n\nWe noticed a generalized reducing trend of the TD over the weeks with a ΔTS between the first and the fourth week of 4 points at baseline condition, as well as a significant intra-intervention decrease in severity and number of TD, with a maximal TS decrease of 7.5 (Figure 1). During the first week, the mean TS before sessions = 12, the mean TS during sessions = 4.5, and Δ = 7.5; the mean OSI before sessions = 3, the mean OSI during sessions = 2, and Δ = 1. During the second week, the mean TS before sessions = 9, the mean TS during sessions = 3.3, and Δ = 5.7; the mean OSI before sessions = 3, the mean OSI during sessions = 1.3, and Δ = 1.6. During the third week, the mean TS before sessions = 8, the mean TS during sessions = 1.5, and Δ = 6.5; the mean OSI before sessions = 3, the mean OSI during sessions = 1, and Δ = 1.5. During the fourth week, the mean TS before sessions = 8, the mean TS during sessions = 1, and Δ = 7; the mean OSI before sessions = 3, the mean OSI during sessions = 1, and Δ = 1.5 (Table 1). AIMS scoring was significantly different between before-meditation and intra-meditation observations (t63 = 7, p < 0.01, paired t tests).\n\nDyskinesia decrease was also objectivised via an EEG with perioral muscles electromyography, performed at the end of the four weeks, with an intra-recording meditation session, where the electromyography recording showed concordance with the AIMS scoring: frequency, amplitude and width of the perioral muscles’ contraction waves decreased consistently during the whole closed eyes, relaxed state. Those three parameters (frequency, amplitude and width) all increased each time the patient was asked to re-emerge from the meditative state.\n\n3. Discussion\n\nWe report here a significant and prolonged clinical improvement of acquired tardive dyskinesia after antipsychotic treatment, following treatment by mindfulness-based cognitive therapy (MBCT) and mindfulness-based stress reduction (MBSR). Research conducted on mindfulness-based interventions suggests that mindfulness meditation produces delta, theta, alpha and beta 1 activity waves, and minimizes incoming signals from immediate surroundings and increases the ability of information processing, particularly related to current states of body [14]. In addition, eye closure and maintenance of a relaxed state are known factors eliciting the insurgence of brain alpha waves, recorded on human brain EEG as a consequence of neuronal discharge synchronization.\n\nThe acute clinical improvement during the MBT session can be explained using many hypotheses; in particular, the role of distractibility and attentional focus, which could participate in improving dyskinesia. However, this explanation does not seem sufficient to us, given the prolongation of the effects of MBT on dyskinesias well after the sessions. The improvement in abnormal motor movements during mindfulness-based therapy (MBT) has already been documented [8], but the mechanism associated with prolonged improvement after treatment remains a mystery.\n\nA first hypothesis would be to consider the effect of MBT on the patient’s anxiety level, assuming that the improvement in anxiety may have participated in a decrease in dyskinesias. Studies suggest a link between abnormal motor movements and environmental stress, in particular, a worsening of pre-existing motor abnormalities in stressful situations [15]. A second hypothesis would be to consider the effect of MBT on brain connectivity, a promising field of research. We can, for example, assume that neuronal electrical synchronisation might overwhelm some subcortical non-vital pathways, impeding non-controlled organized discharge, in particular, those leading to stereotyped movements, notably dyskinesia. In the long term, we suggest there is a stabilization of functional neuronal pathways at the expense of others (dyskinetic pathways), as a consequence of the repeated firing of focused attention circuitries, which may induce the creation of reflex negative pathways and may reduce the dyskinetic pathways.\n\nAnother possible explanation could be due to large-scale modulation of brain networks mediated by mindfulness meditation. The remodulation of resting-state brain networks, meaning anatomically distinct regions co-activated for a function, could explain the long-lasting therapeutic effects for the patient. The modulation of brain networks, such as the central executive network implicated in attentional processes and the default mode network implicated in internally focused processes [16], could explain the decreased TD through improved attention control and emotion regulation [17]. Indeed, for the latter, the regulation of negative emotions generated by TD symptoms could in part explain the alleviation of symptoms, notably of anxious symptoms. Overall, although its mechanisms remain to be elucidated, mindfulness practice has been extensively linked to therapeutic effects in various clinical populations [18]\n\nFurther research using electrophysiology and neuroimaging is needed to understand the effect of MBT on abnormal movements and, in particular, on neuroleptic-induced dyskinesia. Specifically, resting-state functional connectivity (RSFC) methods and structural neuroimaging methods can help us explore how mindfulness meditation can have an impact on neural plasticity [19,20,21]. Parallelly, previous electrophysiological research has suggested long-lasting changes in the resting electroencephalogram patterns during mental practice [22], which is very encouraging for future explorations. This research could be carried out on large samples given the large number of patients with these symptoms in psychiatric hospitals and in outpatient psychiatric care.\n\n4. Conclusions\n\nWe present a case of tardive dyskinesia improvement during mindfulness meditation. We hypothesized the possibility of long-term instauration of neuronal circuits able to overwhelm those inducing the TD. On a larger scale, we hypothesize the remodulation of brain networks modifying attentional processes and regulating the negative affects concomitant to TD. Little data is available on the neurological mechanisms underlying TD, and the specific neurological mechanisms of mindfulness meditation still remain to be understood. However, there is, interestingly, some proof that it might cause neuroplastic changes [17], and these changes may be involved in the long-term efficacy of MBT against these unwanted motor symptoms.\n\nWith regard to this limited knowledge, the above-mentioned proposed mechanisms are only speculative, but we encourage further research for neurobiological explanations, as well as research for greater data strength via protocolized and standardized mindfulness interventions. We present here the results of a case report on a single patient. These results must therefore be considered with caution, and deserve to be replicated on a larger scale. If these findings could be confirmed and validated through a group study bearing statistically significant numerosity, the understanding of the mechanism would be of help in the development of more targeted interventions with probably more stable efficacy, possibly opening further therapeutic horizons.\n\nAuthor Contributions\n\nConceptualization, H.B.; methodology, H.B.; formal analysis, M.A.S. and H.B.; investigation, M.A.S. and H.B.; resources, H.B.; data curation, M.A.S. and H.B.; writing—original draft preparation, M.A.S. and H.B.; writing—review and editing, M.A.S., I.E., I.S., M.A., F.L., E.C., P.C., H.B.; visualization, M.A.S., I.E., I.S., H.B.; supervision, H.B.; project administration, H.B.; funding acquisition, H.B. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Baseline vs. in-meditation AIMS Total Score (TS) and Overall Severity Index (OSI). AIMS: Abnormal Involuntary Movement Scale. TS: Total score (equal the sum of the AIMS scoring given at the items from 1 to 7). OSI: Overall Severity index (equal the AIMS scoring given at the item 8).\n\nneurolint-13-00043-t001_Table 1 Table 1 AIMS scoring divided per intervention weeks.\n\n\tMean TS Baseline\tMean TS in Meditation\tΔ TS\tMean OSI Baseline\tMean OSI in Meditation\tΔ OSI\t\nWeek 1\t12\t4.5\t7.5\t3\t2\t1\t\nWeek 2\t9\t3.3\t5.7\t3\t1.3\t1.6\t\nWeek 3\t8\t1.5\t6.5\t3\t1\t1.5\t\nWeek 4\t8\t1\t7\t3\t1\t1.5\t\nAIMS: Abnormal Involuntary Movement Scale. TS: Total score (equal the sum of the AIMS scoring given at the items from 1 to 7). OSI: Overall Severity index (equal the AIMS scoring given at the item 8).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Cornett E. Novitch M. Kaye A. Kata V. Kaye A. Medication-Induced Tardive Dyskinesia: A Review and Update Ochsner J. 2017 17 162 174 28638290\n2. Waln O. Jankovic J. An update on tardive dyskinesia: From phenomenology to treatment Tremor Other Hyperkinetic Mov. 2013 3 10.5334/tohm.165\n3. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders American Psychiatric Association Arlington, VA, USA 2013\n4. Yoshida K. Bies R.R. Suzuki T. Remington G. Pollock B.G. Mizuno Y. Mimura M. Uchida H. Tardive dyskinesia in relation to estimated dopamine D2 receptor occupancy in patients with schizophrenia: Analysis of the CATIE data Schizophr. Res. 2014 153 184 188 10.1016/j.schres.2014.01.017 24491908\n5. Anusa A. Thavarajah R. Nayak D. Joshua E. Rao U. Ranganathan K. A Study on Drug-Induced Tardive Dyskinesia: Orofacial Musculature Involvement and Patient’s Awareness J. Orofac. Sci. 2018 10 86 95 30655658\n6. Soares-Weiser K. Rathbone J. Ogawa Y. Shinohara K. Bergman H. Miscellaneous treatments for antipsychotic-induced tardive dyskinesia Cochrane Database Syst. Rev. 2018 3 CD000208 10.1002/14651858.CD000208.pub2 29552749\n7. Bergman H. Soares-Weiser K. Anticholinergic medication for antipsychotic-induced tardive dyskinesia Cochrane Database Syst. Rev. 2018 1 CD000204 10.1002/14651858.CD000204.pub2 29341071\n8. Sandhu H. Bernstein C.J. Davies G. Tang N.K.Y. Belhag M. Tingle A. Field M. Foss J. Lindahl A. Underwood M. Combined cognitive-behavioural and mindfulness programme for people living with dystonia: A proof-of-concept study BMJ Open 2016 6 e011495 10.1136/bmjopen-2016-011495 27496234\n9. Szekely B.C. Turner S.M. Jacob R.G. Behavioral control of L-dopa induced dyskinesia in Parkinsonism Biofeedback Self-Regul. 1982 7 443 447 10.1007/BF00998884 6762225\n10. Abnormal Involuntary Movement Scale (117-AIMS) ECDEU Assessment Manual for Psychopharmacology Guy W. National Institute of Mental Health Rockville, MD, USA 1976 534 537\n11. Tang Y.-Y. Ma Y. Wang J. Fan Y. Feng S. Lu Q. Yu Q. Sui D. Rothbart M.K. Fan M. Short-term meditation training improves attention and self-regulation Proc. Natl. Acad. Sci. USA 2007 104 17152 17156 10.1073/pnas.0707678104 17940025\n12. MacCoon D.G. Imel Z.E. Rosenkranz M.A. Sheftel J.G. Weng H.Y. Sullivan J.C. Bonus K.A. Stoney C.M. Salomons T.V. Davidson R.J. The validation of an active control intervention for Mindfulness Based Stress Reduction (MBSR) Behav. Res. Ther. 2012 50 3 12 10.1016/j.brat.2011.10.011 22137364\n13. Hofmann S.G. Sawyer A.T. Witt A.A. Oh D. The effect of mindfulness-based therapy on anxiety and depression: A meta-analytic review J. Consult. Clin. Psychol. 2010 78 169 183 10.1037/a0018555 20350028\n14. Dunn B.R. Hartigan J.A. Mikulas W.L. Concentration and Mindfulness Meditations: Unique Forms of Consciousness? Appl. Psychophysiol. Biofeedback 1999 24 147 165 10.1023/A:1023498629385 10652635\n15. Stegmayer K. Walther S. van Harten P. Tardive Dyskinesia Associated with Atypical Antipsychotics: Prevalence, Mechanisms and Management Strategies CNS Drugs 2018 32 135 147 10.1007/s40263-018-0494-8 29427000\n16. Bauer C. From State-to-Trait Meditation: Reconfiguration of Central Executive and Default Mode Networks Eneuro 2019 6 10.1523/ENEURO.0335-18.2019 31694816\n17. Tang Y.-Y. Hölzel B.K. Posner M.I. The neuroscience of mindfulness meditation Nat. Rev. Neurosci. 2015 16 213 225 10.1038/nrn3916 25783612\n18. Wielgosz J. Goldberg S.B. Kral T.R.A. Dunne J.D. Davidson R.J. Mindfulness Meditation and Psychopathology Annu. Rev. Clin. Psychol. 2019 15 285 316 10.1146/annurev-clinpsy-021815-093423 30525995\n19. Fox M.D. Raichle M.E. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging Nat. Rev. Neurosci. 2007 8 700 711 10.1038/nrn2201 17704812\n20. Greicius M.D. Supekar K. Menon V. Dougherty R.F. Resting-state functional connectivity reflects structural connectivity in the default mode network Cereb. Cortex 2009 19 72 78 10.1093/cercor/bhn059 18403396\n21. Lazar S.W. Kerr C.E. Wasserman R.H. Gray J.R. Greve D.N. Treadway M.T. McGarvey M. Quinn B.T. Dusek J.A. Benson H. Meditation experience is associated with increased cortical thickness Neuroreport 2005 16 1893 1897 10.1097/01.wnr.0000186598.66243.19 16272874\n22. Lutz A. Greischar L.L. Rawlings N.B. Ricard M. Davidson R.J. Long-term meditators self-induce highamplitude gamma synchrony during mental practice Proc. Natl. Acad. Sci. USA 2004 101 16369 16373 10.1073/pnas.0407401101 15534199\n\n",
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"abstract": "A 20-year-old asylum seeker presented with vomiting and left thigh pain, with a biological inflammatory syndrome. Pregnancy was diagnosed. Investigations revealed a pseudo-cystic, 20-cm-long retroperitoneal abscess, biopsy of which confirmed the diagnosis of tuberculosis. Evolution after cyst drainage and under conventional anti-tuberculosis treatment was favourable. An abdominal location of tuberculosis is rare and its diagnosis is difficult especially in countries with a low incidence of the disease. Unexplained abdominal manifestations and/or persistent biological inflammatory syndrome, especially in high-risk groups, should raise the suspicion of tuberculosis.\nAbdominal tuberculosis (TB) is a challenging diagnosis especially in low-incidence countries where the disease is rarely suspected.In low-incidence countries, abdominal TB should be suspected in cases of unexplained abdominal manifestations and/or persistent inflammatory syndrome, especially in high-risk groups.The diagnosis of abdominal TB is based on a range of anamnestic and clinical symptoms and signs, imaging, culture, and invasive procedures for histology.",
"affiliations": "Department of Community Medicine, Primary Care and Emergency Medicine, University Hospitals of Geneva, Switzerland.;Division of Obstetrics, Department of Gynecology and Obstetrics, University Hospitals of Geneva, Switzerland.;Division of Pulmonary Diseases, Department of Internal Medicine Specialties, University Hospitals of Geneva, Switzerland.",
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"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2018_000865865-1-5592-1-10-20180523ArticlesInflammatory Syndrome as the Initial Manifestation of Retroperitoneal Tuberculosis in a Pregnant Woman Grira Marwene 1Boulvain Michel 2Janssens Jean-Paul 3\n1 Department of Community Medicine, Primary Care and Emergency Medicine, University Hospitals of Geneva, Switzerland\n2 Division of Obstetrics, Department of Gynecology and Obstetrics, University Hospitals of Geneva, Switzerland\n3 Division of Pulmonary Diseases, Department of Internal Medicine Specialties, University Hospitals of Geneva, Switzerland2018 26 7 2018 5 7 00086515 2 2018 08 5 2018 © EFIM 20182018This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseA 20-year-old asylum seeker presented with vomiting and left thigh pain, with a biological inflammatory syndrome. Pregnancy was diagnosed. Investigations revealed a pseudo-cystic, 20-cm-long retroperitoneal abscess, biopsy of which confirmed the diagnosis of tuberculosis. Evolution after cyst drainage and under conventional anti-tuberculosis treatment was favourable. An abdominal location of tuberculosis is rare and its diagnosis is difficult especially in countries with a low incidence of the disease. Unexplained abdominal manifestations and/or persistent biological inflammatory syndrome, especially in high-risk groups, should raise the suspicion of tuberculosis.\n\nLEARNING POINTS\nAbdominal tuberculosis (TB) is a challenging diagnosis especially in low-incidence countries where the disease is rarely suspected.\n\nIn low-incidence countries, abdominal TB should be suspected in cases of unexplained abdominal manifestations and/or persistent inflammatory syndrome, especially in high-risk groups.\n\nThe diagnosis of abdominal TB is based on a range of anamnestic and clinical symptoms and signs, imaging, culture, and invasive procedures for histology.\n\nAbdominal tuberculosisinflammatory syndromepregnancy\n==== Body\nCASE DESCRIPTION\nA 20-year-old female Eritrean asylum seeker, who had arrived in Switzerland 6 months previously, presented to our primary care medicine department. She complained of nausea, vomiting and a pain in the left thigh of 15 days’ duration, without a history of trauma.\n\nPhysical examination was unremarkable except for tenderness on palpation of the left thigh. Biological tests revealed microcytic anaemia with a haemoglobin of 85 g/l (normal 120–160 g/l) and an MCV of 78 fl (normal 82–98 fl), an inflammatory syndrome with a CRP of 88 mg/l (normal 0–10 mg/l) and a sedimentation rate of 77 mm/h (normal 0–20 mm/h), and a slight disturbance of liver function with an ALP of 159 U/l (normal 25–102 U/l), GGT of 67 U/l (normal 9–35 U/l), and normal ASAT and ALAT. β-hCG was increased to 181,567 U/l.\n\nObstetrical ultrasound confirmed a 10-week pregnancy and the diagnosis of hyperemesis gravidarum was made. The woman was discharged.\n\nTo investigate the inflammatory syndrome, an extensive infection screen was performed including bacterial (blood, urine and stool cultures, brucellosis and syphilis serologies), viral (VZV, CMV, EBV, parvovirus B19, HTLV 1 and 2, measles, rubella, viral hepatitis and HIV) and parasitic (toxoplasmosis, leishmaniasis and malaria) screens. Tests confirmed past exposure to rubella, varicella and hepatitis A. The other tests were negative. The patient was also screened for TB: IGRA (QuantiFERON®-TB Gold) was positive, but chest X-ray was normal. Finally, the left thigh pain was investigated by an US scan of the soft parts of the thigh, which was normal.\n\nAbdominal and pelvic US performed at 20 weeks of amenorrhoea revealed a large left abdominal mass suggestive of an ovarian cyst, responsible for a left inguinal hernia. An MRI scan of the pelvis confirmed a left pseudo-cystic, 20-cm-long retroperitoneal abscess which extended along the left iliopsoas muscle and was associated with various tissue injuries along the left sympathetic chain (Figs. 1–3)\n\nThe radiological characteristics of the mass suggested a paraganglioma. However, a 24-hour urine and plasma fractionated metanephrines and catecholamines were normal, which excluded the diagnosis. Biopsy of the pseudo-cystic retroperitoneal abscess under US showed a granulomatous inflammation with giant cells, necrosis and acid-fast bacilli. PCR (GeneXpert) confirmed the diagnosis of TB.\n\nA 14F catheter was inserted into the cyst and allowed drainage of about 3,000 ml of fluid over a few days. Conventional TB treatment (rifampicin, isoniazid, pyrazinamide and ethambutol) with fixed-dose combination tablets was started. No immunosuppressive factors or evidence of vertebral involvement were found. Evolution under treatment, and monthly monitoring by US, was favourable, with a transient and spontaneously reversible increase in liver tests.\n\nPregnancy was complicated by umbilical cord prolapse which required a caesarean section at 33 weeks of amenorrhoea. The patient gave birth to a healthy baby boy.\n\nDISCUSSION\nAbdominal TB represents about 6% of extra-pulmonary forms[1]. It can occur at any age with a peak frequency between 21 and 45 years of age[2]. The distribution by sex varies according to studies. A female predominance is observed in endemic countries, while a male predominance is reported in many European countries. This is explained by the larger percentage of males among immigrants, in whom abdominal TB is more frequent than among the local population[3]. The clinical manifestations of abdominal TB are extremely varied, which often results in a misleading picture and delayed diagnosis. Consequently, additional examinations are very important for correct diagnosis[2].\n\nPeritoneal TB is the most frequent form of abdominal TB[1] which can also affect the gastro-intestinal tract, mesentery, abdominal lymph nodes, liver, spleen and pancreas[4]. However, there is no consensus definition of abdominal TB. TB of the genital and urinary systems, which is anatomically considered abdominal TB, is usually excluded from studies and guidelines for abdominal TB. This situation makes comparison between data from different studies difficult[5].\n\nThe treatment of abdominal TB is based on the same protocol as that for pulmonary TB with 2 months of quadritherapy, followed by 4 months of dual therapy[6]. Global mortality varies according to studies, ranging from 3% to 30% [2, 7, 8].\n\nPregnancy does not adversely impact the course of TB infection. However, it may mimic and mask the symptoms of early TB and thus delay its diagnosis[9]. Non-treated TB in the pregnant woman may lead to congenital TB in the infant. Comparative studies from India, Mexico and Taiwan found that infants born to mothers with TB have a two- to three-fold increased risk of neonatal complications such as prematurity and fetal growth retardation, as well as a six-fold increase in perinatal mortality[10–12]. The risk of transmission of TB to the infant is greater than the risks associated with TB treatment administered to the mother[9]. Therefore, treatment should be started whenever the probability of maternal disease is moderate to high. The treatment of a pregnant woman is the same as that of a non-pregnant woman[13]. Antituberculosis drugs do not have teratogenic effects in humans, even though they cross the placenta[13].\n\nMany factors made the diagnosis in this case challenging:\n\nConstitutional symptoms (fever, night sweats, fatigue and weight loss) were absent or hidden by the context of pregnancy (e.g. weight gain).\n\nThere were no digestive symptoms, especially no abdominal pain, which is a usual symptom in 74–94% of patient [7, 14] with abdominal TB.\n\nThe main symptom on which we based our clinical reasoning was the inflammatory syndrome which is a frequent and non-specific sign.\n\nThe patient had misleading symptoms such as the thigh pain due to the inguinal hernia or the hyperemesis gravidarum, which initially diverted the diagnosis.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Sagittal section at 20 weeks of amenorrhoea showing the fetus facing the retroperitoneal mass (yellow arrow)\n\nFigure 2 Cross-section at 20 weeks of amenorrhoea showing the fetus (green arrow) facing the retroperitoneal mass (yellow arrow)\n\nFigure 3 (a) Diffusion sequence b0 and (b) apparent diffusion coefficient (ADC) mapping. The axial plane in the upper abdomen shows ADC restriction (arrow on ‘a’), suggesting a tuberculosis collection. The denser or more cellular the biological tissue (e.g. pus), the less the diffusion of water and so the ADC. Low ADC appears in hypersignal on the diffusion sequence (a)\n==== Refs\nREFERENCES\n1 Mazza-Stalder J Nicod L Janssens JP La tuberculose extrapulmonaire Rev Mal Respir 2012 29 566 578 22542414 \n2 Abdallah M Larbi T Hamzaoui S Mezlini E Harmel A Ennafaa M Tuberculose abdominale: étude rétrospective de 90 cas Rev Med Interne 2011 32 212 217 20971533 \n3 Thoreau N Fain O Babinet P Lortholary O Robineau M Valeyre D Tuberculose péritonéale: 27 cas dans la banlieue nord-est de Paris Int J Tuberc Lung Dis 2002 6 253 258 11936091 \n4 Uygur-Bayramicli O Dabak G Dabak R A clinical dilemma: abdominal tuberculosis World J Gastroenterol 2003 9 1098 1101 12717865 \n5 Fillion A Ortega-Deballon P Al-Samman S Briault A Brigand C Deguelte S Abdominal tuberculosis in a low prevalence country Med Mal Infect 2016 46 140 145 26995289 \n6 Blumberg HM Burman WJ Chaisson RE Daley CL Etkind SC Friedman LN American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis Am J Respir Crit Care Med 2003 167 603 662 12588714 \n7 Chou CH Ho MW Ho CM Lin PC Weng CY Chen TC Abdominal tuberculosis in adult: 10-year experience in a teaching hospital in central Taiwan J Microbiol Immunol Infect 2010 43 395 400 21075706 \n8 Tan KK Chen K Sim R The spectrum of abdominal tuberculosis in a developed country: a single institution’s experience over 7 years J Gastrointest Surg 2009 13 142 147 18769984 \n9 Gould JM Aronoff SC Tuberculosis and pregnancy-maternal, fetal, and neonatal considerations Microbiol Spectr 2016 4 10.1128/microbiolspec.TNMI7-0016-2016 \n10 Jana N Vasishta K Jindal SK Khunnu B Ghosh K Perinatal outcome in pregnancies complicated by pulmonary tuberculosis Int J Gynaecol Obstet 1994 44 119 124 7911094 \n11 Figueroa-Damian R Arredondo-Garcia JL Neonatal outcome of children born to women with tuberculosis Arch Med Res 2001 32 66 69 11282183 \n12 Lin HC Lin HC Chen SF Increased risk of low birthweight and small for gestational age infants among women with tuberculosis BJOG 2010 117 585 590 20156210 \n13 Nahid P Dorman SE Alipanah N Barry PM Brozek JL Cattamanchi A Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis Clin Infect Dis 2016 63 e147 e195 27516382 \n14 Amouri A Boudabbous M Mnif L Tahri N Profil actuel de la tuberculose péritonéale: étude d’une série tunisienne de 42 cas et revue de la littérature Rev Med Interne 2009 30 215 220 19131144\n\n",
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"abstract": "Granuloma annulare (GA) is a common inflammatory skin condition that manifests as annular skin colored to erythematous papules and plaques. Disseminated GA is a subtype of GA that presents with diffuse cutaneous involvement. While topical and intralesional corticosteroids and phototherapy have been used as therapies for GA, there is no consensus on the best course of treatment for GA. Apremilast is a phosphodiesterase 4 (PDE4) inhibitor that has been Food and Drug Administration (FDA) approved for psoriasis, psoriatic arthritis, and oral ulcers associated with Behcet's disease; apremilast has also shown promise off-label for other inflammatory skin conditions. Here, we present the case of a woman in whom apremilast use led to an almost complete resolution of her disseminated GA. Our patient tolerated apremilast well and reported no side effects. We also review the literature on the use of apremilast in other patients with GA.",
"affiliations": "Dermatology, Baylor College of Medicine, Houston, USA.;Dermatology, St. Joseph Dermatopathology, Houston, USA.",
"authors": "Joshi|Tejas P|TP|;Tschen|Jaime|J|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.14918\nDermatology\nApremilast in the Management of Disseminated Granuloma Annulare\nMuacevic Alexander\nAdler John R\nJoshi Tejas P 1\nTschen Jaime 2\n1 Dermatology, Baylor College of Medicine, Houston, USA\n2 Dermatology, St. Joseph Dermatopathology, Houston, USA\nTejas P. Joshi tejas.joshi@bcm.edu\n9 5 2021\n5 2021\n13 5 e149189 5 2021\nCopyright © 2021, Joshi et al.\n2021\nJoshi et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/58846-apremilast-in-the-management-of-disseminated-granuloma-annulare\nGranuloma annulare (GA) is a common inflammatory skin condition that manifests as annular skin colored to erythematous papules and plaques. Disseminated GA is a subtype of GA that presents with diffuse cutaneous involvement. While topical and intralesional corticosteroids and phototherapy have been used as therapies for GA, there is no consensus on the best course of treatment for GA. Apremilast is a phosphodiesterase 4 (PDE4) inhibitor that has been Food and Drug Administration (FDA) approved for psoriasis, psoriatic arthritis, and oral ulcers associated with Behcet’s disease; apremilast has also shown promise off-label for other inflammatory skin conditions. Here, we present the case of a woman in whom apremilast use led to an almost complete resolution of her disseminated GA. Our patient tolerated apremilast well and reported no side effects. We also review the literature on the use of apremilast in other patients with GA.\n\ngranuloma annulare\ndisseminated granuloma annulare\napremilast\noff-label drug use\npsoriasis\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nGranuloma annulare (GA) is a granulomatous skin condition that presents as skin colored to erythematous papules and plaques. Disseminated GA is a subtype of GA with diffuse cutaneous involvement. While the precise etiology of GA remains poorly understood, a Th1 mediated delayed hypersensitivity reaction has been implicated in the development of GA. Histologically, GA is characterized by the presence of palisading histiocytes, degraded collagen, and mucin [1]. Topical corticosteroids or intralesional triamcinolone are considered to be first line therapies for local disease. While phototherapy has shown to be effective for generalized disease, there nevertheless exists no established paradigm of care for disseminated GA [2].\n\nApremilast is a phosphodiesterase 4 (PDE4) inhibitor that has been Food and Drug Administration (FDA) approved for psoriasis, psoriatic arthritis, and oral ulcers associated with Behcet’s disease [3]. As apremilast downregulates cytokines central to the pathogenesis of many inflammatory skin conditions, it has been indicated for off-label use in alopecia areata, atopic dermatitis, cutaneous sarcoidosis, discoid lupus erythematosus, hidradenitis suppurativa, and lichen planus [4]. Here, we report the case of a 77-year-old woman in whom apremilast treatment led to an almost complete resolution of her disseminated GA.\n\nCase presentation\n\nA 77-year-old woman with a history of plaque psoriasis and arthritis presented for evaluation of a burning body rash and plaques on her face and upper extremities. Her medications include levothyroxine and escitalopram. She is allergic to ciprofloxacin, metoprolol, and sulfa drugs. Her past medical history was positive for oral lichen planus. She did not have a relevant family history of plaque psoriasis or disseminated GA.\n\nPhysical examination revealed plaques on her feet, face, and arms that were erythematous, annular, circinate, and non-scaly, as well as a cutaneous horn with an irritated seborrheic keratosis at the base on her right wrist (Figure 1A). The patient’s skin examination was otherwise unremarkable. A 4-mm punch biopsy of the lesion on her right arm revealed granulomatous inflammation with areas of necrobiosis consistent with GA (Figure 2). The patient was started on apremilast 30 mg twice a day. Apart from apremilast, she did not use topical steroids. At three-month follow-up, the GA was found to have spread to her chest, back, left upper extremity, and feet (Figures 1B-1D). Apremilast treatment was continued, and at six-month follow-up, the lesions on the chest and bilateral upper extremities had regressed entirely (Figures 1E-1F). The lesions on her feet improved as well but did not resolve completely. At seven-month follow-up, the patient’s remission was mostly durable, with no new lesions appearing over the upper extremities; furthermore, the GA on the patient’s feet substantially regressed (Figures 1G-1H). Yet, a mild flare-up was noted on the patient’s cervical to lumbar back (Figure 1I). The patient’s skin examination was otherwise unremarkable. Also noteworthy, the patient’s burning sensation from the rash disappeared shortly after starting apremilast, and at seven-month follow-up, reported only slight pruritus over the flare-up on her back. The patient denied any gastrointestinal side effects and tolerated apremilast well. The patient was instructed to continue with apremilast.\n\nFigure 1 (A) Granuloma annulare (GA) on the right arm at initial evaluation. Spread of GA to back (B), left arm (C), and feet (D) at three-month follow-up. Regression of GA lesions on right (E) and left (F) arms at six-month follow-up. Regression of GA on bilateral feet (G) and (H) at seven-month follow-up. (I) Slight flare-up of GA observed on back at seven-month follow-up.\n\nFigure 2 Histopathology of punch biopsy from patient’s right arm displaying characteristic features of granuloma annulare: (A) bracket indicates palisading histiocytes and arrows indicate degraded collagen; 40x magnification (B) arrows point towards regions of necrobiosis; 100x magnification (C) arrow points to multi-nucleated giant cell; 200x magnification.\n\nDiscussion\n\nGA was first described in 1895 by Colcott-Fox as a “ringed eruption”[5]. Classically, GA manifests as annular skin colored to erythematous papules and plaques. Disseminated GA is a variant of GA with more generalized cutaneous involvement. While a Type IV hypersensitivity reaction has been implicated as the mechanism underlying GA pathogenesis, the precise etiology of GA eludes facile explanation. GA has been linked, albeit tenuously, to diabetes mellitus, malignancy, thyroid disease, and dyslipidemias [1]. There is a paucity of literature that offers any consensus on the best course of treatment for GA. Wang and Khachemoune reviewed the treatments for GA and report a wide gamut of treatments to have been used for GA [2]. Nevertheless, some of these treatments have concerning side effect profiles. Chlorambucil, for instance, has been reported in the management of GA [6] yet it is a very risky treatment as it can precipitate hemorrhagic cystitis. Similarly, dapsone was recently reported to be used for the treatment of GA in 26 patients, and while 54% of patients experienced improvement, 31% of patients experienced myelosuppression, which required treatment to be discontinued [7].\n\nApremilast has been indicated as a treatment for psoriasis, psoriatic arthritis, and oral ulcers associated with Behcet’s disease [3]. Apremilast works by inhibiting PDE4, thereby preventing cyclic adenosine monophosphate (cAMP) hydrolysis; elevated cytosolic cAMP levels then work to dampen the production of inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-12, and interferon-γ (IFN-γ)) important in psoriasis pathogenesis. As TNF-α, IL-6, and IL-12 have also been implicated in GA pathogenesis [1], it is mechanistically rational to consider the therapeutic potential of apremilast in the management of GA. Furthermore, apremilast has a mild side effect profile, with mild to moderate gastrointestinal symptoms that typically resolve with continued treatment [8].\n\nIn our literature review, we identified two case series reporting the off-label use of apremilast in the management of GA. Blum and Altman reported two cases in which apremilast was effective for the treatment of GA refractory to steroids. One patient experienced partial resolution of their lesions and the other patient experienced an improvement in erythema and lesion induration. Both patients tolerated apremilast well [9]. Bishnoi et al. reported apremilast to be effective in the treatment of recalcitrant GA in four additional patients. Three patients reported a reduction in lesion number and one patient reported decreased erythema and pruritis. Apremilast was generally well tolerated, with one patient reporting mild gastrointestinal disturbance and myalgia and another patient reporting nausea and myalgia. The other two patients did not experience any adverse effects [10].\n\nAlthough spontaneous improvement of GA in our patient cannot be completely excluded, the temporal clinical and symptomatic improvement makes it likely that the patient’s remission is putatively due to apremilast treatment. The minor flare-up observed at seven-month follow-up is similar to what is reported in the literature in other patients who experienced improvement without complete resolution [9,10]. Furthermore, we note that while spontaneous remission for localized GA is common, the more generalized form of the disease, which was present in our patient, can persist for years [11].\n\nConclusions\n\nGA is a common skin condition with no well-established paradigm of care. Our patient experienced near-complete resolution of GA in response to apremilast treatment. At seven-month follow-up, she is tolerating apremilast well and denies any side effects. Six other cases in the literature demonstrate that apremilast can be a safe and efficacious treatment for GA. Altogether, our case further supports the notion that apremilast may have a seminal application in the management of GA.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Etiology, diagnosis, and therapeutic management of granuloma annulare: an update Am J Clin Dermatol Thornsberry LA English JC III 279 290 14 2013 23696233\n2 Granuloma annulare: a focused review of therapeutic options Am J Clin Dermatol Wang J Khachemoune A 333 344 19 2018 29230666\n3 FDA: Otezla (apremilast) tablets, for oral use 22021 2014 https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205437s000lbl.pdf\n4 Off-label studies on apremilast in dermatology: a review J Dermatolog Treat Maloney NJ Zhao J Tegtmeyer K Lee EY Cheng K 131 140 31 2020 30935262\n5 Granuloma annulare Br J Dermatol Little EG 317 335 20 1908\n6 Disseminated granuloma annulare treated with low-dose chlorambucil Arch Dermatol Rudolph RI 1212 1213 115 1979 507866\n7 Oral dapsone for the treatment of generalized granuloma annulare: a retrospective case series J Am Acad Dermatol Hrin ML Bashyam AM Feldman SR Huang WW 2021\n8 Apremilast: a review in psoriasis and psoriatic arthritis Drugs Keating GM 459 472 77 2017 28213862\n9 Treatment of generalized granuloma annulare with apremilast: a report of 2 cases JAAD Case Rep Blum S Altman D 976 978 5 2019 31763422\n10 Refractory generalized granuloma annulare treated with oral apremilast JAMA Dermatol Bishnoi A Raj D Vinay K Dogra S 1318 1320 155 2019 31433459\n11 Treatment of generalized granuloma annulare - a systematic review J Eur Acad Dermatol Venereol Lukács J Schliemann S Elsner P 1467 1480 29 2015 25651003\n\n",
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"keywords": "apremilast; disseminated granuloma annulare; granuloma annulare; off-label drug use; psoriasis",
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"literaturereference": "TSCHEN J. APREMILAST IN THE MANAGEMENT OF DISSEMINATED GRANULOMA ANNULARE. CUREUS. 2021?13 (5):1?4",
"literaturereference_normalized": "apremilast in the management of disseminated granuloma annulare",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210628",
"receivedate": "20210628",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19468235,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210717"
}
] |
{
"abstract": "OBJECTIVE\nThe benefit of continuing immunomodulators when \"stepping up\" to anti-tumor necrosis factor (anti-TNF) therapy for Crohn's disease (CD) is uncertain. This study assessed the effectiveness and safety of immunomodulators with anti-TNF therapy in CD.\n\n\nMETHODS\nWe conducted a retrospective cohort study of new users of anti-TNF therapy for CD in Medicare. Users of anti-TNF combination therapy with immunomodulators were matched to up to 3 users of anti-TNF monotherapy via propensity score and compared by using 3 metrics of effectiveness-surgery, hospitalization, and discontinuation of anti-TNF therapy or surgery-and 2 metrics of safety-serious infection and non-Candida opportunistic infection. Cox regression was used for all analyses.\n\n\nRESULTS\nAmong new users of infliximab, we matched 381 users of combination therapy to 912 users of monotherapy; among new users of adalimumab, we matched 196 users of combination therapy to 505 users of monotherapy. Combination therapy occurred predominantly as \"step up\" after thiopurine therapy. The rates of surgery (hazard ratio [HR], 1.20; 95% confidence interval, 0.73-1.96), hospitalization (HR, 0.82; 0.57-1.19), discontinuation of anti-TNF therapy or surgery (HR, 1.09; 0.88-1.34), and serious infection (HR, 0.93; 0.88-1.34) did not differ between users of anti-TNF combination therapy and monotherapy. However, the risks of opportunistic infection (HR, 2.64; 1.21-5.73) and herpes zoster (HR, 3.16; 1.25-7.97) were increased with combination therapy.\n\n\nCONCLUSIONS\nWe found that continuation of immunomodulators after \"stepping up\" to anti-TNF therapy did not improve outcomes but was associated with an increased risk of opportunistic infection.",
"affiliations": "Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: mark.osterman@uphs.upenn.edu.;Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Teaching, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama.;Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama.;Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.;Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.;Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama; Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Teaching, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.",
"authors": "Osterman|Mark T|MT|;Haynes|Kevin|K|;Delzell|Elizabeth|E|;Zhang|Jie|J|;Bewtra|Meenakshi|M|;Brensinger|Colleen M|CM|;Chen|Lang|L|;Xie|Fenglong|F|;Curtis|Jeffrey R|JR|;Lewis|James D|JD|",
"chemical_list": "D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "13(7)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Adalimumab; Hospitalization; Infection; Infliximab; Surgery; Thiopurines",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003424:Crohn Disease; D013505:Digestive System Surgical Procedures; D005260:Female; D006760:Hospitalization; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D012189:Retrospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D028761:Withholding Treatment; D055815:Young Adult",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "1293-1301.e5; quiz e70, e72",
"pmc": null,
"pmid": "25724699",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "16009685;12047962;12584368;23142207;19392858;17229796;20393175;21407178;23811254;23061650;19462435;22056398;16931170;17162240;20587545;23460423;24361468;23852763;24053733;18440315;17547858;21254282;12968819;15224278;21708105;18294633;23200919;14985485;23514635",
"title": "Effectiveness and Safety of Immunomodulators With Anti-Tumor Necrosis Factor Therapy in Crohn's Disease.",
"title_normalized": "effectiveness and safety of immunomodulators with anti tumor necrosis factor therapy in crohn s disease"
} | [
{
"companynumb": "US-JNJFOC-20150620041",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
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"drugdosageform": "UNSPECIFIED",
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"medicinalproduct": "METHOTREXATE"
},
{
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"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
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"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "CROHN^S DISEASE",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "AZATHIOPRINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "103772",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "LYOPHILIZED POWDER",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CROHN^S DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INFLIXIMAB, RECOMBINANT"
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Herpes zoster",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Opportunistic infection",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "OSTERMAN MT, HAYNES K, DELZELL E, ZHANG J, BEWTRA M, BRENSINGER CM, ET AL. EFFECTIVENESS AND SAFETY OF IMMUNOMODULATORS WITH ANTI-TUMOR NECROSIS FACTOR THERAPY IN CROHN^S DISEASE. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2015;13(7):1239-1301. E5.",
"literaturereference_normalized": "effectiveness and safety of immunomodulators with anti tumor necrosis factor therapy in crohn s disease",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150701",
"receivedate": "20150701",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11232311,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20151125"
}
] |
{
"abstract": "OBJECTIVE\nBesides chemotherapy drugs, a number of patient-related factors (i.e., gender, age, history of alcohol consumption, and/or motion sickness) may be used to calculate the risk for chemotherapy-induced vomiting. We evaluated data with the intent of identifying a unique variable associated with delayed vomiting in patients receiving moderately emetogenic chemotherapy (MEC).\n\n\nMETHODS\nFrom an ongoing research study, the serotonin metabolite, 5-hydroxyindole acetic acid (5-HIAA), creatinine, and substance P were measured over a 72-h period in 25 patients receiving MEC. All patients were treated with a 5-hydroxytryptamine-3 receptor antagonist plus dexamethasone according to published guidelines; none received aprepitant prophylactically. Urine 5-HIAA/creatinine and serum substance P values were grouped according to the development (+) or absence (-) of delayed emesis. Baseline mean values associated with the two neurotransmitters were analyzed by analysis of variance.\n\n\nRESULTS\nEleven patients developed moderate to severe delayed vomiting; the other 14 were symptom-free. The pretreatment log (mean 5-HIAA/creatinine) was 1.22 and 1.81 in the (+) and (-) emesis groups, respectively, p = 0.0049; the pretreatment log (mean substance P) for the same respective groups was 5.33 and 4.09 pg/mL, p > 0.05. The log (mean ratio of substance P to 5-HIAA/creatinine) between-group difference in those with and without emesis was 4.53 and 2.52, respectively, p = 0.0002. The 5-HIAA/creatinine and ratio of substance P to 5-HIAA/creatinine data were also used to determine cutoff points which resulted in the optimal predictive accuracy.\n\n\nCONCLUSIONS\nThese preliminary findings suggest that an elevated pretreatment ratio of substance P to 5-HIAA/creatinine >70 is associated with the development of delayed vomiting induced by MEC.",
"affiliations": "Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV, USA. ghiga@hsc.wvu.edu",
"authors": "Higa|Gerald M|GM|;Auber|Miklos L|ML|;Hobbs|Gerry|G|",
"chemical_list": "D000932:Antiemetics; D000970:Antineoplastic Agents; D015415:Biomarkers; D058831:Serotonin 5-HT3 Receptor Antagonists; D013373:Substance P; D006897:Hydroxyindoleacetic Acid; D003907:Dexamethasone; D003404:Creatinine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-012-1402-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "20(11)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": null,
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000932:Antiemetics; D000970:Antineoplastic Agents; D015415:Biomarkers; D016022:Case-Control Studies; D003404:Creatinine; D003907:Dexamethasone; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006897:Hydroxyindoleacetic Acid; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011237:Predictive Value of Tests; D058831:Serotonin 5-HT3 Receptor Antagonists; D012720:Severity of Illness Index; D013373:Substance P; D013997:Time Factors; D014839:Vomiting",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "2803-9",
"pmc": null,
"pmid": "22350597",
"pubdate": "2012-11",
"publication_types": "D016428:Journal Article",
"references": "12712486;9028742;8692546;17156592;16717289;1022520;21610704;21125277;7666101;9006746;19731580;7690681;19756774;9917226;15565277;19568773;8692547;8636786;14559886;11251007;15266485;15837996;12115394;9508205;8427724",
"title": "Identification of a novel marker associated with risk for delayed chemotherapy-induced vomiting.",
"title_normalized": "identification of a novel marker associated with risk for delayed chemotherapy induced vomiting"
} | [
{
"companynumb": "US-JNJFOC-20121114173",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MESNA"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
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"drugindication": "NEOPLASM MALIGNANT",
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"medicinalproduct": "MESNA."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOLASETRON MESYLATE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "60 MIN PRIOR TO CHEMOTHERAPY",
"drugenddate": null,
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"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "ANZEMET"
},
{
"actiondrug": "5",
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"activesubstancename": "IFOSFAMIDE"
},
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"medicinalproduct": "IFOSFAMIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
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"drugadministrationroute": "065",
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"drugcharacterization": "1",
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"drugdosageform": "UNSPECIFIED",
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"drugindication": "NEOPLASM MALIGNANT",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CYCLOPHOSPHAMIDE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "60 MIN PRIOR TO CHEMOTHERAPY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
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"drugintervaldosageunitnumb": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "12",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DEXAMETHASONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "050718",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "LIPOSOME INJECTION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NEOPLASM MALIGNANT",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOXORUBICIN HYDROCHLORIDE."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HIGA GM, AUBER ML, HOBBS G. IDENTIFICATION OF A NOVEL MARKER ASSOCIATED WITH RISK FOR DELAYED CHEMOTHERAPY-INDUCED VOMITING. SUPPORT CARE CANCER NOV-2012;20 (11):2803-2809.",
"literaturereference_normalized": "identification of a novel marker associated with risk for delayed chemotherapy induced vomiting",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150524",
"receivedate": "20150412",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11018286,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150821"
}
] |
{
"abstract": "BACKGROUND\nImmune checkpoint inhibitors (ICIs) are the newest class of anticancer drugs. Pneumonitis is increasingly being recognized as a potential complication of these agents.\n\n\nMETHODS\nWe conducted a retrospective study of patients who received ICIs at a comprehensive cancer center. We collected data on demographics, type of malignancy, type of ICI agent, incidence of pneumonitis up to 6 weeks after receiving ICI agent, clinical characteristics, and risk factors for overall survival in patients who develop pneumonitis.\n\n\nRESULTS\nA total of 654 patients received ICIs during the study period. The most common type of cancer for which ICI was given was adenocarcinoma of the lung (29%), followed by renal cell cancer (12%) and squamous cell lung cancer (12%). Among the study patients, 41% received nivolumab and 32% received pembrolizumab. Other patients in the study received combination of ICIs or ICI plus chemotherapeutic agent, or were part of clinical trial involving ICI. Overall 42 (6.4%) patients developed pneumonitis within 6 weeks after the last dose of treatment of any ICI agent. Of these, 81% of patients had Grade ≥ 2 pneumonitis and 45% of these required hospital admission for pneumonitis, with 10% of them requiring admission to intensive care unit. Overall, patients who received pembrolizumab-containing regimen, had prior chemotherapy, or who never had cancer-related surgery had increased risk of death.\n\n\nCONCLUSIONS\nOur large retrospective study shows real-life data of incidence of pneumonitis in patients who are treated with ICIs for cancer treatment. Our data indicate that the incidence of pneumonitis is overall lower than that reported previously with relatively good outcomes.",
"affiliations": "Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI, USA.;Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI, USA.;Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.;Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: asoubani@med.wayne.edu.",
"authors": "Banavasi|Harsha|H|;Kim|Seongho|S|;Alkassis|Samer|S|;Daoud|Asil|A|;Laktineh|Amir|A|;Nagasaka|Misako|M|;Sukari|Ammar|A|;Soubani|Ayman O|AO|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.hemonc.2021.09.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": null,
"journal": "Hematology/oncology and stem cell therapy",
"keywords": "Cancer; Immune checkpoint inhibitors; Pneumonitis; Pulmonary; Toxicity",
"medline_ta": "Hematol Oncol Stem Cell Ther",
"mesh_terms": null,
"nlm_unique_id": "101468532",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34688626",
"pubdate": "2021-10-18",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Immune checkpoint inhibitor-induced pneumonitis: Incidence, clinical characteristics, and outcomes.",
"title_normalized": "immune checkpoint inhibitor induced pneumonitis incidence clinical characteristics and outcomes"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-122944",
"fulfillexpeditecriteria": "2",
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{
"abstract": "Two unrelated women were hospitalized for thyrotoxic crisis complicated by multiple organ failure. Both patients were treated with antithyroid drugs and hydrocortisone, as well as insulin for hyperglycemia, and underwent mechanical ventilation with sedation. Flaccid quadriplegia became apparent after each patient completely recovered their level of consciousness once sedation was discontinued on days 6 and 15, respectively. Three to six months of rehabilitation was required for the muscle strength to fully improve in both cases. Thyrotoxicosis in addition to critical illness polyneuromyopathy and the administration of glucocorticoid therapy may have contributed to the onset of quadriplegia in these two cases. Flaccid quadriplegia is one of the serious neuromuscular conditions experienced during the treatment of thyrotoxic crisis.",
"affiliations": "Division of Endocrinology and Metabolism (Diabetes), St. Mary's Hospital; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan.",
"authors": "Mizokami|Tetsuya|T|;Fukui|Takuko|T|;Imoto|Hirofumi|H|;Fujii|Hiroki|H|;Sato|Yuichi|Y|;Nunoi|Kiyohide|K|;Okamura|Ken|K|",
"chemical_list": "D013956:Antithyroid Agents",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.2954",
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"issn_linking": "0918-2918",
"issue": "54(4)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D013956:Antithyroid Agents; D005260:Female; D006801:Humans; D007564:Japan; D008875:Middle Aged; D053580:Muscle Strength; D011782:Quadriplegia; D013958:Thyroid Crisis; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "421-5",
"pmc": null,
"pmid": "25748960",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Onset of reversible flaccid quadriplegia during treatment of thyrotoxic crisis.",
"title_normalized": "onset of reversible flaccid quadriplegia during treatment of thyrotoxic crisis"
} | [
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] |
{
"abstract": "Cetuximab, a chimeric monoclonal antibody to epidermal growth factor receptor, is an effective chemotherapeutic agent for patients with metastatic colorectal cancer. Whereas several specific adverse reactions to cetuximab such as skin rash and nail toxicity have been reported, there have been few reports of pneumatosis intestinalis related to cetuximab-containing chemotherapy. We describe here three patients with colorectal cancer who developed pneumatosis intestinalis during treatment with cetuximab-containing chemotherapy, which developed after 7, 19 and 47 weeks of cetuximab treatment, and discovered on routine follow-up computed tomographic scans for response evaluations. None of these patients complained of abdominal pain, showed signs of peritoneal irritation on physical examination or had elevated serum concentrations of acute inflammatory markers. Following cessation of cetuximab and conservative medical treatment, all three patients showed complete resolution of pneumatosis intestinalis on abdominal pelvic computed tomographic scans.",
"affiliations": "Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 86 Asanbyeongwon-gil, Poongnap-dong, Songpa-gu, Seoul 138-736, Republic of Korea.",
"authors": "Yoon|Shinkyo|S|;Hong|Yong Sang|YS|;Park|Seong Ho|SH|;Lee|Jae Lyun|JL|;Kim|Tae Won|TW|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000068818:Cetuximab",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyr114",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "41(10)",
"journal": "Japanese journal of clinical oncology",
"keywords": null,
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068818:Cetuximab; D015179:Colorectal Neoplasms; D066246:ErbB Receptors; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011006:Pneumatosis Cystoides Intestinalis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "1225-8",
"pmc": null,
"pmid": "21835823",
"pubdate": "2011-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pneumatosis intestinalis after cetuximab-containing chemotherapy for colorectal cancer.",
"title_normalized": "pneumatosis intestinalis after cetuximab containing chemotherapy for colorectal cancer"
} | [
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"abstract": "The co-existence of hypertrophic obstructive cardiomyopathy (HOCM) and pulmonary arterial hypertension (PAH) is extremely rare and poses a management conundrum. This is the first case report in the published literature to describe the diagnosis and management of a patient with both conditions.\nA 49-year-old female with a history of HOCM and recently diagnosed scleroderma presented to the clinic with progressive dyspnoea. Transthoracic echocardiogram demonstrated left ventricular outflow tract (LVOT) obstruction at rest, and elevated pulmonary artery (PA) pressure. Cardiac catheterization (CC) demonstrated an LVOT gradient of 150 mmHg, PA pressure of 88/32 mmHg, pulmonary capillary wedge pressure (PCWP) 12 mmHg, pulmonary vascular resistance 14.8 Wu, and a cardiac index of 1.6 L/min/m2. The differential diagnosis for the dyspnoea included combined pre- and post-capillary pulmonary hypertension from longstanding HOCM vs. scleroderma associated PAH. Tadalafil was added to the patient's medical regimen of metoprolol but it was stopped because the patient developed pulmonary oedema. Alcohol septal ablation was undertaken with improvement in the LVOT gradient, but only a modest improvement in her dyspnoea. Repeat CC demonstrated worsening PAH. Vasodilatory testing with nitric oxide led to an improvement in the PA pressure with minimal increase of the PCWP. Hence, she was started on treprostinil and macitentan, with significant improvement in her dyspnoea on follow-up.\nIn patients with concurrent HOCM and advanced PAH, a multidisciplinary treatment approach is needed to rapidly and safely optimize the background of HOCM in order to permit the use of PAH-specific medications.",
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"authors": "Hassanin|Ahmed|A|https://orcid.org/0000-0002-8375-0303;Rzechorzek|Wojciech|W|https://orcid.org/0000-0002-9755-0580;Naidu|Srihari S|SS|;Lanier|Gregg M|GM|https://orcid.org/0000-0001-8750-601X",
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"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytab354\nytab354\nCase Report\nAcademicSubjects/MED00200\nA haemodynamic conundrum: a case report of a patient with concurrent pulmonary arterial hypertension and hypertrophic obstructive cardiomyopathy\nhttps://orcid.org/0000-0002-8375-0303\nHassanin Ahmed\nhttps://orcid.org/0000-0002-9755-0580\nRzechorzek Wojciech\nNaidu Srihari S\nhttps://orcid.org/0000-0001-8750-601X\nLanier Gregg M\nWestchester Medical Center, New York Medical College, 100 Woods Road, Valhalla, NY 10595, USA\nTamura Yuichi Handling Editor\nOkumura Takahiro Editor\nPicariello Claudio Editor\nMcNaughton Edwina Editor\nGuella Elhosseyn Editor\nCorresponding author. Tel: +1 914 493 6608, Fax: +1 914 493 1854, Email: dr.hassanein@gmail.com\n9 2021\n07 9 2021\n07 9 2021\n5 9 ytab35403 2 2021\n19 3 2021\n23 8 2021\n10 9 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\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 (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nThe co-existence of hypertrophic obstructive cardiomyopathy (HOCM) and pulmonary arterial hypertension (PAH) is extremely rare and poses a management conundrum. This is the first case report in the published literature to describe the diagnosis and management of a patient with both conditions.\n\nCase summary\n\nA 49-year-old female with a history of HOCM and recently diagnosed scleroderma presented to the clinic with progressive dyspnoea. Transthoracic echocardiogram demonstrated left ventricular outflow tract (LVOT) obstruction at rest, and elevated pulmonary artery (PA) pressure. Cardiac catheterization (CC) demonstrated an LVOT gradient of 150 mmHg, PA pressure of 88/32 mmHg, pulmonary capillary wedge pressure (PCWP) 12 mmHg, pulmonary vascular resistance 14.8 Wu, and a cardiac index of 1.6 L/min/m2. The differential diagnosis for the dyspnoea included combined pre- and post-capillary pulmonary hypertension from longstanding HOCM vs. scleroderma associated PAH. Tadalafil was added to the patient’s medical regimen of metoprolol but it was stopped because the patient developed pulmonary oedema. Alcohol septal ablation was undertaken with improvement in the LVOT gradient, but only a modest improvement in her dyspnoea. Repeat CC demonstrated worsening PAH. Vasodilatory testing with nitric oxide led to an improvement in the PA pressure with minimal increase of the PCWP. Hence, she was started on treprostinil and macitentan, with significant improvement in her dyspnoea on follow-up.\n\nConclusion\n\nIn patients with concurrent HOCM and advanced PAH, a multidisciplinary treatment approach is needed to rapidly and safely optimize the background of HOCM in order to permit the use of PAH-specific medications.\n\nHypertrophic cardiomyopathy\nPulmonary hypertension\nHaemodynamics\nAlcohol septal ablation\n==== Body\npmcLearning points\n\nUnderstand the haemodynamic interaction between World Health Organization group 1 pulmonary hypertension (PH) and hypertrophic obstructive cardiomyopathy (HOCM).\n\nUnderstand the challenges in the management of patients with concomitant PH and HOCM.\n\nIntroduction\n\nThe co-existence of hypertrophic obstructive cardiomyopathy (HOCM) and pulmonary arterial hypertension (PAH) represents a management dilemma that requires an in-depth understanding of cardiac and pulmonary haemodynamics and physiology. In this case report, we describe a patient with both conditions and discuss the management challenges and treatment options.\n\nTimeline\n\n2015\tDiagnosis of hypertrophic obstructive cardiomyopathy. Patient started on metoprolol succinate.\n\n\t\nMay 2019\tEvaluation of possible scleroderma.\n\n\t\nAugust 2019\tProgressive New York Heart Association (NYHA) class III dyspnoea over the past 6 months.\n\nReferral to our institution for evaluation of dyspnoea.\n\nNew diagnosis of Scleroderma.\n\n\t\nSeptember 2019\tTransthoracic echocardiogram (TTE): left ventricular outflow tract (LVOT) obstruction at rest, and elevated pulmonary artery (PA) systolic pressure.\n\nCardiac catheterization (CC): mean PA 88/32 (52), pulmonary capillary wedge pressure (PCWP) 12, transpulmonary gradient 40, pulmonary vascular resistance 14.81, cardiac index of 1.6 L/min/m2.\n\nPulmonary function tests and computed tomography chest: unremarkable, no pulmonary embolism.\n\n\t\nNovember 2019\tInitiation of tadalafil lead to worsening of dyspnoea.\n\nAlcohol septal ablation undertaken.\n\n\t\nFebruary 2020\tSymptoms unchanged.\n\nTTE: improvement in the resting LVOT gradient.\n\n\t\nMay 2020\tPersistent dyspnoea NYHA III.\n\nImplantable cardioverter-defibrillator settings changed to chronically pace the right ventricle which led to abolition of the resting LVOT gradient, and further reduction of the provocable gradient.\n\n\t\nOctober 2020\tModest improvement in her dyspnoea.\n\nRepeat CC demonstrated worsening pulmonary arterial hypertension. Vasodilatory testing with nitric oxide: non-responder. However, some improvement in the PA pressure noted with minimal increase of the PCWP.\n\nPatient started on treprostinil and macitentan.\n\n\t\nMarch 2021\tSignificant improvement in her dyspnoea at 6-month follow-up.\n\nFollow-up TTE demonstrated improved PA systolic pressure and right ventricular function.\n\n\t\n\nCase presentation\n\nA 49-year-old Caucasian female with a history of HOCM was evaluated in the office for worsening New York Heart Association class III dyspnoea over the past 6 months. Initial history and examination were remarkable for prior Raynaud’s phenomenon, a crescendo systolic murmur that increased with the Valsalva manoeuvre and hand telangectasias without sclerodactyly. The patient had been diagnosed with obstructive HOCM 6 years earlier and was treated with metoprolol succinate 100 mg daily and an implantable cardioverter-defibrillator (ICD) for primary prevention. She was recently referred to a rheumatologist for evaluation of possible scleroderma.\n\nTransthoracic echocardiogram (TTE) demonstrated asymmetrical left ventricular hypertrophy (LVH) with a maximal septal thickness of 2.2 cm (Figure 1), systolic anterior motion (SAM) of the mitral valve (Video 1), and a dynamic left ventricular outflow tract (LVOT) gradient of 56 mmHg at rest and 125 mmHg with Valsalva (Figure 2). Right ventricular (RV) function was mildly reduced, and the pulmonary artery (PA) systolic pressure was estimated at 75 mmHg. Subsequently, left and right cardiac catheterization (RHC) revealed normal coronary arteries, provocable LVOT gradient of 150 mmHg, PA pressure of 88/32 (52) mmHg, pulmonary capillary wedge pressure (PCWP) 12 mmHg, transpulmonary gradient (TPG) 40, pulmonary vascular resistance (PVR) 14.8 Woods units (Wu), and a cardiac index (CI) of 1.6 L/min/m2. Anti-centromere antibodies were positive. Computed tomography of the lungs, pulmonary function tests, and a ventilation-perfusion scan were unremarkable.\n\nFigure 1 Parasternal long-axis view demonstrating septal thickness.\n\nFigure 2 Apical three-chambers view demonstrating Doppler estimation of the provocable left ventricular outflow tract gradiet during valsalva manoeuvre.\n\nThe differential diagnosis included combined pre- and post-capillary pulmonary hypertension (PH) from her longstanding HOCM, with the scleroderma features being incidental. Alternatively, limited scleroderma involving the pulmonary vasculature and contributing to her PH was considered.\n\nThe patient was started on tadalafil but this was stopped because of increased dyspnoea and gastric reflux symptoms. Surgical myectomy was considered but given the increased risk in the presence of severe PH, the decision was made to proceed with alcohol septal ablation (ASA). Over the months following the ASA, the patient had a modest initial improvement in her symptoms, but then the dyspnoea worsened. Transthoracic echocardiogram performed 6 months after ASA showed significant improvement of the provocable and resting gradients across the LVOT. To further optimize her prior to starting PAH-specific medications, her ICD was reprogrammed to pace the RV apex to induce left ventricular (LV) dyssynchrony, which led to abolition of the resting LVOT gradient, and further reduction of the provocable gradient to 32 mmHg.\n\nGiven the resolution of gradients, it was felt that her dyspnoea was due to progression of scleroderma-associated World Health Organization (WHO) 1 PAH. Repeated RHC showed a PA pressure mean 61 mmHg, PVR 34.1 Wu, and CI 1 L/min/m2 in the setting of a PCWP of 4 mmHg. Vasodilatory testing with nitric oxide (NO) showed improvement in the PA mean pressure 56 mmHg, PVR 20.9 Wu, and CI 1.4 L/min/m2, and minimal increase of the PCWP (6 mmHg). However, the improvement in the patient’s haemodynamics did not meet the threshold for considering calcium channel blocker treatment (non-responder). She was subsequently started on intravenous treprostinil, a direct vasodilator acting through the prostacyclin pathway, and macitentan, an endothelin receptor antagonist. The combination therapy of treprostinil and macitentan was well tolerated by the patient. Three months after initiation of PAH-specific medication, she reports a significant improvement in dyspnoea and overall energy. Follow-up TTE demonstrated improved PA systolic pressure from 76 to 63 mmHg and improved RV function, with tricuspid annular plane systolic excursion increasing from 1.4 to 1.8 cm. Accordingly, the treprostinil dose was uptritrated from 25 to 45 ng/kg/min.\n\nDiscussion\n\nHypertrophic obstructive cardiomyopathy is the most common genetic cardiac condition with a prevalence of up to 1:200 in the general population.1 Up to two-thirds of HCM patients show evidence of dynamic LVOT obstruction related to SAM of the mitral valve with septal contact.2 Obstructive physiology and diastolic dysfunction can lead to progressive heart failure symptoms. In several series of HCM patients, a PA systolic pressure >35 mmHg, has been identified in 18–38% of patients, with higher prevalence seen in the obstructive HCM phenotype.3,4 Interestingly, in one series, 9% of the HCM patients with PH had a PCWP ≤15 mmHg with high PVR, raising the possibility of co-existent combined pre and post-capillary PH.5 PH was found to be an independent predictor of HCM morbidity3 and mortality4 in non-obstructive and obstructive Hypertrophic Cardiomyopathy (HCM) patients who did not undergo septal reduction therapy (SRT).\n\nPulmonary arterial hypertension WHO group 1 is a rare condition with a prevalence of 15–50 cases per million.6 It is defined as a mean PA pressure ≥25 mmHg, a PCWP <15 mmHg, and a PVR of >3 Wu. Pulmonary arterial hypertension has complex pathophysiology characterized by an imbalance of vasoconstrictor and vasodilator peptides leading to remodelling of the pulmonary arterioles. Pulmonary arterial hypertension can be associated with connective tissue disease, especially in scleroderma patients, with a prevalence of up to 19%.7 The prognosis of scleroderma associated PAH is poor with 3-year survival of approximately 60%.8\n\nTo our knowledge, this is the first case report of a patient with concurrent HOCM and WHO group 1 PAH-scleroderma, two disease states that are rising in prevalence due to heightened awareness and screening. Although PH had been reported in patients with HOCM (WHO group 2), a very high TPG and PVR should raise the possibility of another contributing process.\n\nThe haemodynamic interaction of these two pathologies poses several challenges. While several vasoactive agents are indicated in the treatment of WHO group 1 PAH, vasodilation of the pulmonary arterioles in the setting of elevated left atrial pressure due to LVOT obstruction and diastolic dysfunction from HOCM can lead to pulmonary oedema. Paradoxically, increased pre-load to the left ventricle as a result of PAH medications could potentially improve SAM and LVOT obstruction and decrease the PCWP. In this case, the use of pulmonary arterial vasodilators (tadalafil) prior to optimization of HOCM physiology lead to significant dyspnoea and early discontinuation of the medication.\n\nHCM-related LVOT obstruction that is resistant to medical therapy can be relieved by SRT. These treatments also improve diastolic dysfunction in patients with HOCM over time.9 Surgical myectomy is the preferred approach in most young patients, particularly with massive LVH and very large gradients. In this case, severe PH made induction of general anaesthesia high risk for acute haemodynamic collapse. In addition, a minimally invasive SRT, as in ASA, is more reasonable in patients with concomitant PAH and limited life expectancy.\n\nOptimization of her HOCM physiology alone was not associated with improvement in dyspnoea, suggesting that her scleroderma-associated severe PAH was contributing to her progressive symptoms. The NO challenge administered during the RHC, 6 months after optimization of the HOCM physiology, decreased PA pressure and increased CI without increasing the PCWP. NO is a potent pulmonary arterial vasodilator that increases PA flow to the left ventricle. The lack of significant elevation of PCWP after the NO challenge reflects the success of the ASA in relieving the LVOT obstruction, and normalization of the left atrial and the diastolic LV pressures. The NO challenge helped predict that the patient is likely to tolerate PAH medications and the associated increase in the PA flow. Therefore, the ASA was pivotal in improving the LV ability to tolerate increases in preload from pulmonary vasodilator treatment. Frequent assessment of her symptoms will be necessary, as there may come a point where the improved PVR may lead to eventual elevated PCWP and shortness of breath, requiring augmented diuretics. An additional practical consideration in patients with severe PH and RV dysfunction is that they may not tolerate beta-blockers. However, in her case, some degree of negative chronotropy and contractility may be necessary for any residual LVOT gradient.\n\nConclusion\n\nThis case describes the management dilemma in caring for patients that have two uncommon, yet increasingly recognized diseases. Since the prognosis of untreated PAH-scleroderma is very poor, a multidisciplinary treatment approach is needed to rapidly and safely optimize the background of HCM with obstruction in order to permit the use of PAH-specific medications.\n\nLead author biography\n\nAhmed Hassanin, MD, MPH is a cardiovascular disease fellow at Westchester Medical Center in New York. His hometown is Alexandria, Egypt, where he graduated from the University of Alexandria School of Medicine in 2010. His areas of interest include hypertrophic cardiomyopathy and ST-segment elevation myocardial infarction (STEMI) systems of care in resource limited communities. Dr Hassanin plans to pursue a career in interventional cardiology and global cardiovascular health.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: G.M.L. is on the speakers’ bureau for United Therapeutics. The other authors of this manuscript have no relationship with industry that could be perceived to bias their work.\n\nFunding: None declared.\n\nSupplementary Material\n\nytab354_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n\n1 SemsarianC, InglesJ, MaronMS, MaronBJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol 2015;65 :1249–1254.25814232\n2 MaronMS, HauserTH, DubrowE, HorstTA, KissingerKV, UdelsonJE et al Right ventricular involvement in hypertrophic cardiomyopathy. Am J Cardiol 2007;100 :1293–1298.17920373\n3 MusumeciMB, MastromarinoV, CasenghiM, TiniG, FranciaP, MaruottiA et al Pulmonary hypertension and clinical correlates in hypertrophic cardiomyopathy. Int J Cardiol 2017;248 :326–332.28733069\n4 OngKC, GeskeJB, HeblVB, NishimuraRA, SchaffHV, AckermanMJ et al Pulmonary hypertension is associated with worse survival in hypertrophic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2016;17 :604–610.26922089\n5 CovellaM, RowinEJ, HillNS, PrestonIR, MilanA, OpotowskyAR et al Mechanism of progressive heart failure and significance of pulmonary hypertension in obstructive hypertrophic cardiomyopathy. Circ Heart Fail 2017;10 :e003689.28396501\n6 McGoonMD, BenzaRL, Escribano-SubiasP, JiangX, MillerDP, PeacockAJ et al Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol 2013;62 :D51–D59.24355642\n7 CoghlanJG, DentonCP, GrunigE, BondermanD, DistlerO, KhannaD, Muller-LadnerU et al ; DETECT study group. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis 2014;73 :1340–1349.23687283\n8 LaunayD, SitbonO, HachullaE, MouthonL, GressinV, RottatL et al Survival in systemic sclerosis-associated pulmonary arterial hypertension in the modern management era. Ann Rheum Dis 2013;72 :1940–1946.23178295\n9 SitgesM, ShiotaT, LeverHM, QinJX, BauerF, DrinkoJK et al Comparison of left ventricular diastolic function in obstructive hypertrophic cardiomyopathy in patients undergoing percutaneous septal alcohol ablation versus surgical myotomy/myectomy. Am J Cardiol 2003;91 :817–821.12667567\n\n",
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"abstract": "Intrapericardial triamcinolone can be used to treat chronic pericardial effusion (PE) in adults; however, pediatric data are lacking. In this case series we aim to evaluate the efficacy, safety, and side effects of intrapericardial triamcinolone in children with PE. The incidence and treatment of post-surgical PE from 2009 to 2019 were determined using the institutional surgical database and electronic patient records. Furthermore, a retrospective analysis of efficacy, safety, and side effects of intrapericardial triamcinolone treatment for chronic post-surgical PE was performed. The incidence of postoperative PE requiring treatment was highest after atrial septal defect (ASD) closure when compared to other types of cardiac surgery (9.7% vs 4.3%). Intrapericardial treatment with triamcinolone resolved pericardial effusion in 3 out of 4 patients. All patients developed significant systemic side effects. Surgical ASD closure is associated with an increased risk of development of PE requiring treatment. Intrapericardial triamcinolone is an effective treatment for chronic postoperative PE in children, but is always associated with significant systemic side effects. Close monitoring and treatment of adrenal insufficiency are mandatory in these cases.",
"affiliations": "Department of Pediatric Cardiology, University Medical Center, PO Box 85090, 3508 AB, Utrecht, The Netherlands. m.h.vanderwerff@students.uu.nl.;Department of Pediatric Endocrinology, University Medical Center, PO Box 85090, 3508 AB, Utrecht, The Netherlands.;Department of Pediatric Cardiology, University Medical Center, PO Box 85090, 3508 AB, Utrecht, The Netherlands.",
"authors": "van der Werff|Manon H|MH|http://orcid.org/0000-0001-6742-4084;van der Kamp|Hetty J|HJ|;Breur|Johannes M P J|JMPJ|",
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"doi": "10.1007/s00246-021-02704-z",
"fulltext": "\n==== Front\nPediatr Cardiol\nPediatr Cardiol\nPediatric Cardiology\n0172-0643\n1432-1971\nSpringer US New York\n\n34405257\n2704\n10.1007/s00246-021-02704-z\nOriginal Article\nThe Efficacy, Safety, and Side Effects of Intrapericardial Triamcinolone Treatment in Children with Post-surgical Pericardial Effusion: A Case Series\nhttp://orcid.org/0000-0001-6742-4084\nvan der Werff Manon H. m.h.vanderwerff@students.uu.nl\n\n1\nvan der Kamp Hetty J. 2\nBreur Johannes M. P. J. 1\n1 grid.7692.a 0000000090126352 Department of Pediatric Cardiology, University Medical Center, PO Box 85090, 3508 AB Utrecht, The Netherlands\n2 grid.7692.a 0000000090126352 Department of Pediatric Endocrinology, University Medical Center, PO Box 85090, 3508 AB Utrecht, The Netherlands\n17 8 2021\n17 8 2021\n2022\n43 1 142146\n20 4 2021\n4 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/.\nIntrapericardial triamcinolone can be used to treat chronic pericardial effusion (PE) in adults; however, pediatric data are lacking. In this case series we aim to evaluate the efficacy, safety, and side effects of intrapericardial triamcinolone in children with PE. The incidence and treatment of post-surgical PE from 2009 to 2019 were determined using the institutional surgical database and electronic patient records. Furthermore, a retrospective analysis of efficacy, safety, and side effects of intrapericardial triamcinolone treatment for chronic post-surgical PE was performed. The incidence of postoperative PE requiring treatment was highest after atrial septal defect (ASD) closure when compared to other types of cardiac surgery (9.7% vs 4.3%). Intrapericardial treatment with triamcinolone resolved pericardial effusion in 3 out of 4 patients. All patients developed significant systemic side effects. Surgical ASD closure is associated with an increased risk of development of PE requiring treatment. Intrapericardial triamcinolone is an effective treatment for chronic postoperative PE in children, but is always associated with significant systemic side effects. Close monitoring and treatment of adrenal insufficiency are mandatory in these cases.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1007/s00246-021-02704-z\n\nKeywords\n\nPericardial effusion\nIntrapericardial\nTriamcinolone\nAdrenal insufficiency\nissue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2022\n==== Body\npmcIntroduction\n\nThe reported prevalence of postoperative pericardial effusion (PE) ranges between 1 and 53% [1–8] in children and adults. PE is often responsive to anti-inflammatory therapy, but in a minority of the cases PE becomes chronic. Possible treatment options for chronic PE are pericardiocentesis, creation of a surgical pericardial window, and intrapericardial triamcinolone. Intrapericardial triamcinolone has been associated with dramatic symptomatic improvement in adults [9]. There are no recommendations on intrapericardial triamcinolone treatment of PE in children. It is only known that corticosteroid use should be restricted because of the side effects [10]. The aim of this study was to establish the incidence of PE requiring treatment after pediatric cardiac surgery and to evaluate the efficacy, safety, and side effects of intrapericardial triamcinolone treatment in chronic postoperative pediatric PE.\n\nMethods\n\nStudy Population\n\nThe institutional surgical database was used to identify all pediatric patients who received cardiac surgery for congenital heart disease (CHD) in 2019 and all surgical atrial septal defect (ASD) closures from 2009 to 2019. Electronic patient records and echo database were checked for postoperative occurrence and treatment of PE. PE treatment was initiated when echocardiography showed hemodynamically significant PE with or without clinical signs of cardiac tamponade.\n\nFurthermore all patients receiving intrapericardial triamcinolone treatment between 2014 and July 2020 were identified using the hospital database. Medical records, echocardiography reports, laboratory markers, medication, and operation reports from before and after the treatment with triamcinolone were reviewed.\n\nIntervention\n\nIntrapericardial triamcinolone was administered to patients with postoperative chronic (> 3 months) and/or recurrent PE, despite other treatments. Installation of triamcinolone (300 mg/m2—according to Maisch et al. [9]) was performed using a pigtail drain after pericardiocentesis. After 24 h the remaining pericardial fluid was aspirated and the drain was removed.\n\nOutcome\n\nThe outcome measures were efficacy of PE treatment, the presence of side effects, and the adrenal function. The efficacy of triamcinolone was measured by the persistence or disappearance of PE on echocardiograms performed after treatment. The presence of side effects was extracted from the medical records. The adrenal function was determined by low-dose (1mcg) ACTH-tests.\n\nResults\n\nAll patients who developed significant post-surgical PE were primarily treated with prednisone. In the CHD group (ASD surgery excluded) 4.3% (7/164) required PE treatment versus 9.7% (28/289) in the ASD group. Prednisone treatment alone was effective in all patients in the CHD group (7/7) and in 82% (23/28) of the ASD group. Recovery occurred after a mean of 8 days (range 4–16) in the CHD group and after 7 days (range 4–27) in the ASD group. Pericardiocentesis was performed in 1.7% (5/289 patients) of the ASD group.\n\nFour patients were treated with intrapericardial triamcinolone treatment. Patient characteristics and outcome are summarized in Table 1. Three of these patients underwent surgical ASD closure and one patient underwent epicardial pacemaker implantation. The time between onset of PE and triamcinolone administration varied between 1.5 and 9 months. All patients were treated with prednisone and pericardiocentesis (1–4 times) before triamcinolone administration. One patient was treated with intravenous immunoglobulins (IVIG) [11]. In three out of four patients PE did not reoccur after triamcinolone administration. In one patient PE reoccurred and a surgical pericardial window was created.Table 1 Patient characteristics and the efficacy of triamcinolone\n\nNo\tAge (years) / sex\tOperation\tTime between onset PE and triamcinolone administration\tNumber of times pericardiocentesis before triamcinolone administration\tNumber of times prednisone was started or dose was increased before triamcinolone administration\tNumber of times treated with IVIG before triamcinolone administration\tDeveloped reoccurrence\nPE after triamcinolone administration\t\n1\t11/F\tASD surgical closure\t9 months\t1\t4\t2\tNo\t\n2\t11/M\tPacemaker implantation\t2.5 months\t1\t2\t0\tNo\t\n3\t1/F\tASD surgical closure\t7 months\t4\t2\t0\tNo\t\n4\t14/M\tASD surgical closure\t1.5 months\t3\t2\t0\tYes\t\nPE pericardial effusion, IVIG intravenous immunoglobulin, ASD closure atrial septal defect closure\n\nThe course of the side effects of triamcinolone treatment is summarized in Table 2. All patients developed symptoms within 3 weeks lasting up to several years.Table 2 Specifics of the symptoms after triamcinolone administration\n\nNo\tTime between triamcinolone administration and start symptoms\tType of symptoms\tDuration of symptoms\tTime between triamcinolone administration and adequate ACTH-test\t\n1\t1 week\tFatigue, low energy levels\tNot clear\t1 year and 9 months\t\n2\t1 week\tFatigue, easily tired, irritable, quickly bad-tempered\t3 years and 5 monthsa\tNot adequate yet\t\n3\t1 day\tFatigue, low energy levels, whiny, bad-tempered, mood swings, restless\t4 monthsa\tNot performed yet\t\n4\t3 weeks\tFatigue, low energy levels, decreased fitness, difficulty falling asleep\t3 years and 7 months\t3 years and 7 months\t\naStill ongoing\n\nACTH-test adrenocorticotropic hormone test\n\nCase Reports\n\nPatient 1\n\nA 10-year-old girl with multiple congenital dysmorphisms and a spontaneously closed ventricular septal defect underwent surgical ASD closure. PE developed 1 month later and prednisone was started. In a period of 9 months prednisone was unsuccessfully tapered 4 times. Two months after prednisone initiation a Cushingoid face developed and after 5 months she developed fatigue (low energy levels, early bedtimes, and missing school). Additional treatment consisted of pericardiocentesis IVIG (twice) and colchicine [10], all without success. After 9 months of persisting PE pericardiocentesis was performed with administration of 420 mg triamcinolone and 80 mg gentamycin (sclerotherapy). Three days after triamcinolone administration, the morning cortisol concentration was < 0.02 µmol/L. Thereafter PE did not reoccur. However she developed extreme fatigue. Hydrocortisone supplementation (12 mg/m2) was added for 8 months because of those signs and symptoms. Five months after hydrocortisone initiation a small improvement in fitness was seen, but it took one year and 9 months (after triamcinolone administration) until the ACTH-test normalized.\n\nPatient 2\n\nAn 11-year-old boy underwent epicardial pacemaker implantation for paroxysmal atrioventricular block. PE occurred 1 week later and prednisone was started. Because of progressive PE and echocardiographic signs of tamponade pericardiocentesis was performed. Two attempts were made to taper prednisone without success. Two months after the start of prednisone a Cushingoid face developed. After 2.5 months a second pericardiocentesis was performed with administration of 420 mg triamcinolone. On the same day colchicine was started and prednisone was continued. There has been no recurrence of PE after the triamcinolone administration. One week after triamcinolone administration he developed symptoms of fatigue, expressed by being easily tired, irritable, and bad-tempered. Prednisone and colchicine were tapered within 2 and 3.5 months, respectively. Because of fatigue symptoms, expressed by low energy levels, missing school, and not having fun, prednisone was restarted 9 months later and the dose increased considerably in the following months. His listless feeling and increased need of sleep persisted despite a “physiologic” morning dose of prednisone. No other explanation for the fatigue could be established. Symptoms persist to date and ACTH-tests remain inadequate.\n\nPatient 3\n\nA 5-month-old girl underwent surgical ASD closure. PE with tamponade occurred one month later for which immediate pericardiocentesis was performed and prednisone was started. In a period of 7 months two attempts to taper prednisone were unsuccessful despite the addition of colchicine in the 6th month. Furthermore pericardiocentesis had to be performed twice. In the 6th month fatigue symptoms started, expressed by being easily tired, bad-tempered, and whiny. After the 7th month 140 mg triamcinolone was administered intrapericardially without recurrence of PE thereafter. One day after triamcinolone treatment fatigue symptoms started, expressed by being bad-tempered, listless, whiny, and having low energy levels. Three days after triamcinolone administration, the morning cortisol concentration was < 0.02 µmol/L. Because of these symptoms hydrocortisone (12 mg/m2) was started. Symptoms like being restless, mood swings, being bad-tempered, and sleeping badly continued for 2 months. Because of the suspicion of adrenal insufficiency, hydrocortisone was tapered. Up till now, the symptoms persist and hydrocortisone therapy is still necessary.\n\nPatient 4\n\nA 14-year-old boy with a history of surgically corrected esophageal atresia underwent surgical ASD closure. Two days later cardiac tamponade developed and acute pericardiocentesis was performed. After 1 week a second cardiac tamponade developed and another pericardial drainage was performed. Prednisone, NSAID, and colchicine were started. Three weeks after initiation of prednisone, a Cushingoid face was developed. One attempt was made to taper prednisone, which resulted in a relapse of PE and another pericardiocentesis. One and a half month after the onset of PE, pericardiocentesis was performed and 320 mg triamcinolone was administered intrapericardially. Nevertheless PE reoccurred and 1 week later a surgical pericardial window was created with continuation of prednisone treatment without reoccurrence of PE. One week later fatigue symptoms started, expressed by low energy levels, decreased fitness, and difficulty falling asleep causing tiredness during the day. As a result this patient was only able to attend half days at school. Melatonin and rehabilitation were initiated to improve sleep and physical fitness. Three months after creation of the pericardial window, prednisone was completely tapered. However it took 3 years and 4 months to obtain a normal ACTH-test. During this period the fatigue symptoms were varyingly present, only improving at the time of the adequate ACTH-test.\n\nDiscussion\n\nThe incidence of pericardial effusion requiring medical treatment is high after surgical ASD closure (9.7%). In the vast majority of cases oral anti-inflammatory therapy led to complete resolution of PE. Chronic PE developed in 10% of patients after surgical ASD closure. The intrapericardial administration of triamcinolone resolved chronic PE in 3 out of 4 patients. However all patients had long lasting serious side effects.\n\nThe incidence of PE (requiring at least prednisone) after ASD closure was more than twice as high as the incidence after all cardiac surgeries (9.7% versus 4.3%). These findings are in line with other reports identifying ASD closure as an independent risk factor for readmission with PE and intervention [12]. It is assumed that chronic volume overload of the right atrium may support altered mechanics of PE production, combined with the inflammatory reaction secondary to the pericardiotomy and right atriotomy.\n\nTo the best of our knowledge, this is the first study evaluating the efficacy of intrapericardial triamcinolone in children. Maisch et al. [9] treated 84 adult patients with intrapericardial triamcinolone—54 patients with 600 mg/m2 and 30 patients with 300 mg/m2—preventing PE recurrence in 92.6% vs. 86.7% of patients after 3 months and in 86.0% vs 82.1% after 1 year. In this study intrapericardial triamcinolone (300 mg/m2) was immediately effective in three of four patients with chronic postoperative and/or recurrent PE. It is debatable whether or not a higher triamcinolone dose could have changed the course of the unresponsive patient. A lower dose than 300 mg/m2 was never considered, as those patients did not respond to already high doses of prednisone. However, the results suggest that a lower initial dose may be considered in a dose–response study.\n\nAll patients treated with intrapericardial triamcinolone developed side effects shortly after administration including fatigue, low energy levels, being easily tired, and bad-tempered. Patient 2 and 4 newly developed these symptoms after the administration and patient 1 and 3 had worsening of these symptoms not otherwise explained. All patients had good systolic and diastolic function, therefore a cardiac cause of the side effects is unlikely. The side effects lasted at least 2 years (excluding patient 3), much longer than the known duration of side effects for oral corticosteroids [12].\n\nAlthough it may be assumed that intrapericardial administration of corticosteroids avoids major side effects as seen in systemic treatment, iatrogenic Cushing’s syndrome was described earlier by Grubb et al. [13]. It may be recommended to monitor the morning plasma cortisol shortly after treatment to confirm adrenal suppression. However, this is only a warning sign, as it takes 14–21 days to develop adrenal insufficiency. A concentration > 0.5 µmol/L (depending on the assay used) excludes triamcinolone absorption and systemic side effects.\n\nMaisch et al. [9] report that iatrogenic Cushing syndrome developed in 13.3% of adult patients receiving 300 mg/m2 intrapericardial triamcinolone, without specifying their symptoms. Known symptoms of Cushing syndrome in children are growth retardation, delayed puberty, obesity, hypertension, severe fatigue, mood swings, anxiety, irritability, and loss of emotional control [14]. The patients in our case study had all those systemic side effects.\n\nAlthough triamcinolone has a 1.25 stronger anti-inflammatory effect than prednisone and a longer biologic half-life, there must be another explanation for the prolonged duration of adrenal insufficiency and the extreme side effects despite supplementation of a maintenance dose of hydrocortisone [15].\n\nIntrapericardial treatment with agents like steroids, gentamycin or chemotherapy may be associated with the development constrictive pericarditis due to sclerosing properties of the medication [10]. However this complication has not been described for triamcinolone to date. Diastolic function was closely monitored and remained normal in all patients.\n\nRecommendation\n\nIntrapericardial triamcinolone is of additional value in the treatment of chronic pediatric postoperative pericardial effusion. However adrenal insufficiency is likely to develop. Therefore treatment should always be performed in close collaboration with a pediatric endocrinologist.\n\nLimitations\n\nThe number of patients treated with intrapericardial triamcinolone administration is low. It is hard to draw definite conclusions on treatment efficacy with these low numbers. An international registration could help to develop optimal treatment for chronic postoperative PE.\n\nConclusion\n\nPE is more common after pediatric surgical ASD closure compared to other congenital heart surgeries. The majority of cases can be managed by anti-inflammatory treatment, such as prednisone. Chronic and/or recurrent post-surgical PE can successfully be treated with intrapericardial triamcinolone administration in the majority of cases, but is always associated with serious systemic side effects. Therefore, patients receiving intrapericardial triamcinolone therapy should be closely monitored for development and treatment of adrenal insufficiency.\n\nSupplementary Information\n\nBelow is the link to the electronic supplementary material.Supplementary file1 (XLSX 23 KB)\n\nAcknowledgements\n\nNone.\n\nSupporting Information\n\nSupplementary Table S1—Data Table 1.\n\nAuthor Contribution\n\nMVDW performed Conceptualization, Validation, Investigation, Writing—Original draft, and Visualization. HVDK performed Conceptualization, Validation, Resources, Writing—Review & Editing, Visualization, and Supervision. HB performed Conceptualization, Validation, Resources, Writing—Review & Editing, Visualization, and Supervision.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nData Availability\n\nData from Table S1 is available.\n\nCode Availability\n\nNot applicable.\n\nDeclarations\n\nConflicts of interest\n\nThe authors have no conflicts of interest to declare.\n\nEthical Approval\n\nFor this type of study, formal consent is not required.\n\nInformed Consent\n\nInformed consent was obtained from all individual participants and/or legal guardians included in the study.\n\nManon H. van der Werff, Hetty J. van der Kamp, and Johannes M.P.J. Breur take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.\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. Elias MD Glatz AC O’Connor MJ Schachtner S Ravishankar C Mascio CE Prevalence and risk factors for pericardial effusions requiring readmission after pediatric cardiac surgery Pediatr Cardiol 2017 38 3 484 494 10.1007/s00246-016-1540-2 27900408\n2. Imazio M Brucato A Rovere ME Gandino A Cemin R Ferrua S Colchicine prevents early postoperative pericardial and pleural effusions Am Heart J 2011 162 3 527 32.e1 10.1016/j.ahj.2011.05.017 21884871\n3. Cheung EWY Ho SA Tang KKY Chau AKT Chiu CSW Cheung YF Pericardial effusion after open heart surgery for congenital heart disease Heart 2003 89 7 780 783 10.1136/heart.89.7.780 12807856\n4. Yip AS Chau EM Chow WH Kwok OH Cheung KL Pericardial effusion in adults undergoing surgical repair of atrial septal defect Am J Cardiol 1997 79 12 1706 1708 10.1016/s0002-9149(97)00231-2 9202373\n5. Prabhu AS Ross RD Heinert MR Walters HL 3rd Hakimi M Decreased incidence of postoperative pericardial effusions after cardiac surgery for congenital heart disease Am J Cardiol 1996 77 9 774 776 10.1016/s0002-9149(97)89218-1 8651135\n6. Dalili M Zamani H Aarabi-Moghaddam M Pericardial effusion after pediatric cardiac surgeries: a single center observation Res Cardiovasc Med 2012 1 1 28 32 10.5812/cardiovascmed.4601 25478485\n7. Kuvin JT Harati NA Pandian NG Bojar RM Khabbaz KR Postoperative cardiac tamponade in the modern surgical era Ann Thorac Surg 2002 74 4 1148 1153 10.1016/s0003-4975(02)03837-7 12400760\n8. Clapp SK Garson A Jr Gutgesell HP Cooley DA McNamara DG Postoperative pericardial effusion and its relation to postpericardiotomy syndrome Pediatrics 1980 66 4 585 588 10.1542/peds.66.4.585 7432845\n9. Maisch B Ristić AD Pankuweit S Intrapericardial treatment of autoreactive pericardial effusion with triamcinolone; the way to avoid side effects of systemic corticosteroid therapy Eur Heart J 2002 23 19 1503 1508 10.1053/euhj.2002.3152 12242070\n10. Adler Y Charron P The 2015 ESC Guidelines on the diagnosis and management of pericardial diseases Eur Heart J 2015 36 42 2873 2874 10.1093/eurheartj/ehv479 26547486\n11. Wendelin G Fandl A Beitzke A High-dose intravenous immunoglobulin in recurrent postpericardiotomy syndrome Pediatr Cardiol 2008 29 2 463 464 10.1007/s00246-007-9025-y 17674080\n12. Brown ES Chandler PA Mood and cognitive changes during systemic corticosteroid therapy Prim Care Companion J Clin Psychiatry 2001 3 1 17 21 10.4088/pcc.v03n0104 15014624\n13. Paragliola RM Papi G Pontecorvi A Corsello SM Treatment with synthetic glucocorticoids and the hypothalamus-pituitary-adrenal axis Int J Mol Sci 2017 18 10 2201 10.3390/ijms18102201\n14. Jameson JL et al (eds) (2016) Cushing’s syndrome. In: Endocrinology: Adult and Pediatric, 7th edn. Saunders Elsevier, Philadelphia, PA\n15. Paragliola RM Papi G Pontecorvi A Corsello SM Treatment with synthetic glucocorticoids and the Hypothalamus–Pituitary–Adrenal Axis Int J Mol Sci 2017 18 10 2201 10.3390/ijms18102201\n\n",
"fulltext_license": "CC BY",
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"keywords": "Adrenal insufficiency; Intrapericardial; Pericardial effusion; Triamcinolone",
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] |
{
"abstract": "A case of acute hydralazine induced lupus syndrome is described. No case has previously been described in which a small daily dose and a small accumulation dose have evoked this syndrome in such a short period of time. A pertinent and selective review of this syndrome is presented. The need for awareness of this syndrome manifesting in a patient exposed to small doses of hydralazine for short periods of time is emphasized.",
"affiliations": null,
"authors": "Chisholm|J C|JC|",
"chemical_list": "D006830:Hydralazine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0027-9684",
"issue": "73(3)",
"journal": "Journal of the National Medical Association",
"keywords": null,
"medline_ta": "J Natl Med Assoc",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D006830:Hydralazine; D006973:Hypertension; D008180:Lupus Erythematosus, Systemic",
"nlm_unique_id": "7503090",
"other_id": null,
"pages": "278-80",
"pmc": null,
"pmid": "7205989",
"pubdate": "1981-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14485567;4143707;4581906;4898319;7224;14485570;5263687;4536815;5932578;16188;4584155;13117684;4912962;6037131",
"title": "Acute low-dose hydralazine induced lupus syndrome (HILS).",
"title_normalized": "acute low dose hydralazine induced lupus syndrome hils"
} | [
{
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"medicinalproduct": "HYDROCHLOROTHIAZIDE."
}
],
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"reaction": [
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}
],
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},
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"literaturereference": "CHISHOLM JC JR. ACUTE LOW-DOSE HYDRALAZINE INDUCED LUPUS SYNDROME (HILS). J NATL MED ASSOC. 1981?73(3):278-80",
"literaturereference_normalized": "acute low dose hydralazine induced lupus syndrome hils",
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},
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},
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}
] |
{
"abstract": "CBL is a mammalian gene encoding the protein CBL, which is an E3 ubiquitin-protein ligase involved in cell signaling and protein ubiquitination. Pathogenic variants in this gene have been implicated in a number of human cancers, particularly acute myeloid leukemia (AML). Here, we present a 5-year-old male patient with a history of AML, diffuse midline glioma, and left brain lesion with histiocytic features. A variant of uncertain significance (VUS): p.L493F was detected in his CBL gene via clinical evaluation. Protein modeling predicts this variant to be pathogenic. Details of the clinical evaluation and modeling assay are discussed.",
"affiliations": "Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO USA.;Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO USA.;Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO USA.;Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO USA.;Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA; Mayo Graduate School, Neurobiology of Disease, Mayo Clinic, Jacksonville, FL USA.;Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO USA; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, CO USA. Electronic address: adam.green@cuanschutz.edu.",
"authors": "Norris|Gregory A|GA|;Tsai|Anne Chun-Hui|AC|;Schneider|Kami Wolfe|KW|;Wu|Yuan-Haw|YH|;Caulfield|Thomas|T|;Green|Adam L|AL|",
"chemical_list": "D050721:Proto-Oncogene Proteins c-cbl",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cancergen.2021.01.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "254-255()",
"journal": "Cancer genetics",
"keywords": "Acute myeloid leukemia; CBL; Cancer; Cancer predisposition; Cell signaling; Diffuse midline glioma; Germline; Protein modeling; Protein ubiquitination; Variant",
"medline_ta": "Cancer Genet",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009369:Neoplasms; D010375:Pedigree; D000072417:Protein Domains; D050721:Proto-Oncogene Proteins c-cbl",
"nlm_unique_id": "101539150",
"other_id": null,
"pages": "18-24",
"pmc": null,
"pmid": "33550024",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A novel, germline, deactivating CBL variant p.L493F alters domain orientation and is associated with multiple childhood cancers.",
"title_normalized": "a novel germline deactivating cbl variant p l493f alters domain orientation and is associated with multiple childhood cancers"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202107633",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VEMURAFENIB"
},
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"drugdosageform": "UNKNOWN",
"drugdosagetext": "BRAF V600E INHIBITOR",
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"medicinalproduct": "VEMURAFENIB."
},
{
"actiondrug": "1",
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"activesubstancename": "VINBLASTINE"
},
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"drugindication": "BRAIN NEOPLASM",
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"medicinalproduct": "VINBLASTINE (MANUFACTURER UNKNOWN)"
}
],
"patientagegroup": null,
"patientonsetage": "5",
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"reaction": [
{
"reactionmeddrapt": "Mood altered",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neuralgia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Photosensitivity reaction",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "NORRIS G, TSAI A, SCHNEIDER K, WU Y, CAULFIELD T, GREEN A. A NOVEL, GERMLINE, DEACTIVATING CBL VARIANT P.L493F ALTERS DOMAIN ORIENTATION AND IS ASSOCIATED WITH MULTIPLE CHILDHOOD CANCERS. CANCER GENETICS. 2021 JUN?254:18?24.",
"literaturereference_normalized": "a novel germline deactivating cbl variant p l493f alters domain orientation and is associated with multiple childhood cancers",
"qualification": "3",
"reportercountry": "US"
},
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"receivedate": "20210723",
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},
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"senderorganization": "FDA-Public Use",
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},
"serious": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
}
] |
{
"abstract": "Denosumab is a highly effective treatment for postmenopausal osteoporosis, significantly improving BMD and reducing risk of fracture. However, denosumab's effect is transient with the risk of a rebound increase in bone turnover following withdrawal of this potent RANKL inhibitor. This poses challenges, particularly in individuals seeking to discontinue denosumab, such as those experiencing a direct complication of prolonged antiresorptive therapy or those in whom an antiresorptive drug holiday would be ordinarily considered. Bisphosphonate strategies to mitigate postdenosumab bone loss are being actively studied. We describe the case of a 73-year-old woman who developed a spontaneous vertebral fracture following denosumab discontinuation, despite prolonged treatment with bisphosphonate therapy both before her course of denosumab (20 years of use) and following denosumab discontinuation (1 year of use). This is a cautionary case seeking to highlight uncertainties around the safe withdrawal of denosumab therapy despite intervening treatment with bisphosphonates. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.",
"affiliations": "Department of Diabetes and Endocrinology Royal North Shore Hospital Sydney New South Wales Australia.;Department of Diabetes and Endocrinology Royal North Shore Hospital Sydney New South Wales Australia.",
"authors": "Davidoff|Dahlia F|DF|https://orcid.org/0000-0003-4084-9239;Girgis|Christian M|CM|https://orcid.org/0000-0001-8746-5529",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/jbm4.10396",
"fulltext": "\n==== Front\nJBMR Plus\nJBMR Plus\n10.1002/(ISSN)2473-4039\nJBM4\nJBMR Plus\n2473-4039 John Wiley & Sons, Inc. Hoboken, USA \n\n10.1002/jbm4.10396\nJBM410396\nCase Report\nCase Reports\nFailure of Oral Risedronate Therapy to Prevent Spontaneous Vertebral Fracture in a Patient Ceasing Denosumab: A Cautionary Case\nFAILURE OF ORAL RISEDRONATE THERAPYDavidoff and GirgisDavidoff Dahlia F https://orcid.org/0000-0003-4084-9239\n1\n\n2\nddav9259@uni.sydney.edu.au Girgis Christian M https://orcid.org/0000-0001-8746-5529\n1\n\n2\n\n3\n \n1 \nDepartment of Diabetes and Endocrinology\nRoyal North Shore Hospital\nSydney\nNew South Wales\nAustralia\n\n\n2 \nDepartment of Diabetes and Endocrinology\nRoyal North Shore Hospital, University of Sydney\nSydney\nNew South Wales\nAustralia\n\n\n3 \nDepartment of Diabetes and Endocrinology\nWestmead Hospital\nSydney\nNew South Wales\nAustralia\n\n* Address correspondence to: Dahlia F Davidoff, Department of Endocrinology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. E‐mail:ddav9259@uni.sydney.edu.au\n21 8 2020 \n10 2020 \n4 10 10.1002/jbm4.v4.10e1039602 6 2020 26 6 2020 07 7 2020 © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nDenosumab is a highly effective treatment for postmenopausal osteoporosis, significantly improving BMD and reducing risk of fracture. However, denosumab's effect is transient with the risk of a rebound increase in bone turnover following withdrawal of this potent RANKL inhibitor. This poses challenges, particularly in individuals seeking to discontinue denosumab, such as those experiencing a direct complication of prolonged antiresorptive therapy or those in whom an antiresorptive drug holiday would be ordinarily considered. Bisphosphonate strategies to mitigate postdenosumab bone loss are being actively studied. We describe the case of a 73‐year‐old woman who developed a spontaneous vertebral fracture following denosumab discontinuation, despite prolonged treatment with bisphosphonate therapy both before her course of denosumab (20 years of use) and following denosumab discontinuation (1 year of use). This is a cautionary case seeking to highlight uncertainties around the safe withdrawal of denosumab therapy despite intervening treatment with bisphosphonates. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n\nANTIRESORPTIVESBISPHOSPHONATESDENOSUMABOSTEOPOROSISRISEDRONATESPONTANEOUS VERTEBRAL FRACTURE source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:20.10.2020\n==== Body\nIntroduction\nDenosumab is a human IgG2 monoclonal antibody to RANKL.(\n\n1\n\n) By binding to RANKL, denosumab prevents the RANKL/RANK receptor interaction on osteoclasts, resulting in reduced osteoclast formation and function.(\n\n1\n\n) Denosumab has revolutionized the management of postmenopausal osteoporosis because of its dramatic impact on BMD and its reduction of fracture risk.(\n\n2\n\n) Current guidelines recommend the consideration of an intermission in antiresorptive therapy after prolonged treatment following careful evaluation of patient characteristics, BMD, and prior history of fracture.(\n\n3\n\n) The risk of atypical femur fracture (AFF) in patients on antiresorptive therapy is time‐dependent, with the risk increasing steadily after 5 years of treatment.(\n\n4\n\n) Patients on prolonged denosumab therapy,(\n\n5\n\n) particularly those on lengthy prior treatment with bisphosphonate,\n(6\n\n) are also at risk of AFF. We describe a case of a postmenopausal woman who had received a quarter century of antiresorptive therapy, first with oral bisphosphonate therapy for 20 years, followed by 5 years of denosumab. After careful consideration, she was transitioned from denosumab to an oral bisphosphonate in an effort to initiate an antiresorptive treatment intermission. Despite cautious treatment with a bisphosphonate and her many years of preceding bisphosphonate treatment, she sustained a spontaneous single vertebral fracture 13 months after denosumab discontinuation.\n\nClinical Vignette\nA 73‐year‐old woman with a lengthy history of osteoporosis and an extensive fracture history received 25 years of treatment with antiresorptive therapy. For the first 20 years, she received alendronate, followed by denosumab for 5 years. Because of her prolonged history of antiresorptive use, in the absence of recent minimal trauma fractures and with improved BMD values performed by DXA (lumbar spine density, 0.885 g/cm2, T‐score, 1.5 SD; left femoral neck density, 0.613 g/cm2, T‐score, 2.1 SD; left total hip, 0.683 g/cm2, T‐score, 2.1 SD), an antiresorptive treatment holiday was planned. She was subsequently transitioned from denosumab to a weekly oral bisphosphonate risedronate to protect from a rebound loss of bone density.(\n\n7\n, \n8\n\n) Of note, she had a remote history of vertebral and pelvic fractures occurring over three decades, but not recently. A bone scan prior to transition to risedronate showed non‐avid old vertebral fractures. Her lengthy prior treatment with bisphosphonate was also considered to potentially alleviate a rebound increase in bone turnover postdenosumab withdrawal. Six months after switching from denosumab to the oral bisphosphonate, bone turnover markers reassuringly remained within the reference range with P1NP 35 μg/L (15 to 115) and CTx 360 ng/L (100 to 1000) as assessed with a Roche cobas immunoassay analyzer (Roche Diagnostics, Mannheim, Germany).\n\nThirteen months after transitioning to the oral bisphosphonate, the patient sustained a T8 minimal trauma fracture after lifting a heavy metal pan (Fig. 1A and 1B). The patient reported compliance to risedronate. Bone turnover marker analysis performed 6 weeks after the fracture were stable compared to previous results with P1NP 38 μg/L (15 to 115) and CTx 310 ng/L (100 to 1000). A secondary osteoporosis screen was unremarkable including replete 25‐hydroxyvitamin D of 134 nmol/L (50 to 140) and normal corrected calcium of 2.44 mmol/L (2.15 to 2.55), serum phosphate of 1.31 mmol/L (0.8 to 1.5), intact PTH of 20 ng/L (15 to 68), thyroid‐stimulating hormone of 0.70 mIU/L (0.40 to 5.00), negative celiac serology by deamidated gliadin and tissue transglutaminase IgA and IgG, and normal serum protein electrophoresis and immunofixation. However, a DXA showed a decline in lumbar spine bone density (0.806 g/cm2, T‐score, 2.2; 8.9% decline over 19 months) and minor reductions in the left total hip left femoral neck density (Fig. 2, Table 1). Given the decline in BMD, denosumab treatment was resumed and will continue indefinitely.\n\nFig 1 T1‐weighted MRI imaging of the thoracic (A) and lumbar spine (B) showing an acute compression fracture identified in T8 (arrow) and evidence of prior vertebral compression fractures in T7, T12, and L2.\n\nFig 2 BMD and bone turnover marker response to denosumab and risedronate. D‐mab = denosumab; R = risedronate.\n\nTable 1 Change in Lumbar Spine BMD, CTx, and P1NP Over Time\n\nMonths from baseline\tLumbar spine density (g/cm2)\tLumbar spine T‐score\tLumbar spine density (% change) from baseline\tCTx (ng/L)\tTotal P1NP (μg/L)\t\n0\t0.776\t−2.5\tNA\t‐\t‐\t\n45\t0.897\t−1.4\t15.6%\t‐\t‐\t\n54\t‐\t‐\t‐\t72\t20\t\n57\t0.885\t−1.5\t14.0%\t‐\t‐\t\n67\t‐\t‐\t‐\t360\t35\t\n76\t0.806\t−2.2\t3.9%\t310\t38\t\nDiscussion\nDenosumab is a highly effective treatment for postmenopausal osteoporosis, which results in continued increases in BMD over time(\n\n9\n\n) and is well‐tolerated.(\n\n10\n\n) In the Freedom Extension [Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension): An Open Label, Single Arm, Extension Study to Evaluate the Long Term Safety and Sustained Efficacy of Denosumab (AMG162) in the Treatment of Postmenopausal Osteoporosis] Trial, the mean change in lumbar spine BMD from baseline to 5 years was +13.7%, comparable to our patient's improvement and by 10 years, up to +21.7%.(\n\n9\n\n) However, denosumab withdrawal is problematic with a risk of rapid loss in bone density gained(\n\n11\n, \n12\n, \n13\n\n) and a risk of vertebral fractures, especially in those with prior vertebral fracture.(\n\n13\n, \n14\n, \n15\n\n)\n\n\nStrategies for mitigating postdenosumab bone loss are under examination, but the literature suggests that an oral bisphosphonate may be the most indefinitely approach at this time.(\n\n7\n, \n8\n\n) Post‐FRAME (Fracture Study in Postmenopausal Women with Osteoporosis) Trial data found that following denosumab cessation, treatment with oral risedronate (n = 5) provided a 41% retention of the increase in BMD achieved with denosumab.(\n\n7\n\n) The DAPS (Denosumab Adherence Preference Satisfaction ) Study further addressed the question of transition to an oral bisphosphonate with a 24‐month open‐label randomized cross‐over study.(\n\n8\n\n) A majority of postmenopausal women with osteopenia who switched to alendronate after 24 months of denosumab maintained or gained bone density in the DAPS Study in the lumbar spine, total hip, and femoral neck (84.1%, 92.4%, and 78.3% of participants, respectively).(\n\n8\n\n) Bisphosphonates may vary in the potency of their antiresorptive effect and the CTx rise following denosumab may be mitigated by a potent bisphosphonate, whereby alendronate may be more effective than risedronate.(\n\n16\n\n) Studies of BMD retention in patients who switched from denosumab to zoledronic acid have been conflicting. A series of six postmenopausal women found a lack of bone density retention in patients transitioned to zoledronic acid,(\n\n17\n\n) whereas post‐FRAME data showed that the 11 women who switched to zoledronic acid had 73% retention of the gains in BMD after 1 year.(\n\n7\n\n)\n\n\nThe rapid loss of bone postdenosumab is not uniform among denosumab users, and the risk is considered greatest in patients who were bisphosphonate‐naïve prior to denosumab,(\n\n18\n, \n19\n\n) and those who achieved a marked increase in BMD on denosumab treatment.(\n\n8\n\n) Optimal bisphosphonate treatment strategies to mitigate postdenosumab bone loss are under investigation.(\n\n20\n\n)\n\n\nIn our patient, two decades of prior treatment with a bisphosphonate and a postdenosumab course of risedronate failed to prevent a rebound vertebral fracture following denosumab cessation. The vertebral fracture was speculated to relate to a rebound phenomenon postdenosumab in light of the bone density decline and increase in bone turnover markers following denosumab cessation. Interestingly, our patient's CTx following denosumab was not particularly high, and fell within the reference range for postmenopausal women. Our management was consistent with current recommendations to consider an intermission in antiresorptive therapy after prolonged treatment, in individuals who do not exhibit a high fracture risk, those without recent fracture, or with T‐score > − 2.5 SD, and to consider bisphosphonate transition postdenosumab withdrawal.(\n\n3\n\n) The aim of an antiresorptive “drug holiday” is to reduce the risk of medication adverse events such as atypical femoral fracture.(\n\n3\n\n) Nonetheless, the patient still fractured postdenosumab.\n\nThis case highlights the uncertain efficacy of bisphosphonate use to adequately suppress bone turnover following denosumab discontinuation and raises three important points: (i) Patients with previous history of vertebral fracture, no matter how remote, are at greatest risk of postdenosumab spontaneous vertebral fractures despite bisphosphonate use; (ii) standard markers of bone turnover may not adequately herald the onset of spontaneous vertebral fractures or decline in bone density following denosumab; and (iii) the dynamics of bone loss following denosumab withdrawal are poorly understood and unpredictable. Until further research emerges regarding the safe withdrawal of denosumab in patients on long‐term antiresorptive treatment, a high degree of caution is necessary. An individualized assessment of the risk: benefit ratio of long‐term treatment with denosumab is required, bearing in mind that this an otherwise highly effective fracture‐preventing treatment.\n\nDisclosures\nThere are no disclosures.\n\nPeer Review\nThe peer review history for this article is available at https://publons.com/publon/10.1002/jbm4.10396.\n\nAcknowledgments\nWe would like to thank Ms Susan Davis at the Northern Metabolic Bone Centre for performing the bone mineral density scans. Written informed consent was obtained from the patient.\n==== Refs\nReferences\n1 \n\nBekker \nPJ \n, \nHolloway \nDL \n, \nRasmussen \nAS \n, et al. A single‐dose placebo‐controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women\n. J Bone Mineral Res. \n2004 ;19 (7 ):1059 –66\n.\n2 \n\nCummings \nSR \n, \nSan Martin \nJ \n, \nMcClung \nMR \n, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis\n. N Engl J Med. \n2009 ;361 (8 ):756 –65\n.19671655 \n3 \n\nTsourdi \nE \n, \nLangdahl \nB \n, \nCohen‐Solal \nM \n, et al. Discontinuation of Denosumab therapy for osteoporosis: a systematic review and position statement by ECTS\n. Bone. \n2017 ;105 :11 –7\n.28789921 \n4 \n\nDell \nRM \n, \nAdams \nAL \n, \nGreene \nDF \n, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur\n. J Bone Mineral Res. \n2012 ;27 (12 ):2544 –50\n.\n5 \n\nFerrari \nS \n, \nLewiecki \nEM \n, \nButler \nPW \n, et al. Favorable skeletal benefit/risk of long‐term denosumab therapy: a virtual‐twin analysis of fractures prevented relative to skeletal safety events observed\n. Bone. \n2020 ;134 :115287.32092479 \n6 \n\nAdler \nRA \n, \nEl‐Hajj Fuleihan \nG \n, \nBauer \nDC \n, et al. Managing osteoporosis in patients on long‐term bisphosphonate treatment: report of a Task Force of the American Society for Bone and Mineral Research\n. J Bone Mineral Res. \n2016 ;31 (1 ):16 –35\n.\n7 \n\nHorne \nAM \n, \nMihov \nB \n, \nReid \nIR \n. Bone loss after romosozumab/denosumab: effects of bisphosphonates\n. Calcif Tissue Int. \n2018 ;103 (1 ):55 –61\n.29445836 \n8 \n\nKendler \nD \n, \nChines \nA \n, \nClark \nP \n, et al. Bone mineral density after transitioning from denosumab to alendronate\n. J Clin Endocrinol Metab. \n2020 ;105 (3 ):e255–e264.\n9 \n\nBone \nHG \n, \nWagman \nRB \n, \nBrandi \nML \n, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open‐label extension\n. Lancet Diabetes Endocrinol. \n2017 ;5 (7 ):513 –23\n.28546097 \n10 \n\nFreemantle \nN \n, \nSatram‐Hoang \nS \n, \nTang \nET \n, et al. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24‐month, randomized, crossover comparison with alendronate in postmenopausal women\n. Osteoporos Int. \n2012 ;23 (1 ):317 –26\n.21927922 \n11 \n\nMcClung \nMR \n, \nWagman \nRB \n, \nMiller \nPD \n, \nWang \nA \n, \nLewiecki \nEM \n. Observations following discontinuation of long‐term denosumab therapy\n. Osteoporos Int. \n2017 ;28 (5 ):1723 –32\n.28144701 \n12 \n\nPopp \nAW \n, \nVarathan \nN \n, \nBuffat \nH \n, \nSenn \nC \n, \nPerrelet \nR \n, \nLippuner \nK \n. Bone mineral density changes after 1 year of denosumab discontinuation in postmenopausal women with long‐term denosumab treatment for osteoporosis\n. Calcif Tissue Int. \n2018 ;103 (1 ):50 –4\n.29380013 \n13 \n\nZanchetta \nMB \n, \nBoailchuk \nJ \n, \nMassari \nF \n, \nSilveira \nF \n, \nBogado \nC \n, \nZanchetta \nJR \n. Significant bone loss after stopping long‐term denosumab treatment: a post FREEDOM study\n. Osteoporos Int. \n2018 ;29 (1 ):41 –7\n.\n14 \n\nAnastasilakis \nAD \n, \nPolyzos \nSA \n, \nMakras \nP \n, \nAubry‐Rozier \nB \n, \nKaouri \nS \n, \nLamy \nO \n. Clinical features of 24 patients with rebound‐associated vertebral fractures after denosumab discontinuation: systematic review and additional cases\n. J Bone Mineral Res. \n2017 ;32 (6 ):1291 –6\n.\n15 \n\nCummings \nSR \n, \nFerrari \nS \n, \nEastell \nR \n, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo‐controlled FREEDOM trial and its extension\n. J Bone Mineral Res. \n2018 ;33 (2 ):190 –8\n.\n16 \n\nLamy \nO \n, \nStoll \nD \n, \nAubry‐Rozier \nB \n, \nRodriguez \nEG \n. Stopping denosumab\n. Curr Osteoporos Rep. \n2019 ;17 (1 ):8 –15\n.30659428 \n17 \n\nReid \nIR \n, \nHorne \nAM \n, \nMihov \nB \n, \nGamble \nGD \n. Bone loss after denosumab: only partial protection with zoledronate\n. Calcif Tissue Int. \n2017 ;101 (4 ):371 –4\n.28500448 \n18 \n\nUebelhart \nB \n, \nRizzoli \nR \n, \nFerrari \nSL \n. Retrospective evaluation of serum CTX levels after denosumab discontinuation in patients with or without prior exposure to bisphosphonates\n. Osteoporos Int. \n2017 ;28 (9 ):2701 –5\n.28540505 \n19 \n\nAubry‐Rozier \nB \n, \nLiebich \nG \n, \nStoll \nD \n, \nGonzalez‐Rodriguez \nE \n, \nHans \nD \n, \nLamy \nO \n. Can we avoid the loss of bone mineral density one year after denosumab discontinuation? The Relaus bone project\n. Ann Rheum Dis. \n2019 ;78 (Suppl 2 ):115 .\n20 \nClinicalTrials.gov \n. NCT03396315: Bisphosphonates for Prevention of Post‐Denosumab Bone Loss. Bethesda, MD: U.S. National Library of Medicine; 2018 .\n\n",
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"medicinalproduct": "RISEDRONATE SODIUM."
},
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"activesubstancename": "ALENDRONATE SODIUM"
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
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"medicinalproduct": "DENOSUMAB"
}
],
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"patientonsetageunit": "801",
"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Spinal fracture",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DAVIDOFF DF, GIRGIS CM. FAILURE OF ORAL RISEDRONATE THERAPY TO PREVENT SPONTANEOUS VERTEBRAL FRACTURE IN A PATIENT CEASING DENOSUMAB: A CAUTIONARY CASE. JBMR PLUS. 2020?4 (10):1-4",
"literaturereference_normalized": "failure of oral risedronate therapy to prevent spontaneous vertebral fracture in a patient ceasing denosumab a cautionary case",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20201127",
"receivedate": "20201127",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18552661,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210114"
},
{
"companynumb": "AU-TEVA-2020-AU-1848679",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISEDRONIC ACID"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "77132",
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"medicinalproduct": "RISEDRONIC ACID"
}
],
"patientagegroup": "6",
"patientonsetage": "73",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Spinal fracture",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DAHLIA F DAVIDOFF + CHRISTIAN M GIRGIS. FAILURE OF ORAL RISEDRONATE THERAPY TO PREVENT SPONTANEOUS VERTEBRAL FRACTURE IN A PATIENT CEASING DENOSUMAB: A CAUTIONARY CASE. JBMR PLUS. 2020 AUG 21?4(10):E10396. DOI: 10.1002/JBM4.10396. .",
"literaturereference_normalized": "failure of oral risedronate therapy to prevent spontaneous vertebral fracture in a patient ceasing denosumab a cautionary case",
"qualification": "1",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20201111",
"receivedate": "20201111",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18489333,
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"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210114"
}
] |
{
"abstract": "The death rate from asthma has been increasing in the U.S. and in many other countries and is considered unacceptably high. There is little information as to circumstances surrounding these fatalities that would lead to effective interventions to prevent deaths. In this study, cases of asthma deaths from the Office of the Medical Examiner in Cook County, (Chicago), Illinois were identified in subjects 45 years of age or less who died from asthma. We reviewed clinical information surrounding the deaths, contacted surviving kin, friends, or informants, and reviewed autopsy findings and toxicologic results. Deaths were classified as (1) from asthma, (2) probably from asthma, (3) of indeterminate cause, and (4) coincidental to but not from asthma. From 39 cases from one pathologist's cases of asthma deaths during 1985-1992, deaths were from or probably from asthma in 22/39 (56.4%) of cases. Eight (20.5%) cases were classified as indeterminate because of a positive or unknown asthma prodrome but in which toxicologic results were positive. Nine (23.1%) cases were classified as death coincidental to but not from asthma because of the absence of a prodrome of increased symptoms associated with positive toxicologic results. Overall from 23 cases where some toxicologic testing was performed, 14 (60.8%) were positive, individually or in combination, for cocaine, benzoylecgonine (cocaine metabolite), codeine, phencyclidine (animal tranquilizer), morphine, methadone, and ethanol (> 0.8 g/L). Out-of-hospital asthma deaths in 39 subjects were complicated by a high incidence of illicit drug use, lack of identifiable managing physicians, lack of antiinflammatory medications, and in some cases not having been examined by a physician in the past year.(ABSTRACT TRUNCATED AT 250 WORDS)",
"affiliations": "Department of Medicine, Northwestern University Medical School, Chicago, Illinois.",
"authors": "Greenberger|P A|PA|;Miller|T P|TP|;Lifschultz|B|B|",
"chemical_list": "D000893:Anti-Inflammatory Agents",
"country": "United States",
"delete": false,
"doi": "10.2500/108854193778773994",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-9354",
"issue": "14(5)",
"journal": "Allergy proceedings : the official journal of regional and state allergy societies",
"keywords": null,
"medline_ta": "Allergy Proc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000893:Anti-Inflammatory Agents; D001249:Asthma; D015984:Causality; D002423:Cause of Death; D002641:Chicago; D002648:Child; D015897:Comorbidity; D003266:Continuity of Patient Care; D003334:Coroners and Medical Examiners; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance; D019966:Substance-Related Disorders",
"nlm_unique_id": "8902396",
"other_id": null,
"pages": "321-6",
"pmc": null,
"pmid": "8288113",
"pubdate": "1993",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Circumstances surrounding deaths from asthma in Cook County (Chicago) Illinois.",
"title_normalized": "circumstances surrounding deaths from asthma in cook county chicago illinois"
} | [
{
"companynumb": "US-PFIZER INC-2020406349",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENCYCLIDINE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"medicinalproduct": "PHENCYCLIDINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "071849",
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"drugcharacterization": "1",
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"medicinalproduct": "MORPHINE SULFATE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "METHADONE"
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Asthma",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Drug abuse",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GREENBERGER, P.. CIRCUMSTANCES SURROUNDING DEATHS FROM ASTHMA IN COOK COUNTY (CHICAGO) ILLINOIS. ALLERGY PROCEEDINGS. 1993?14 (5):321-326",
"literaturereference_normalized": "circumstances surrounding deaths from asthma in cook county chicago illinois",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20201102",
"receivedate": "20201102",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 18453435,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210114"
}
] |
{
"abstract": "Localized neuropathic pain symptoms are reported after knee surgery in 30% to 50% of patients. 5% lidocaine plaster (LP5) is recommended for localized neuropathic pain, but evidence in postsurgery neuropathic pain is missing. This study focuses on the effectiveness of LP5 on allodynia, hyperalgesia, and thermal stimuli in postsurgery knee localized neuropathic pain. A randomized double-blind, 2 parallel groups, controlled trial (NCT02763592) took place in 36 patients (age, 69.4 ± 7.3 years) at the Clinical Pharmacology Center, University Hospital Clermont-Ferrand, France. Patients randomly received LP5 or placebo plaster during 3 months. Neuropathic pain intensity and several parameters (dynamic mechanical allodynia, mechanical [von Frey], heat and cold detection and pain thresholds [Pathway Medoc], and size of the allodynic area were recorded at each visit [inclusion, day 7, 15, month 1, 2, and 3]). From day 7 onwards, dynamic mechanical allodynia diminished progressively of ≥ 30% over 3 months (P = 0.003) in 96% of patients (23/24) and of ≥ 50% in 83% of patients (20/24). Cold pain and maximal mechanical pain thresholds improved over 3 months (P = 0.001 and P = 0.007, respectively). This study shows for the first time the effectiveness of LP5 on dynamic mechanical allodynia, pain, pressure, and cold thresholds over 3 months in knee localized neuropathic pain. Beyond the inhibition of sodium channels by LP5, these findings suggest the involvement of cold and mechanical receptors that participate to pain chronicisation and also of the non-negligible placebo effect of the patch, items that need to be explored further and challenged in other etiologies of localized neuropathic pain.",
"affiliations": "Université Clermont Auvergne Neurodol, Inserm 1107, Clermont-Ferrand, France.;Clinical Pharmacology Department CPC/CIC Inserm 1405, University Hospital, CHU F-63000 Clermont-Ferrand, France.;Clinical Pharmacology Department CPC/CIC Inserm 1405, University Hospital, CHU F-63000 Clermont-Ferrand, France.;Hergan Consulting 4U, Courbevoie, France.;CHU Clermont-Ferrand, DRCI, Clermont-Ferrand, France.",
"authors": "Pickering|Gisèle|G|;Voute|Marion|M|;Macian|Nicolas|N|;Ganry|Hervé|H|;Pereira|Bruno|B|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1097/j.pain.0000000000001502",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0304-3959",
"issue": "160(5)",
"journal": "Pain",
"keywords": null,
"medline_ta": "Pain",
"mesh_terms": "D000368:Aged; D000779:Anesthetics, Local; D019645:Arthroplasty, Replacement, Knee; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006930:Hyperalgesia; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D009437:Neuralgia; D010147:Pain Measurement; D017288:Pain Threshold; D010149:Pain, Postoperative; D016896:Treatment Outcome",
"nlm_unique_id": "7508686",
"other_id": null,
"pages": "1186-1195",
"pmc": null,
"pmid": "31009419",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effectiveness and safety of 5% lidocaine-medicated plaster on localized neuropathic pain after knee surgery: a randomized, double-blind controlled trial.",
"title_normalized": "effectiveness and safety of 5 lidocaine medicated plaster on localized neuropathic pain after knee surgery a randomized double blind controlled trial"
} | [
{
"companynumb": "FR-TEIKOKU PHARMA USA-TPU2020-00131",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": null,
"drugadministrationroute": "061",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "POULTICE OR PATCH",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROCEDURAL PAIN",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PLACEBO"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
"drugadministrationroute": "061",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "POULTICE OR PATCH",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROCEDURAL PAIN",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VERSATIS"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cardiac operation",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Presyncope",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Skin disorder",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "General symptom",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PICKERING G. EFFECTIVENESS AND SAFETY OF 5% LIDOCAINE-MEDICATED PLASTER ON LOCALIZED NEUROPATHIC PAIN AFTER KNEE SURGERY: A RANDOMIZED, DOUBLE-BLIND CONTROLLED TRIAL. PAIN. 2019?160:1186-1195.",
"literaturereference_normalized": "effectiveness and safety of 5 lidocaine medicated plaster on localized neuropathic pain after knee surgery a randomized double blind controlled trial",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "FR",
"receiptdate": "20200311",
"receivedate": "20200311",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 17531155,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "BACKGROUND\nHepatoid adenocarcinoma (HAC) occurs in extrahepatic organs such as the gastrointestinal tract, testes, ovaries, lungs, mediastinum and pancreas, and frequently produces α-fetoprotein (AFP). HAC of the lung (HAL) is rare, characterized by difficult treatment and poor prognosis. There are no reports of HAL in Yunnan-Guizhou Plateau, China.\n\n\nMETHODS\nA 60-year-old male patient was clinically diagnosed with HAL pT3N0M0, stage IIB. Chest computed tomography revealed a 7.5 cm × 7.2 cm soft tissue mass located in the right lung upper lobe and the adjacent superior mediastinum. Right upper lobectomy was performed. The diagnosis of HAL was confirmed by pathological examination, and the patient received paclitaxel and carboplatin as adjuvant chemotherapy after surgery.\n\n\nCONCLUSIONS\nClinical manifestations, pathological features, imaging findings, auxiliary examination, and treatment planning of HAL are presented to help clinicians improve their diagnosis and treatment.",
"affiliations": "Department of Thoracic Surgery in the Elderly, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China.;Department of Thoracic Surgery in the Elderly, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China.;Department of Thoracic Surgery in the Elderly, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China.;Department of Thoracic Surgery in the Elderly, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China.;Department of Thoracic Surgery in the Elderly, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China.;Department of Thoracic Surgery in the Elderly, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China.;Department of Thoracic Surgery in the Elderly, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China. 823039079@qq.com.",
"authors": "Shi|Yun-Fei|YF|;Lu|Jia-Gui|JG|;Yang|Qing-Mei|QM|;Duan|Jin|J|;Lei|You-Ming|YM|;Zhao|Wei|W|;Liu|Yin-Qiang|YQ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v7.i13.1711",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2307-8960",
"issue": "7(13)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Hepatic adenocarcinoma; Immunohistochemistry; Lung cancer; α-Fetoprotein",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "1711-1716",
"pmc": null,
"pmid": "31367631",
"pubdate": "2019-07-06",
"publication_types": "D002363:Case Reports",
"references": "11490220;11940206;14508391;1694332;18043368;18570977;23372352;24030743;24408270;24959228;25870375;26943677;27347123;27692141;7689918;9298890",
"title": "Primary hepatoid adenocarcinoma of the lung in Yungui Plateau, China: A case report.",
"title_normalized": "primary hepatoid adenocarcinoma of the lung in yungui plateau china a case report"
} | [
{
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],
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}
],
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},
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"literaturereference": "SHI YF, LU JG, YANG QM, DUAN J, LEI YM, ZHAO W, LIU YQ. PRIMARY HEPATOID ADENOCARCINOMA OF THE LUNG IN YUNGUI PLATEAU, CHINA: A CASE REPORT. WORLD J CLIN CASES. 2019 JUL 6?7(13):1711-1716.",
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},
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"receivedate": "20190816",
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"receivertype": "6"
},
"reporttype": "1",
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191004"
}
] |
{
"abstract": "Discordant elevations of cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) ribonucleic acid (RNA) in chronically treated patients known as 'CSF escape' may present as acute encephalitis. Infectious encephalitis caused by herpes simplex virus (HSV) and other neurotropic viruses have been identified as potential triggers of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Autoantibody-mediated encephalitis has been infrequently reported in HIV infected patients and may mimic HIV encephalitis. We report two adults infected with HIV presenting with encephalopathy and seizures. Case 1 had a monophasic encephalopathy with detection of NMDAR antibodies in the context of HIV CSF escape. There was a clinical response to immunotherapy and anti-retroviral therapy adjustment. Case 2 initially presented in non-convulsive status epilepticus associated with HIV CSF escape. He responded to treatment with anti-epileptic drugs and anti-retroviral therapy alteration, but had two further neurological relapses. NMDAR antibodies were detected during the relapses and a clinical response was observed following treatment with immunotherapy. Clinicians should consider autoimmune encephalitis in HIV infected patients presenting with encephalopathy and seizures, particularly in cases with concomitant HIV CSF escape.",
"affiliations": "Department of Neurology and Neurophysiology, St. James's Hospital, Dublin, Ireland.;Department of Neurology and Neurophysiology, St. James's Hospital, Dublin, Ireland.;Department of Genitourinary Medicine and Infectious Diseases, St. James's Hospital, Dublin, Ireland.;Department of Genitourinary Medicine and Infectious Diseases, St. James's Hospital, Dublin, Ireland.;Department of Neurology and Neurophysiology, St. James's Hospital, Dublin, Ireland.;Department of Immunology, St. James's Hospital, Dublin, Ireland.;Departments of Neurology, Neurosurgery and Medicine (Infectious Disease), Boston University Medical Center, Boston, MA, USA.;Departments of Neurology, Neurosurgery and Medicine (Infectious Disease), Boston University Medical Center, Boston, MA, USA.;Departments of Neurology, Neurosurgery and Medicine (Infectious Disease), Boston University Medical Center, Boston, MA, USA. ancervan@bu.edu.",
"authors": "Moloney|Patrick B|PB|;Hutchinson|Siobhan|S|;Heskin|Joseph|J|;Mulcahy|Fiona|F|;Langan|Yvonne|Y|;Conlon|Niall P|NP|;Linas|Benjamin P|BP|;Takahashi|Courtney|C|;Cervantes-Arslanian|Anna M|AM|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-019-09693-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-5354",
"issue": "267(5)",
"journal": "Journal of neurology",
"keywords": "Anti-NMDA receptor encephalitis; Autoimmune encephalitis; CSF escape; HIV",
"medline_ta": "J Neurol",
"mesh_terms": "D000328:Adult; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D015658:HIV Infections; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D013226:Status Epilepticus",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "1348-1352",
"pmc": null,
"pmid": "31960135",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Possible N-methyl-D-aspartate receptor antibody-mediated encephalitis in the setting of HIV cerebrospinal fluid escape.",
"title_normalized": "possible n methyl d aspartate receptor antibody mediated encephalitis in the setting of hiv cerebrospinal fluid escape"
} | [
{
"companynumb": "IE-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-248747",
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},
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"medicinalproduct": "VALPROIC ACID."
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},
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"medicinalproduct": "LEVETIRACETAM."
}
],
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"reaction": [
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"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MOLONEY PB, HUTCHINSON S, HESKIN J, MULCAHY F, LANGAN Y, CONLON NP, ET AL. POSSIBLE N-METHYL-D-ASPARTATE RECEPTOR ANTIBODY-MEDIATED ENCEPHALITIS IN THE SETTING OF HIV CEREBROSPINAL FLUID ESCAPE. J NEUROL. 2020?267(5):1348-1352",
"literaturereference_normalized": "possible n methyl d aspartate receptor antibody mediated encephalitis in the setting of hiv cerebrospinal fluid escape",
"qualification": "3",
"reportercountry": "IE"
},
"primarysourcecountry": "IE",
"receiptdate": "20200602",
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"receiver": {
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200714"
}
] |
{
"abstract": "Cytomegalovirus retinitis (CMVR) may occur after allogeneic hematopoietic stem cell transplantation (HSCT). However, little is known about its incidence, strategies for ophthalmic surveillance, and timely implementation of adequate antiviral treatment in pediatric allogeneic HSCT recipients. We provide a retrospective analysis of the epidemiology and clinical features of CMVR in pediatric allogeneic HSCT patients transplanted at our center over a 16-year period. Two patients of this cohort with leukemia are presented. Our analysis is supplemented by a systematic review on pediatric patients with leukemia and CMVR in the setting of allogeneic HSCT. The overall incidence of CMVR in our cohort was 1% (4/338) and 14.2% (3/21) in leukemic patients. In published cases, CMVR occurred at a median of 143 days after transplantation, and, in the majority of patients, was preceded by CMV detection in blood by a median of 93 days. Continued immune suppression following engraftment likely triggers CMVR. Preemptive treatment with ganciclovir as standard is usually successful. Foscarnet is used in case of resistance to ganciclovir or drug-induced granulocytopenia. Overall, CMVR after HSCT in pediatric leukemic patients is rare, but a potentially higher vulnerability of this population for involvement of the eye warrants a standardized ophthalmological examination plan.",
"affiliations": "Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany.;Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany.;Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany.;Department of Ophthalmology, University Hospital Muenster, Muenster, Germany.;Department of Ophthalmology, University Hospital Muenster, Muenster, Germany.;Department of Medicine A, University Hospital Muenster, Muenster, Germany.;Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany.;Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany.",
"authors": "Zöllner|Stefan K|SK|https://orcid.org/0000-0001-5888-7327;Herbrüggen|Heidrun|H|;Kolve|Hedwig|H|;Mihailovic|Natasa|N|;Schubert|Friederike|F|;Reicherts|Christian|C|;Rössig|Claudia|C|;Groll|Andreas H|AH|",
"chemical_list": "D000998:Antiviral Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13089",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "children; cytomegalovirus; leukemia; retinitis; transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000293:Adolescent; D000998:Antiviral Agents; D002648:Child; D017726:Cytomegalovirus Retinitis; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D015994:Incidence; D007223:Infant; D015470:Leukemia, Myeloid, Acute; D008297:Male; D012189:Retrospective Studies; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13089",
"pmc": null,
"pmid": "30972869",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Cytomegalovirus retinitis in children and adolescents with acute leukemia following allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "cytomegalovirus retinitis in children and adolescents with acute leukemia following allogeneic hematopoietic stem cell transplantation"
} | [
{
"companynumb": "DE-BAXTER-2019BAX020581",
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},
{
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"medicinalproduct": "ENDOXAN LYOPHILISAT"
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"drugindication": "ALLOGENIC STEM CELL TRANSPLANTATION",
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"medicinalproduct": "BUSULFAN."
}
],
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"patientonsetage": "13",
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"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cytomegalovirus infection",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Acute graft versus host disease in skin",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Graft versus host disease in gastrointestinal tract",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Cytomegalovirus chorioretinitis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "4"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ZOLLNER S, HERBRUGGEN H, KOLVE H, MIHAILOVIC N, SCHUBERT F, REICHERTS C, ROSSIG C, GROLL A. CYTOMEGALOVIRUS RETINITIS IN CHILDREN AND ADOLESCENTS WITH ACUTE LEUKEMIA FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION. TRANSPLANT INFECTIOUS DISEASE. 2019?21:1-13.",
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{
"abstract": "To describe the case of a patient with infection due to a KPC-producing Klebsiella pneumoniae (K. pneumoniae) isolate developing ceftazidime-avibactam resistance with restored carbapenem susceptibility during ceftazidime-avibactam therapy. To review the clinical/microbiological cure and survival rates using carbapenems in other similar case reports and case series.\n\n\n\nA patient with an intra-abdominal infection due to K. pneumoniae producing the KPC-48 variant (L169P-A172T) (resistant to ceftazidime/avibactam and susceptible to carbapenems) who was treated with imipenem-cilastatin in combination with tigecycline and gentamicin. The literature was reviewed in order to summarise the in vivo (clinical/microbiological cure and survival rate) use of carbapenems in this emerging scenario.\n\n\n\nThe patient was successfully treated with the indicated regimen. In other reported cases (mostly with pneumonia) all-cause mortality was 50% and clinical cure was 62.5%. Meropenem-vaborbactam has been successful used in an additional case.\n\n\n\nA carbapenem-based regimen of combination therapy seems to be an option for treating patients infected with K. pneumoniae resistant to ceftazidime/avibactam and susceptible to carbapenems, at least when the risk of mortality is low.",
"affiliations": "Unit of Infectious Diseases, Hospital Universitario Reina Sofía-IMIBIC-Universidad de Cordoba, Cordoba, Spain; Spanish Network of Research in Infectious Diseases (REIPI RD16/0016/0008), Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain.;Unit of Microbiology, Hospital Universitario Reina Sofía-IMIBIC-Universidad de Cordoba, Cordoba, Spain; Spanish Network of Research in Infectious Diseases (REIPI RD16/0016/0008), Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain.;Unit of Infectious Diseases, Hospital Universitario Reina Sofía-IMIBIC-Universidad de Cordoba, Cordoba, Spain; Spanish Network of Research in Infectious Diseases (REIPI RD16/0016/0008), Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain.;Unit of Infectious Diseases, Hospital Universitario Reina Sofía-IMIBIC-Universidad de Cordoba, Cordoba, Spain; Spanish Network of Research in Infectious Diseases (REIPI RD16/0016/0008), Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain.;Unit of Microbiology, Hospital Universitario Reina Sofía-IMIBIC-Universidad de Cordoba, Cordoba, Spain; Spanish Network of Research in Infectious Diseases (REIPI RD16/0016/0008), Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain.;Spanish Network of Research in Infectious Diseases (REIPI RD16/0016/0008), Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain.;Unit of Infectious Diseases, Hospital Universitario Reina Sofía-IMIBIC-Universidad de Cordoba, Cordoba, Spain.;Spanish Network of Research in Infectious Diseases (REIPI RD16/0016/0008), Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain.;Unit of Microbiology, Hospital Universitario Reina Sofía-IMIBIC-Universidad de Cordoba, Cordoba, Spain; Spanish Network of Research in Infectious Diseases (REIPI RD16/0016/0008), Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain.;Unit of Microbiology, Hospital Universitario Reina Sofía-IMIBIC-Universidad de Cordoba, Cordoba, Spain; Spanish Network of Research in Infectious Diseases (REIPI RD16/0016/0008), Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain. Electronic address: luis.martinez.martinez.sspa@juntadeandalucia.es.;Unit of Infectious Diseases, Hospital Universitario Reina Sofía-IMIBIC-Universidad de Cordoba, Cordoba, Spain; Spanish Network of Research in Infectious Diseases (REIPI RD16/0016/0008), Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain.",
"authors": "Cano|Ángela|Á|;Guzmán-Puche|Julia|J|;García-Gutiérrez|Manuel|M|;Castón|Juan José|JJ|;Gracia-Ahufinger|Irene|I|;Pérez-Nadales|Elena|E|;Recio|Manuel|M|;Natera|Alejandra M|AM|;Marfil-Pérez|Eduardo|E|;Martínez-Martínez|Luis|L|;Torre-Cisneros|Julian|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D015780:Carbapenems; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; C543519:avibactam; D002442:Ceftazidime",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jgar.2019.11.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2213-7165",
"issue": "22()",
"journal": "Journal of global antimicrobial resistance",
"keywords": "Carbapenems; Ceftazidime/avibactam-resistance; Klebsiella pneumoniae",
"medline_ta": "J Glob Antimicrob Resist",
"mesh_terms": "D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D015780:Carbapenems; D002442:Ceftazidime; D004338:Drug Combinations; D006801:Humans; D007711:Klebsiella pneumoniae; D008826:Microbial Sensitivity Tests; D011014:Pneumonia",
"nlm_unique_id": "101622459",
"other_id": null,
"pages": "9-12",
"pmc": null,
"pmid": "31733412",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Use of carbapenems in the combined treatment of emerging ceftazidime/avibactam-resistant and carbapenem-susceptible KPC-producing Klebsiella pneumoniae infections: Report of a case and review of the literature.",
"title_normalized": "use of carbapenems in the combined treatment of emerging ceftazidime avibactam resistant and carbapenem susceptible kpc producing klebsiella pneumoniae infections report of a case and review of the literature"
} | [
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"literaturereference": "CANO A, GUZMAAN?PUCHE J, GARCIA?GUTIERREZ M, CASTON JJ, GRACIA?AHUFINGER I, PEREZ?NADALES E. USE OF CARBAPENEMS IN THE COMBINED TREATMENT OF EMERGING CEFTAZIDIME/AVIBACTAM?RESISTANT AND CARBAPENEM?SUSCEPTIBLE KPC?PRODUCING KLEBSIELLA PNEUMONIAE INFECTIONS: REPORT OF A CASE AND REVIEW OF THE LITERATURE. JOURNAL OF GLOBAL ANTIMICROBIAL RESISTANCE. 2020?9?12",
"literaturereference_normalized": "use of carbapenems in the combined treatment of emerging ceftazidime avibactam resistant and carbapenem susceptible kpc producing klebsiella pneumoniae infections report of a case and review of the literature",
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{
"abstract": "OBJECTIVE\nVismodegib is a targeted agent recently approved for treating patients who develop recurrent or locally advanced basal cell carcinoma (BCC), and will inevitably be integrated into existing therapy for advanced BCC as it becomes increasingly used. Improved understanding of how vismodegib interacts with other treatment modalities, including radiotherapy, would help optimize multidisciplinary therapy and clinical outcomes.\n\n\nMETHODS\nWe report 2 cases of recurrent, advanced BCC treated from April 1, 2012, through October 31, 2014, with concurrent radiotherapy and vismodegib. Concurrent treatment appeared to be well tolerated and efficacious, with both patients having no evidence of progressive disease at last follow-up.\n\n\nCONCLUSIONS\nWe found that the combination of vismodegib and radiotherapy is feasible for patients with recurrent or locally advanced BCC and that combined use of currently available therapies for advanced BCC warrants further prospective study.",
"affiliations": "Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.;Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.;Department of Dermatology, Stanford University School of Medicine, Stanford, California.;Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, California.;Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.",
"authors": "Pollom|Erqi L|EL|;Bui|Timothy T|TT|;Chang|Anne Lynn S|AL|;Colevas|A Dimitrios|AD|;Hara|Wendy Y|WY|",
"chemical_list": "D000813:Anilides; C538724:HhAntag691; D011725:Pyridines",
"country": "United States",
"delete": false,
"doi": "10.1001/jamadermatol.2015.0326",
"fulltext": null,
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"issn_linking": "2168-6068",
"issue": "151(9)",
"journal": "JAMA dermatology",
"keywords": null,
"medline_ta": "JAMA Dermatol",
"mesh_terms": "D000368:Aged; D000813:Anilides; D002280:Carcinoma, Basal Cell; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011446:Prospective Studies; D011725:Pyridines; D012878:Skin Neoplasms",
"nlm_unique_id": "101589530",
"other_id": null,
"pages": "998-1001",
"pmc": null,
"pmid": "25874733",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Concurrent Vismodegib and Radiotherapy for Recurrent, Advanced Basal Cell Carcinoma.",
"title_normalized": "concurrent vismodegib and radiotherapy for recurrent advanced basal cell carcinoma"
} | [
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{
"abstract": "The prevalence of esophageal stenosis caused by immune checkpoint inhibitors in the context of induced immune mucositis and esophagitis is extremely rare.\n\n\n\nWe report the case of a patient with stage IV pulmonary adenocarcinoma treated for 6 months with nivolumab who developed bilateral sterile conjunctivitis followed by oropharyngeal mucositis and esophagitis complicated by a severe esophageal stenosis. The laryngeal margin and hypopharyngeal mucosa appeared highly inflammatory with fibrinous deposits. Esophagogastroduodenoscopy revealed mucositis with a scar-like structure immediately below the upper esophageal sphincter with nonulcerative mucosa and an inflammatory aspect of the entire esophagus. No involvement of the stomach was observed. Oropharynx biopsies displayed marked lymphocytic T cell-infiltration with several foci of monocellular necrosis in the squamous epithelium. No morphologic evidence of adenocarcinoma and no signs of mycotic, bacterial or viral infection were noted. A blood sample revealed a discrete increase in the erythrocyte sedimentation rate (ESR) with no eosinophilia or leukocytosis. Liver and kidney function panel tests were normal. A thoracoabdominal CT scan reported no evidence of disease recurrence. Despite multiple boluses of methylprednisolone and high doses of prednisone continued for several months, the patient experienced very rapid symptomatological reappearance during three steroid tapering attempts and aggravation of his esophageal stenosis to an aphagic stage, requiring a nasogastric tube. This long course of high-dose corticosteroid treatment was complicated with osteoporosis-induced fractures with several spontaneous compressions of thoracolumbar vertebrae requiring an enlarged T10 to L5 cementoplasty. Anti-IL-6 blockade therapy with tocilizumab resulted in excellent clinical response, allowing the total resolution of the immune-related adverse events (irAEs) and leading to successful steroid tapering.\n\n\n\nHerein, we describe the first case of a patient who developed autoimmune mucositis and esophagitis complicated by a severe refractory esophageal stenosis induced during treatment by nivolumab, which completely resolved after personalized treatment with tocilizumab, suggesting a role of IL-6 blockade in the management of severe steroid refractory esophageal stenosis and more broadly in refractory immune-related adverse events.",
"affiliations": "Department of Medicine, Division of Immunology and Allergy, Lausanne University Hospital CHUV, rue du Bugnon 46, CH-1011, Lausanne, Switzerland.;Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital CHUV, rue du Bugnon 25, CH-1011, Lausanne, Switzerland.;Department of Oncology, Lausanne University Hospital CHUV, rue du Bugnon 46, CH-1011, Lausanne, Switzerland.;Department of Oncology, Lausanne University Hospital CHUV, rue du Bugnon 46, CH-1011, Lausanne, Switzerland.;Department of Medicine, Division of Immunology and Allergy, Lausanne University Hospital CHUV, rue du Bugnon 46, CH-1011, Lausanne, Switzerland.;Department of Oncology, Lausanne University Hospital CHUV, rue du Bugnon 46, CH-1011, Lausanne, Switzerland.;Department of Medicine, Division of Immunology and Allergy, Lausanne University Hospital CHUV, rue du Bugnon 46, CH-1011, Lausanne, Switzerland. michel.obeid@chuv.ch.",
"authors": "Horisberger|Alice|A|;La Rosa|Stefano|S|;Zurcher|Jean-Philippe|JP|;Zimmermann|Stefan|S|;Spertini|Francois|F|;Coukos|George|G|;Obeid|Michel|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1186/s40425-018-0481-0",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 48110.1186/s40425-018-0481-0Case ReportA severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy Horisberger Alice 1La Rosa Stefano 2Zurcher Jean-Philippe 3Zimmermann Stefan 3Spertini Francois 1Coukos George 34Obeid Michel michel.obeid@chuv.ch 1561 0000 0001 0423 4662grid.8515.9Department of Medicine, Division of Immunology and Allergy, Lausanne University Hospital CHUV, rue du Bugnon 46, CH-1011 Lausanne, Switzerland 2 0000 0001 0423 4662grid.8515.9Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital CHUV, rue du Bugnon 25, CH-1011 Lausanne, Switzerland 3 0000 0001 0423 4662grid.8515.9Department of Oncology, Lausanne University Hospital CHUV, rue du Bugnon 46, CH-1011 Lausanne, Switzerland 4 0000 0001 2165 4204grid.9851.5Ludwig Institute for Cancer Research, University of Lausanne, chemin des Boveresses 155, CH-1066 Epalinges, Switzerland 5 0000 0001 0423 4662grid.8515.9Vaccination and Immunotherapy Center, Lausanne University Hospital CHUV, rue du Bugnon 17, CH-1011 Lausanne, Switzerland 6 0000 0001 2308 1657grid.462844.8Medical school Pitié-Salpêtrière, Sorbonne University, 91 Boulevard de l’Hôpital, F-75013 Paris, France 27 12 2018 27 12 2018 2018 6 1563 10 2018 13 12 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\nThe prevalence of esophageal stenosis caused by immune checkpoint inhibitors in the context of induced immune mucositis and esophagitis is extremely rare.\n\nCase presentation\nWe report the case of a patient with stage IV pulmonary adenocarcinoma treated for 6 months with nivolumab who developed bilateral sterile conjunctivitis followed by oropharyngeal mucositis and esophagitis complicated by a severe esophageal stenosis. The laryngeal margin and hypopharyngeal mucosa appeared highly inflammatory with fibrinous deposits. Esophagogastroduodenoscopy revealed mucositis with a scar-like structure immediately below the upper esophageal sphincter with nonulcerative mucosa and an inflammatory aspect of the entire esophagus. No involvement of the stomach was observed. Oropharynx biopsies displayed marked lymphocytic T cell-infiltration with several foci of monocellular necrosis in the squamous epithelium. No morphologic evidence of adenocarcinoma and no signs of mycotic, bacterial or viral infection were noted. A blood sample revealed a discrete increase in the erythrocyte sedimentation rate (ESR) with no eosinophilia or leukocytosis. Liver and kidney function panel tests were normal. A thoracoabdominal CT scan reported no evidence of disease recurrence. Despite multiple boluses of methylprednisolone and high doses of prednisone continued for several months, the patient experienced very rapid symptomatological reappearance during three steroid tapering attempts and aggravation of his esophageal stenosis to an aphagic stage, requiring a nasogastric tube. This long course of high-dose corticosteroid treatment was complicated with osteoporosis-induced fractures with several spontaneous compressions of thoracolumbar vertebrae requiring an enlarged T10 to L5 cementoplasty. Anti-IL-6 blockade therapy with tocilizumab resulted in excellent clinical response, allowing the total resolution of the immune-related adverse events (irAEs) and leading to successful steroid tapering.\n\nConclusions\nHerein, we describe the first case of a patient who developed autoimmune mucositis and esophagitis complicated by a severe refractory esophageal stenosis induced during treatment by nivolumab, which completely resolved after personalized treatment with tocilizumab, suggesting a role of IL-6 blockade in the management of severe steroid refractory esophageal stenosis and more broadly in refractory immune-related adverse events.\n\nKeywords\nCheckpoint inhibitorsImmune-related adverse eventsNivolumabPD-1Esophageal stenosisissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nImmune checkpoint inhibitors (CPIs) have brought oncology into a new era by improving the overall survival of several malignancies [1, 2]. Among them, advanced non-small cell lung cancer (NSCLC) has become a major indication for the use of inhibitors of programmed cell death 1 (PD-1) and its ligand (PD-L1). The PD-1/PD-L1 axis is a crucial mediator of immune homeostasis, preventing autoimmune processes in the physiological setting, but also used by cancer to escape cellular immunity [3]. By blocking this T-cell downregulator, the medical community has been facing an entirely new spectrum of drug-induced autoimmune diseases classically reported as immune-related adverse events (irAEs). Although some organ systems are predominantly involved depending on the CPIs used, any organ can be affected [4]. Lower gastrointestinal (GI) tract irAEs, such as diarrhea and colitis, are described in up to one-third of patients treated with inhibitors of cytotoxic lymphocyte associated protein 4 (CTLA-4), with almost 10% of events classified as grade ≥ 3 [5]; however, these irAEs are less frequent and severe with anti-PD1 therapies [6]. In contrast, upper GI tract involvement has been more frequently reported with PD-1 inhibitors, although it is far less common and still poorly characterized. Recently, three cases of severe upper GI tract irAEs have been reported, displaying either gastroesophagitis or mucositis [7–9]. Here, we present the case of an immune mucositis and pharyngitis complicated by severe esophageal stenosis developed during nivolumab treatment and refractory to multiple corticosteroid lines but treated successfully with personalized anti-IL-6 blockade therapy (tocilizumab mAbs). To our knowledge, this is the first case of nivolumab-induced esophageal stenosis subject to personalized tocilizumab treatment reported to date.\n\nCase report\nA 67-year-old male patient diagnosed with stage IV pulmonary adenocarcinoma was first treated with 6 cycles of carboplatin and pemetrexed followed by a maintenance regimen. Progression occurred within fourteen month after the start of the initial treatment. Consequently, second-line nivolumab was initiated at a dose of 3 mg/kg every two weeks.\n\nAfter thirteen doses of nivolumab, the patient complained of irritated red eyes without visual impairment. He did not exhibit skin involvement, arthralgia or urinary tract or digestive symptoms. The conjunctiva swab test was negative, and no improvement was observed with antibiotic ocular drops. The ophthalmologist’s examination revealed bilateral sterile conjunctivitis with no signs of uveitis or retinal lesions (Fig. 1a). The patient was treated with topical steroids with partial improvement.Fig. 1 Patient bilateral conjunctivitis (a) and the esophageal stenosis, 1.5 cm immediately below the upper esophageal sphincter as observed by esophagogastroduodenoscopy (OGD) (b)\n\n\n\nA few days later, he developed fatigue and progressive dysphagia which became severe after two months followed by rapid 10-kg weight loss without symptoms of associated colitis or gastritis. At that point, the main differential diagnosis was esophageal infection, tumor progression with gastrointestinal (GI) upper tract involvement, paraneoplastic syndrome [10] or an atypical checkpoint inhibitor-related adverse event. Of note, the patient had no history of personal or familial autoimmune disease, conjunctivitis or upper digestive tract abnormality prior to nivolumab treatment. The oral examination initially revealed evidence for oral candidiasis, but treatment with a 7-day course of fluconazole did not improve dysphagia despite the resolution of the stomatitis. Bacterial culture of the oropharyngeal swab was negative, and PCR results for herpes simplex 1 and 2 infection were also negative. A blood sample revealed a discrete increase in the erythrocyte sedimentation rate (ESR) with no eosinophilia or leukocytosis. Liver and kidney function panel tests were normal. Thoracoabdominal CT scan reported no evidence of disease recurrence. Due to patient fatigue, a therapeutic break was implemented for one month with the introduction of prednisone at 30 mg per day with rapid tapering over 1 month. Although the patient initially experienced a partial resolution of dysphagia, a quick recurrence of symptoms was noticed as the prednisone dose was tapered. One month later, nivolumab was restarted, and the patient noticed a rapid deterioration of his dysphagia and mucositis. The clinical situation deteriorated despite the introduction of nystatin and steroid mouthwash, and the patient continued to lose weight. An esophagogastroduodenoscopy was done, which revealed diffuse mucositis with a scar-like stenosis immediately below the upper esophageal sphincter (Fig. 1b). Unlike the upper esophagus, the lower part and the stomach were of normal appearance.\n\nBiopsies of the oropharynx were performed, but esophageal dilatation was not performed due to the highly inflammatory mucosal status and patient anticoagulation. Faced with this significant loss of weight and the impossibility of an oral diet, a nasogastric tube was placed. Biopsies of the oropharynx displayed marked lymphocytic inflammation and several foci of monocellular necrosis in the squamous epithelium. Morphologic evidence of adenocarcinoma and signs of mycotic, bacterial or viral infection were not observed. Immunohistochemical stainings were performed in an automated stainer (Benchmark XT; Ventana Medical Systems, Tucson, AZ) using 3 μm-thick sections and the following antibodies: CD45 (monoclonal, clone 2B11 + PD7/26, Dako, Glostrup, Denmark), CD19 (monoclonal, clone BT51E, Novocastra, New Castle, UK), CD20 (monoclonal, clone L26, Novocastra), CD3 (monoclonal, 2GV6, Ventana), CD4 (monoclonal, SP35, Ventana), CD8 (monoclonal, C8/144B, Dako), CD68 (monoclonal, clone KP1, Dako), and PD-1 (polyclonal, R&D System, Inc., Minneapolis, MN, USA). Immunohistochemistry revealed a florid immune infiltrate, predominantly with T cells (90% CD45+CD19−CD20−CD3+), with only 10% of B cells (CD45+CD19+CD20+CD3−). Among T cells, the majority (80%) were CD4+. Few T cells expressed PD-1+. Rare macrophages were also observed (Fig. 2).Fig. 2 Morphological examination of oropharynx biopsies showed marked lymphocytic inflammation of the submucosa (a, original magnification × 40) with infiltration of the epithelial layer, where scattered apoptotic cells were observed (b, original magnification × 200). Immunohistochemical staining revealed that a minor population of lymphocytes (about 10%) was CD20 positive (c, original magnification × 100), while the majority of lymphocytic infiltration (about 90%) was represented by CD3-positive T-cells (d, original magnification × 100). Among T-lymphocytes, about 80% were CD4 positive (e, original magnification × 100) and about 20% were CD8 positive (f, original magnification × 100)\n\n\n\nBased on these results, esophageal stenosis was considered a severe irAE secondary to an important mucosal inflammatory infiltrate. This severe dysphagia required enteral feeding, and nivolumab was permanently discontinued after seventeen doses. The patient was treated with 125 mg methylprednisolone followed by 1 mg/kg oral prednisone (total dose: 80 mg). After 3 days of treatment, the patient reported significant improvement, enabling him to eat solid food. Prednisone was tapered by 20 mg every two weeks until reaching a daily dose of 40 mg after 45 days of prednisone tapering, when he again presented increasing symptoms of severe dysphagia.\n\nThe patient was treated a second time with 125 mg methylprednisolone for 3 days followed by 1 mg/kg oral prednisone (total dose: 80 mg) with amelioration of dysphagia. Three weeks later, after the reduction of prednisone to 60 mg/daily, the patient noticed a new severe dysphagia deterioration, remaining aphagic. In this context, quick endoscopic esophageal dilatation was attempted. The laryngeal margin and hypopharyngeal mucosa appeared highly inflamed with fibrinous deposits on the direct laryngoscopy with no sign of salivary stasis or tumor invasion. Rigid esophagoscopy revealed erythema of the oropharynx with friable nonulcerative mucosa and an inflammatory aspect of the entire esophagus. Concomitant high-dose steroids at a dose of 125 mg of methylprednisolone for 3 days followed by 1 mg/kg prednisone again allowed transient symptomatic improvement.\n\nOne month later, recurrent dysphagia did not permit steroid tapering under 50 mg/d. Furthermore, the long course of high-dose corticosteroid treatment was complicated with severe osteoporosis and several spontaneous compression fractures of thoracolumbar vertebrae. Pathologic fracture due to metastases was ruled out by bone biopsy.An enlarged T10 to L5 vertebral cementoplasty was carried out. One month later due to a new episode of recurrent major dysphagia, the patient received a new bolus of 125 mg of methylprednisolone for 3 days followed by 1 mg/kg prednisone. The serum level of IL-6 was 3.10 pg/ml (normal range < 1.5 pg/ml), measured the same day before tocilizumab administration. Serum levels of IL-6 were assessed by electrochemiluminescence (ECL) Elecsys® IL-6 (Roche; Switzerland) according to the manufacturer instructions.\n\nAt this point, a second line of immunosuppressive treatment was considered. Based on the oropharynx biopsy, histological analysis and the presence of a predominantly T-cell infiltrate, a single intravenous administration of the interleukin 6 receptor (IL-6R) neutralizing antibody tocilizumab at a dose of 8 mg/kg was given. This led to rapid amelioration of the symptomatology, with successful prednisone tapering without recurrent dysphagia. At the present time, 3 months after the administration of tocilizumab, the patient has experienced no relapse of dysphagia. A recent rigid endoscopy confirmed complete resolution of orolaryngopharyngeal and upper esophageal inflammation (Fig. 3).Fig. 3 Patient timeline chart along with key dates for clinical manifestations, specific treatments and investigations. The dose of prednisone (PDN) labelled is the one at which the dysphagia relapse took place before the introduction of tocilizumab. PDN = prednisone, EGD = esophagogastroduodenoscopy, Bx = Biopsy of the oropharynx\n\n\n\nDuring immunosuppressive therapy we observed no tumor progression. Eight months after discontinuing nivolumab treatment, the patient remains in complete remission with no radiographic evidence of tumor relapse.\n\nDiscussion\nClinicians are progressively confronted with new types of irAEs with increasingly pleomorphic presentation [11]. Herein, we report the case of a patient displaying a severe and atypical upper GI tract irAE related to nivolumab immunotherapy. Oral mucositis and upper digestive tract irAEs are likely underestimated in clinical trials due to a lack of reporting given their primarily low-grade presentations. Mild stomatitis and mucositis have been reported in 5 to 9% of patients treated with nivolumab or pembrolizumab [6, 12] in prospective trials. A case of severe mucositis and esophagitis with histological documentation was reported in a patient receiving dose-escalated pembrolizumab (200 mg/arm every 3 weeks) in the Keynote 012 trial [8]. The endoscopic presentation matched ulcerative mucositis. Another patient treated with pembrolizumab for thymoma displayed severe cutaneo-mucositis, including esophagitis, mimicking Steven-Johnson syndrome [9]. The third case of severe upper GI tract irAE described in the literature involved a patient with Hodgkin’s lymphoma presenting diffuse esophagitis and gastritis secondary to nivolumab treatment [7]. All three patients presented heterogeneous clinical patterns, and no case involving esophageal stenosis has been described in the literature to date. Due to the close anatomical proximity of these mediastinal malignancies with the upper GI tract, contiguous collateral inflammation secondary to immune-checkpoint response is not excluded [13]. In contrast, our patient is the only reported patient with a tumor localized at distance from the involved upper GI tract.\n\nThe pathophysiology of irAEs is related to the loss of immune homeostasis, although the precise mechanism remains incompletely characterized. Interestingly, upper GI tract irAEs are mostly described with PD-1 inhibitors in contrast to lower GI tract irAEs, which are more prevalent with CTLA-4 inhibitors. These differences highlight the probability of distinct functions of CTLA-4 and PD-1 in gut immune-homeostasis [4]. Given the increased frequency and severity of ipilimumab-induced colitis, research efforts have been more extensively focusing on these agents. CTLA-4 plays a major role in microbiota immune-tolerance, and reciprocally its expression seems also to be influenced by the quality of the gut flora. In contrast, further research is needed to evaluate the role of PD-1 in the oropharynx and esophageal immune homeostasis. Recent reports suggest that the upper mucosal flora is less sensitive and thus more stable compared with its lower digestive counterpart [14]. The impact of chemotherapy and antibiotics on the lower GI tract microbiota is more pronounced given its increased bacterial load compared with the stomach and esophagus as well as the fact that the oral microbiota is less qualitatively sensitive to these agents [15]. These elements could explain the differences between the incidence of upper and lower GI tract irAEs. The occurrence of dysbiosis may stimulate the immune system, inducing a significant increase in immune activity in patients treated with CPIs. Interestingly, gut colonization with Klebsiella pneumonia isolated from the salivary microbiota in patients with Crohn’s disease induces Th1-driven inflammation in inoculated germ-free mice [16]. In our patient, we cannot exclude that the occurrence of concomitant oral candidiasis may have participated in triggering this irAE.\n\nThe clinical course of our patient was very challenging, with recurring severe symptomatic stenosis of the upper esophagus upon small steroid tapers, requiring each time boluses of methylprednisolone and increased steroid doses. Several agents have been proposed for the management of steroid-refractory or steroid-dependent irAEs, including antibodies blocking tumor necrosis factor alpha (TNFα) or mycophenolate mofetil, but the two molecules have not been approved by the patient’s insurance.\n\nIL-6 is a principal acute inflammatory phase mediator that plays a major role in cytotoxic T-cell differentiation and activation and also exhibits protumor properties [17, 18]. Thus, the use of an IL-6 blockade strategy is particularly interesting given that it offers the advantage of a double effect without potentially compromising the efficacy of immunotherapy. Very interestingly, the combined blockade of IL-6 and PD-1/PD-L1 axe provides the synergistic effects not only on CD4+ Th1 response but also on the recruitment and function of CD8+ T cells in the tumor and its microenvironment [19, 20]. Moreover, the lack of interleukin-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy [21].\n\nAfter a single administration of tocilizumab, our patient showed an excellent response, allowing steroid tapering. Importantly, Stroud et al. proposed tocilizumab as a second-line therapy for irAEs [22]. Clinical improvement was observed in 79.4% of patients, with 52.9% of the patients requiring only a single dose for symptomatic response. Thereby, Stroud et al. proposed tocilizumab as a second-line therapy for steroid-refractory irAEs.\n\nIt is important to point out that pathogenic pro-inflammatory IL-17A-expressing CD4+ T cells subset (c-Kit−CD161+MDR1+ Th17 cells) have been reported to be key effectors of autoimmune inflammation refractory to glucocorticoids [23], which might suggest a role for this Th17 subset in steroid refractory irAEs. Importantly, IL-6 induces the development of Th-17 cells from naïve CD4+ T cells [24]. Thus, the IL-6 - Th-17 pathway could play a major role in the pathogenesis of irAEs, especially in steroid refractory cases.\n\nThis case report supports the use of anti-IL-6 therapy in complicated irAEs with unsatisfactory response to steroids as well as the rationale to use the predominant type of immune infiltrate on the biopsy (in this case T cells) as a biomarker to personalize treatment in steroid-refractory irAEs as we had just proposed in our recent therapeutic personalized algorithm based on selective inhibition of key inflammatory components involved in the pathophysiological processes of irAE without compromising cancer immunotherapy efficiency [25].\n\nIn our patient, the serum level of IL-6 was discreetly high, which is frequently observed in cancer patients [26]. Unfortunately, we do not have a kinetics of IL-6 serum concentrations to follow the temporal variation of IL-6 in our patient throughout this long period of irAEs and more particularly during corticosteroid therapy.\n\nBetween 10 and 20% of patients treated with PD-1 inhibitors develop unpredictable severe complications. At this time, no risk factor has been identified to predict severe irAEs, although some baseline aspects have been noted [27]. Autoimmunity risk is associated with personal or familial history of autoimmune disease; tumor location; and previous history of infections such as HIV, or concomitant medications. These factors have been proposed by Champiat et al. as predisposing factors for the development of irAEs [28]. Few baseline biomarkers have been identified in ipilimumab-treated melanoma patients, such as increased circulating eosinophil count, increased IL-17 blood levels and neutrophil infiltration of the colon lamina propria [29]. Recently, Gowen et al. observed a treatment-specific autoantibody signature using a proteomic microarray approach in the baseline serum from a subset of metastatic melanoma patients who developed severe irAEs [30]. These potential predictive biomarkers and their specificity for CTLA-4 and PD-1 blockade must be further examined in extended studies to confirm previous results and potentially guide immunotherapy management.\n\nTo the best of our knowledge, this is the first case report to detect intraoropharyngeal T cell infiltration followed by durable tumor response during PD-1 blockade therapy. Further studies may reveal whether tocilizumab could be considered also as secondary prevention, allowing to resume ICIs following irAEs.\n\nAbbreviations\nCPIsCheckpoint inhibitors\n\nCTL4Cytotoxic T-lymphocyte-associated protein 4\n\nESRErythrocyte sedimentation rate\n\nGIGastrointestinal\n\nirAEsImmune-related adverse events\n\nNSCLCNon-small cell lung cancer\n\nPD-1Programmed cell death 1\n\nPD-L1Programmed cell death-ligand 1\n\nThe authors would like to thank Dr. Timothy Edney from Morges Hospital.\n\nFunding\nNot applicable\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthor's contributions\nAH wrote the manuscript, MO conceived, wrote the manuscript, and prepared the figures, SLR did the immunostaining work. All authors wrote, commented on and corrected the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable\n\nConsent for publication\nYes\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. Topalian SL Sznol M McDermott DF Kluger HM Carvajal RD Sharfman WH Brahmer JR Lawrence DP Atkins MB Powderly JD Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab J Clin Oncol 2014 32 10 1020 1030 10.1200/JCO.2013.53.0105 24590637 \n2. Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE Chow LQ Vokes EE Felip E Holgado E Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung Cancer N Engl J Med 2015 373 17 1627 1639 10.1056/NEJMoa1507643 26412456 \n3. Okazaki T Chikuma S Iwai Y Fagarasan S Honjo T A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application Nat Immunol 2013 14 12 1212 1218 10.1038/ni.2762 24240160 \n4. Postow MA Sidlow R Hellmann MD Immune-related adverse events associated with immune checkpoint blockade N Engl J Med 2018 378 2 158 168 10.1056/NEJMra1703481 29320654 \n5. Hodi FS O'Day SJ McDermott DF Weber RW Sosman JA Haanen JB Gonzalez R Robert C Schadendorf D Hassel JC Improved survival with ipilimumab in patients with metastatic melanoma N Engl J Med 2010 363 8 711 723 10.1056/NEJMoa1003466 20525992 \n6. Freeman-Keller M Kim Y Cronin H Richards A Gibney G Weber JS Nivolumab in resected and Unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes Clin Cancer Res 2016 22 4 886 894 10.1158/1078-0432.CCR-15-1136 26446948 \n7. Boike J Dejulio T Severe esophagitis and gastritis from Nivolumab therapy ACG Case Rep J 2017 4 e57 28459081 \n8. Acero Brand FZ Suter N Adam JP Faulques B Maietta A Soulieres D Blais N Severe immune mucositis and esophagitis in metastatic squamous carcinoma of the larynx associated with pembrolizumab J Immunother Cancer 2018 6 1 22 10.1186/s40425-018-0332-z 29548299 \n9. Zander T Aebi S Rast AC Zander A Winterhalder R Brand C Diebold J Gautschi O Response to Pembrolizumab in a patient with relapsing Thymoma J Thorac Oncol 2016 11 12 e147 e149 10.1016/j.jtho.2016.07.018 27498287 \n10. Camidge DR The causes of dysphagia in carcinoma of the lung J R Soc Med 2001 94 11 567 572 10.1177/014107680109401104 11691893 \n11. Ghosn J Vicino A Michielin O Coukos G Kuntzer T Obeid M A severe case of neuro-Sjogren's syndrome induced by pembrolizumab J Immunother Cancer 2018 6 1 110 10.1186/s40425-018-0429-4 30348223 \n12. Motzer RJ Escudier B McDermott DF George S Hammers HJ Srinivas S Tykodi SS Sosman JA Procopio G Plimack ER Nivolumab versus Everolimus in advanced renal-cell carcinoma N Engl J Med 2015 373 19 1803 1813 10.1056/NEJMoa1510665 26406148 \n13. Tumeh PC Harview CL Yearley JH Shintaku IP Taylor EJ Robert L Chmielowski B Spasic M Henry G Ciobanu V PD-1 blockade induces responses by inhibiting adaptive immune resistance Nature 2014 515 7528 568 571 10.1038/nature13954 25428505 \n14. Hall MW Singh N Ng KF Lam DK Goldberg MB Tenenbaum HC Neufeld JD GB R Senadheera DB Inter-personal diversity and temporal dynamics of dental, tongue, and salivary microbiota in the healthy oral cavity NPJ Biofilms Microbiomes 2017 3 2 10.1038/s41522-016-0011-0 28649403 \n15. Zaura E Brandt BW Teixeira de Mattos MJ Buijs MJ Caspers MP Rashid MU Weintraub A Nord CE Savell A Hu Y Same exposure but two radically different responses to antibiotics: resilience of the salivary microbiome versus long-term microbial shifts in feces MBio 2015 6 6 e01693 e01615 10.1128/mBio.01693-15 26556275 \n16. Atarashi K Suda W Luo C Kawaguchi T Motoo I Narushima S Kiguchi Y Yasuma K Watanabe E Tanoue T Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation Sci 2017 358 6361 359 365 10.1126/science.aan4526 \n17. Fisher DT Appenheimer MM Evans SS The two faces of IL-6 in the tumor microenvironment Semin Immunol 2014 26 1 38 47 10.1016/j.smim.2014.01.008 24602448 \n18. Landskron G De la Fuente M Thuwajit P Thuwajit C Hermoso MA Chronic inflammation and cytokines in the tumor microenvironment J Immunol Res 2014 2014 149185 10.1155/2014/149185 24901008 \n19. Tsukamoto H Fujieda K Miyashita A Fukushima S Ikeda T Kubo Y Senju S Ihn H Nishimura Y Oshiumi H Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment Cancer Res 2018 78 17 5011 5022 10.1158/0008-5472.CAN-18-0118 29967259 \n20. Mace TA Shakya R Pitarresi JR Swanson B McQuinn CW Loftus S Nordquist E Cruz-Monserrate Z Yu L Young G IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer Gut 2018 67 2 320 332 10.1136/gutjnl-2016-311585 27797936 \n21. Ohno Y Toyoshima Y Yurino H Monma N Xiang H Sumida K Kaneumi S Terada S Hashimoto S Ikeo K Lack of interleukin-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy Cancer Sci 2017 108 10 1959 1966 10.1111/cas.13330 28746799 \n22. Stroud CR, Hegde A, Cherry C, Naqash AR, Sharma N, Addepalli S, Cherukuri S, Parent T, Hardin J, Walker P: Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade. J Oncol Pharm Pract 2017:1078155217745144.\n23. Ramesh R Kozhaya L McKevitt K Djuretic IM Carlson TJ Quintero MA McCauley JL Abreu MT Unutmaz D Sundrud MS Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids J Exp Med 2014 211 1 89 104 10.1084/jem.20130301 24395888 \n24. Bettelli E Carrier Y Gao W Korn T Strom TB Oukka M Weiner HL Kuchroo VK Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells Nature 2006 441 7090 235 238 10.1038/nature04753 16648838 \n25. Martins F, Sykiotis G, M. M, M. F, C. R, T. K, O. M, S. P, G. C, F. S et al: New therapeutic perspectives to manage refractory immune checkpoint-related toxicities. Lancet Oncol. 2018, In press.\n26. Lippitz BE Harris RA Cytokine patterns in cancer patients: a review of the correlation between interleukin 6 and prognosis Oncoimmunology 2016 5 5 e1093722 10.1080/2162402X.2015.1093722 27467926 \n27. Hopkins AM Rowland A Kichenadasse G Wiese MD Gurney H McKinnon RA Karapetis CS Sorich MJ Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers Br J Cancer 2017 117 7 913 920 10.1038/bjc.2017.274 28950287 \n28. Champiat S Lambotte O Barreau E Belkhir R Berdelou A Carbonnel F Cauquil C Chanson P Collins M Durrbach A Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper Ann Oncol 2016 27 4 559 574 10.1093/annonc/mdv623 26715621 \n29. Manson G Norwood J Marabelle A Kohrt H Houot R Biomarkers associated with checkpoint inhibitors Ann Oncol 2016 27 7 1199 1206 10.1093/annonc/mdw181 27122549 \n30. Gowen MF Giles KM Simpson D Tchack J Zhou H Moran U Dawood Z Pavlick AC Hu S Wilson MA Baseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors J Transl Med 2018 16 1 82 10.1186/s12967-018-1452-4 29606147\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-1426",
"issue": "6(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "Checkpoint inhibitors; Esophageal stenosis; Immune-related adverse events; Nivolumab; PD-1",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D003231:Conjunctivitis; D004940:Esophageal Stenosis; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": "156",
"pmc": null,
"pmid": "30587227",
"pubdate": "2018-12-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16648838;29207939;24901008;29967259;29548299;28746799;26412456;26446948;24395888;29320654;26715621;29606147;28950287;24602448;26406148;30348223;11691893;20525992;27797936;27467926;28649403;24590637;27498287;29051379;25428505;26556275;28459081;24240160;27122549",
"title": "A severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy.",
"title_normalized": "a severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy"
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"abstract": "Molar pregnancy or a hydatidiform mole, also referred to as gestational trophoblastic disease, is an abnormal type of pregnancy, in which a potentially anomalous egg is abnormally fertilized resulting in a subsequently non-viable conceptus becoming an enlarged growth in the uterus with dangerous complications. These moles can occur as either complete or partial moles, each with its own unique features. In this article, we report a case of a pregnant woman who presented to her primary care doctor with the chief complaint of shortness of breath. Upon further questioning, she was found to have slight vaginal bleeding. Further workup of the unexplained bleeding revealed a small, yet concerning molar pregnancy, and led to our encounter with the patient on her operating day for a dilation and curettage. As these moles are somewhat rare occurrences, this case report aims to describe the condition, with a focus on management and outcomes.",
"affiliations": "Obstetrics and Gynecology, Touro University Nevada College of Medicine, Las Vegas, USA.;Obstetrics and Gynecology, Women's Health Associates of Southern Nevada, Las Vegas, USA.",
"authors": "Prabhu|Indraneel K|IK|;Rosenbaum|Amy|A|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.10319\nObstetrics/Gynecology\nHydatidiform Mole in a Patient With a Concern for Neoplasia: A Case Report\nMuacevic Alexander Adler John R Prabhu Indraneel K 1 Rosenbaum Amy 2 \n1 \nObstetrics and Gynecology, Touro University Nevada College of Medicine, Las Vegas, USA \n\n2 \nObstetrics and Gynecology, Women’s Health Associates of Southern Nevada, Las Vegas, USA \n\nIndraneel K. Prabhu do21.indraneel.prabhu@nv.touro.edu\n8 9 2020 \n9 2020 \n12 9 e1031917 8 2020 8 9 2020 Copyright © 2020, Prabhu et al.2020Prabhu et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/39380-hydatidiform-mole-in-a-patient-with-a-concern-for-neoplasia-a-case-reportMolar pregnancy or a hydatidiform mole, also referred to as gestational trophoblastic disease, is an abnormal type of pregnancy, in which a potentially anomalous egg is abnormally fertilized resulting in a subsequently non-viable conceptus becoming an enlarged growth in the uterus with dangerous complications. These moles can occur as either complete or partial moles, each with its own unique features. In this article, we report a case of a pregnant woman who presented to her primary care doctor with the chief complaint of shortness of breath. Upon further questioning, she was found to have slight vaginal bleeding. Further workup of the unexplained bleeding revealed a small, yet concerning molar pregnancy, and led to our encounter with the patient on her operating day for a dilation and curettage. As these moles are somewhat rare occurrences, this case report aims to describe the condition, with a focus on management and outcomes.\n\nhydatidiformmolegestational trophoblastic diseasechoriocarcinomamolar pregnancyThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nGestational trophoblastic disease (GTD) is defined as a nonviable conceptus causing a progressively enlarging uterine mass. It can initially present similar to a normal pregnancy: positive pregnancy test, physiologic changes of pregnancy, morning sickness, etc., especially when it is still small, making it easily missed. This is compounded by factors such as limited access to proper obstetric care, inconsistent follow-up, and presence of comorbidities that may confound the symptoms of molar pregnancy (as is the case with this patient). One feared complication of a molar pregnancy is progression to choriocarcinoma, a cancer that commonly metastasizes to the lungs, with some characteristic features detailed later. Although this cancer is quite chemosensitive and has a good prognosis, it is worth discussing molar pregnancy in further detail, so that signs may be recognized early, and an effective diagnostic and a timely treatment plan can be established to optimize outcomes, both mentally and medically, for the patient; this report aims to highlight these details while identifying obstacles to a proper diagnosis.\n\nCase presentation\nThis is a case of 37-year-old G0P0 who presented to a primary care doctor to establish care and for a routine well-visit, but did complain of worsening shortness of breath. She stated that she had had asthma ever since she was a child, well-controlled with an albuterol inhaler, but that for the past few months, her shortness of breath had been getting progressively worse, with only minimal relief with the inhaler. Outdoor exercise seemed to exacerbate her symptoms, and she generally felt “normal” while sitting. Although the symptoms were worse than her usual baseline, the patient described the “discomfort” severity as ~4/10. She did not have any associated chest pain, and the review of systems was negative for fever, chills, diarrhea, musculoskeletal pain, and dysuria but was positive for headache, mild nausea and vomiting, and slight urinary incontinence and frequency. Her family history was noncontributory. Her surgical history is significant for tonsillectomy some time in her early childhood, as well as an elective C-section from a personal request. The patient's social history was noncontributory. She was currently sexually active with her husband, and they did not use any barrier contraceptive method. The patient had no known drug allergies, and she used to take ibuprofen for painful menstrual cycle each month, but told her primary that she had stopped three months prior, as her periods had stopped completely. Further questioning revealed that the patient was pregnant, per a home pregnancy test, and it came to light that she had not had any prenatal or antenatal care. At this point, the patient also mentioned that she had bouts of irregular bloody-brown vaginal discharge that occurred in unpredictable patterns for the past three months, previously occurring regularly in 24-day cycles. This prompted a focused obstetric and gynecologic history and physical examination, with a prompt referral to an obstetrician/gynecologist.\n\nAt her first visit, the routine tests were run, and in addition, a speculum exam was done, along with a pap smear, to fully establish care. Due to her complaint of the bloody-brown discharge, a transvaginal ultrasound was also performed to assess fetal well-being, and was further supplemented with a serum pregnancy test to confirm the initial positive result from the home pregnancy test. On physical exam, the patient had stable vitals. Lungs were mostly clear to auscultation bilaterally, with some wheezing noted on both inspiration and expiration, without rales or rhonchi. An abdominal exam showed mild suprapubic tenderness with distention. The uterus was palpable and was smooth without irregularities, and was consistent with a 20-week gestation (palpable at the umbilicus), though her last menstrual period was 16 weeks prior. The speculum exam showed a closed nulliparous cervix with no discharge or bleeding present in the vaginal vault. The rest of the exam was unremarkable.\n\nLaboratory results (initial antenatal) are presented in Table 1.\n\nTable 1 Initial antenatal laboratory results\nRBC: red blood cell; WBC: white blood cell; Hgb: hemoglobin; hCG: human chorionic gonadotropin; VDRL: venereal disease research laboratory test; CBC: complete blood count; PCR: polymerase chain reaction; Hbs: hepatitis B surface antibody; Hbc: hepatitis B core antibody; HbsAg: hepatitis B surface antigen; hpf: high power field\n\nTest\tValue\t\nUrinalysis + dipstick\tCreatinine 0.9 mg/dL, urea nitrogen 19 mg/dL, negative nitrites, negative leukocyte esterase, specific gravity 1.011, no casts, <3 RBC per hpf, <3 WBC per hpf, negative for protein, mild glucosuria\t\nUrine culture\tNegative for bacteria\t\nRh(D) antibody screen\t(-) for antibodies\t\nHepatitis B\t(+) anti-Hbs antibody, (-) HbsAg, (-) anti-Hbc antibody\t\nRubella\tImmune\t\nVaricella\tImmune\t\nHIV\tNegative\t\nSyphillis\t(-) VDRL\t\nChlamydia\t(-) PCR\t\nSerum beta-hCG\t192,000 mIU/mL\t\nCBC\tRBC count: 4.0 million cells/mcL, Hgb: 11.5 g/dL, Hct: 43.5%, WBC count: 9500 cells/mcL, platelet count: 300,000/mcL\t\nThe transvaginal ultrasound report described a “mass within the uterus with a snowstorm appearance” and noted that “no viable intrauterine pregnancy was seen, with no sign of fetal heart tones that one would expect given the gestational age and serum beta-human chorionic gonadotropin (HCG) levels”. The report also noted “bilateral cystic masses seen in both adnexa, without necrosis of ovaries”. The masses were hypoechoic, fluid filled, and were without septations or calcifications, and measured approximately 3.5 cm in diameter on each side. Due to suspicion for molar pregnancy, a histological sample was obtained from the mass to confirm the diagnosis. Histopathology showed cells with marked cytological atypia, diffuse hydropic villi enlargement, with hyperplasia of the trophoblastic cells within the sample. In addition, many of the hydropic villi exhibited a sort of fibrillary separation within the core, leading to the appearance of being widely separated from one another, described as having a “cistern formation”. Her bilateral adnexal cystic masses were very likely benign theca lutein cysts that resulted from the markedly high levels of beta-HCG within the bloodstream, causing hyperplasia of the theca interna cells within the ovary, and the patient was advised that these would likely resolve with treatment of the molar pregnancy itself. Given the risk for choriocarcinoma, which most commonly metastasizes to lung, and her worsening shortness of breath, a chest X-ray was obtained. The results were unremarkable and thus no further imaging was pursued.\n\nWith the diagnosis of molar pregnancy confirmed by histology, the first priority was to evacuate the mole via dilation and curettage (D&C). An incomplete evacuation could lead to persistent GTD from retained molar tissue. The next step was to monitor that all of the trophoblastic tissue that had proliferated was truly eradicated; beta-HCG monitoring was started, comparing each obtained value to the baseline pre-treatment value of 192,000 mIU/mL. Oral contraceptives were initiated to ensure that any beta-HCG being monitored would be from remnant mole alone, and not a new intrauterine or ectopic pregnancy. The patient was advised on this course of action, and recommended to follow up every week, and she agreed to this plan.\n\nDiscussion\nA molar pregnancy, also known as hydatidiform mole or GTD, is an abnormal, nonviable pregnancy that results from the anomalous fertilization of a potentially empty ovum by one or more sperm. The resulting mole is a benign but rapidly growing mass that is cystic, and can mimic the signs and symptoms of normal pregnancy quite early on, and can therefore go undetected. Once diagnosed, the patient must be treated quickly, as the complications associated with this condition can be life threatening, and there is a risk of malignant transformation to choriocarcinoma.\n\nPartial mole\n\nNormal fertilization is the process by which one single sperm fuses with one single egg, or oocyte, leading to a zygote. This process occurs in the ampulla of the Fallopian tube, and over time, the zygote travels down the Fallopian tube to reach the uterus, where it will implant, leading to a normal pregnancy. Normally, the sperm enters the oocyte through an acrosomal reaction to penetrate the zona pellucida (ZP) and implants. At this point, an important step known as the cortical reaction takes place, with cortical granules in the secondary oocyte releasing into the ZP, causing glycoprotein ZP2 to undergo hydrolysis. The extracellular matrix within the ZP is now known as ZP2f [1], and is tightly cross-linked and impermeable to entry by any new sperm - an important mechanism to prevent polyspermy. Failure of this process can lead to more than one sperm fertilizing the egg and leading to subsequent secondary meiosis with an eventual partial mole. Because partial moles are resultant from (usually) two sperm fertilizing one complete egg (incidence ~3 per 1000 pregnancies) [2], the karyotype generally seen is 69XXX or 69XXY. Since the egg did contain its normal genetic material (compare to section \"Complete mole\"), there will be some fetal parts evident, but not enough to see a living conceptus or any viable organism. More often than not, an amniotic sac will also form, leading to a potential confounder when trying to diagnose this condition on ultrasound, depending on the user’s skill. With the presence of this somewhat normal tissue, the amount of villous edema that is seen is focal in nature, and less widespread than that of a complete mole. The amount of trophoblastic tissue available to proliferate is less so than that of a complete mole, and as such, the uterus does not rapidly enlarge, and without a completely viable fetus, is much smaller than the gestational age would suggest at a given point in time. The beta-HCG levels in a partial mole are not as markedly high as in a complete mole, and as such any medical sequelae resulting from elevated beta-HCG are generally not seen. These include hyperemesis gravidarum (HG), hyperthyroidism, theca lutein cysts, and/or preeclampsia with severe features. Though present, the theoretical risk of progression of a partial mole to full-on choriocarcinoma is less than 2%-3% [2]. There is, however, a 5% risk of persistent GTD, where some of the mole is retained within the uterus even after adequate treatment. Partial moles commonly result in uterine sizes much smaller than what is expected given a particular gestational age, as there is a lack of proliferation of normal fetal tissue.\n\nComplete mole\n\nThere are two main mechanisms by which a complete mole (~1-2 per 1000 pregnancies) can arise [2]. About 85%-90% of the time, normal fertilization occurs, but soon after, the maternal genetic material is destroyed and expelled. The single sperm then duplicates itself, giving rise to the majority monospermic, androgenetic 46XY genotype of the complete mole. The other 5%-10% of the time, two sperm are able to fertilize a normal oocyte, with subsequent destruction/expulsion of the maternal genetic material, leading to the minority dispermic androgenetic 46XY genotype of the complete mole [3]. The overexpression of paternal genes through these mechanisms causes the proliferation of synctiotrophoblasts, and it has been hypothesized that sperm have the genetic code allowing them to proliferate as much as possible to have the highest chance of producing a successful fertilization [4]. The oocyte genes code to maximize the chance of having the successful development of a normal conceptus once fertilization has occurred. There have also been theories supporting the loss of maternal genetic material within an oocyte prior to penetration by any number of sperm, but no data has been found to support these claims. Although triploid karyotypes are in the realm of a genetic possibility for a complete mole, by far the vast majority are diploid with the 46XY genotype. With the maternal chromosomal material being lost in the “fertilization” process, there will not be any fetal parts present, without the normal zygotic tissue, and thus, no amniotic sac will be evident either. The lack of any normal fetal tissue allows for more space for the trophoblastic proliferation of tissue, as evidenced by diffuse proliferation of this tissue, leading to the classic “cistern formation” with widespread hydropic villi throughout the resultant uterine mass. The villi within a complete mole, as seen histologically, do not have a clustered appearance, as the foci of villi in a partial mole would suggest, but rather have a swollen sort of appearance due to the widespread edema within the mass itself.\n\nComplete moles secrete high levels of beta-HCG, much higher than what would be expected of a normal pregnancy, at a given point in time. This proves to have an important role as a tool when trying to diagnose a complete mole. The rapid rise in the beta-HCG level can differentiate this from a normal pregnancy, and is responsible for the potential complications such as hyperthyroid features, HG, theca lutein cysts, and/or preeclampsia with or without severe features. There is also a 6%-32% chance of progression to malignant choriocarcinoma, and about a 12%-15% chance of progression to persistent GTD [5]. These all depend on many patient factors, but must be carefully monitored, as they can all prove to be damaging, or even fatal. Commonly, a complete mole results in a uterus that is much larger in size than what would be expected given a certain gestational age, and must always be included in the differential diagnosis when this is found. There are a few mechanisms that have been proposed as to the development of the proliferative and rather invasive nature of complete moles, namely, placental regulatory factors. Uteroplacental regulators have been studied as a means of communicating between maternal cells and trophoblastic cells in the developing placenta and fetus to maintain normal pregnancy and development. During the first trimester, a relatively hypoxic environment promotes the development of the trophoblast while avoiding the toxicity of oxygen radicals through the reduction of oxidative stress [4]; this allows for the proliferation to not go unchecked and prevents extravillous tissue from becoming invasive. More specifically, the lack of oxygen during the first trimester leads to the upregulation of hypoxia-inducible factor 1-alpha, which in turn activates transforming growth factor (TGF)-beta. TGF-beta, along with another molecule called decorin, is postulated to be responsible for negatively regulating the proliferation and migration of trophoblastic tissue [4]. The rapidly growing tissue within a complete mole potentially has resistance to this negative downregulation of growth by TGF-beta, and is one growingly supported hypothesis for how GTD develops [5]. After around nine weeks of gestation, the partial pressure of oxygen (pO2) of the feto-maternal environment increases to allow for proper spiral artery development and proper perfusion of the placenta, an expected phenomenon [5]. More research in this regard is needed before any cause-and-effect relationships can be definitively drawn.\n\nRisk factors\n\nAlthough the causes of molar pregnancy and hydatidiform moles have not been clearly defined, there are several risk factors that have been proposed and studied. One of the most important factors is having a past history of a complete mole. With a positive history, the risk of developing a complete mole in a subsequent pregnancy is 1%-1.5%, a seemingly small, yet significant number when one considers the implications [6]. This association with a previous occurrence of molar pregnancy has not been linked to partial moles, and the reason behind this has not been well-established. Advanced maternal age is another significant risk factor, with women over the age of 35 being at a slightly elevated risk, and those over the age of 45 having over 2.5 times the risk of that in a 35-year-old pregnant woman [6]. Interestingly, however, the same risk is not seen for mothers at the opposite extreme (young age), for reasons not yet established in the literature. A 2018 study analyzing these risk factors found them to be statistically significant, with P = 0.001, for advanced maternal age, and P = 0.05, for a previous mole [6]. In addition, a molar pregnancy towards the end of the first trimester was a strongly associated risk factor, with P = 0.04. These studies also showed that oral contraceptive use did not reduce or increase the risk of mole formation upon cessation of the contraceptive.\n\nAn interesting link was also tied to the mother’s blood group. A study in 1985 examined the incidence of having both partial and complete moles in mothers with varying blood types. It was found that having a Type A blood group conferred a relative risk (RR) = 1.4, and having Type AB conferred an RR = 2.310 [7]. After stratification for potential confounding by paternal blood typing, both A and AB blood types still showed a statistically significant increased risk for having a molar pregnancy. Interestingly, Type O and Type B blood groupings did not have this same risk increase for molar pregnancy. Researchers have purported potential differences in immunity factors circulating in the bloodstream of mothers with these different blood groups, but a definitive cause has not yet been established. A study conducted in 1987 also found that living in North America seemed to be a protective factor against the development of a mole, be it partial or complete [1]. Living in Europe conferred a slightly higher risk, but was not statistically significant; however, living in Asia had an RR of 1.9 (P < 0.05) for mole development [1]. One theory suggested was the lack of access to adequate healthcare in many of the countries that were studied. However, the same study posited that it was not a lack of medical resources, but rather a deficiency in vitamin A and carotene in the world outside of North America that caused these findings. Though vitamin A in excess can be quite teratogenic, women who consumed a diet with carotene levels slightly higher than the daily recommended value (DRV) had an RR of 0.6 (P < 0.02), for molar pregnancy [1], showing a statistically significant protective benefit. The reverse also proved to be true: a deficiency of carotene showed a statistically significantly elevated risk of GTD.\n\nA few other less studied risk factors have also been put forth by researchers, and much less data on these claims exists, but for completeness will be briefly discussed here. A 2017 study sought to analyze paternal factors potentially increasing the risk of a molar pregnancy [8]. Of all the factors studied, the only statistically significant finding was the father having a job that required physical labor involving dust and soil, with an odds ratio (OR) of 18.2 (P < 0.001). The researchers involved noted in their discussion that further studies would need to examine why this relationship existed, as the number of confounding variables was indeterminate at the time of study.\n\nDiagnosis\n\nAs in the case of most clinical cases, a thorough history and physical exam should be considered the utmost gold standard when diagnosing and managing a patient. This became even more evident in the case of this patient, where the chief complaint led to a nearly nonexistent index of suspicion for a molar pregnancy. The patient volunteered information about her pregnancy status as well as bloody vaginal discharge only after being prompted through a thorough interview, and led to the subsequent workup. This workup was extensive, as the patient had never established prenatal or antenatal care, and bleeding from the vagina was concerning for threatened or missed abortion. As the speculum exam was normal in this patient, the next step, in addition to tests listed in Table 1, was a transvaginal ultrasound and a serum beta-HCG level, used to properly confirm and date the pregnancy. Given the patient’s account of her last menstrual period, the finding of a markedly elevated beta-HCG level, and uterine size significantly larger than expected given her gestational age, a list of differentials began to form, which included partial and complete hydatidiform moles. The transvaginal ultrasound, which uses a transducer, or “wand” to send sound waves throughout the pelvis, shows a characteristic “bunch of grapes” appearance or “snowstorm” pattern, nearly pathognomonic for GTD.\n\nA definitive answer is via biopsy and histological examination, and together with the clinical snapshot of the patient makes for the diagnosis. Histology can not only confirm the diagnosis of a mole, but can also quickly differentiate between a partial and a complete one. A partial mole is generally small, and contains less than 250-300 cc of trophoblastic tissue. As the maternal DNA is still present, there is a somewhat normal amount of fetal tissue present, with an associated placenta, and can be seen under a microscopic examination. With the presence of fetal parts, there is less space for trophoblastic tissue to unnecessarily proliferate, and this is seen in the form of foci of edematous villi that stay contained without becoming widespread. There is little to no cytological atypia within a partial mole. Complete moles, however, have no normal tissue and no fetal parts, giving a large space (approximately 500-600 cc of tissue) to proliferate; this is evidenced by the widespread, diffuse enlargement of hydropic villi and edema. The edema pushes aside many cellular structures and contributes to the classic “central cistern” formation. Complete moles have a much higher risk of malignant transformation, owing much of this risk to the marked cytological atypia seen under a microscope.\n\nComplications\n\nMost, if not all, of the complications from GTD arise due to the markedly elevated beta-HCG levels. At physiologically appropriate levels, beta-HCG maintains pregnancy by upkeep of the corpus luteum, allowing for progesterone secretion until around week 10, when the placenta can make its own. It is also responsible for stimulating Leydig cells to produce testosterone in the male fetus, steroidogenesis in the placenta and adrenal glands, and the maternal thyroid to continue normal functioning during pregnancy. When these levels stay persistently elevated and unchecked, problems begin to arise.\n\nTheca Lutein Cysts\n\nTheca interna cells of the ovary are normally responsible for secreting androgens and estrogens via pregnenolone intermediates, and are responsive to beta-HCG during pregnancy. When beta-HCG levels are persistently and markedly elevated, these cells continue to respond and undergo hyperplasia from the sustained stimulus. This rapid enlargement is most commonly bilateral and creates adnexal masses known as theca lutein cysts. These are mostly benign, usually found incidentally on transvaginal or abdominal ultrasound when examining the ovaries, and are simple, fluid-filled cysts. While most are asymptomatic, patients can complain of feelings of adnexal fullness or peritoneal irritation if the cysts rupture. Due to the mass effect of cysts greater than 3 cm, there is also the risk of ovarian torsion, which would be a medical emergency, but is rare with these cysts in particular, as they rupture before this can happen. It has been documented that women who smoke are at a higher risk of having larger theca lutein cysts as well [9]. Treatment is generally supportive as the cysts resolve once the levels of beta-HCG come back to baseline, which is usually after the pregnancy ends.\n\nHyperthyroidism\n\nBeta-HCG normally stimulates the maternal thyroid to meet the increased metabolic demand of having a growing fetus, but lies on a fine balance. Too much beta-HCG can cause hyperthyroidism, ranging from mild symptoms to overt thyrotoxicosis. The basis for this is the structural homology between these two molecules. Although their alpha subunits differ, the beta subunits of both HCG and thyroid stimulating hormone (TSH) share 85% sequence identity, which explains why beta-HCG has such a high, let alone any, thyrotropic activity. HCG’s beta subunit in addition contains a 31 amino acid extension on the carboxy terminal that has been theorized to attenuate how much thyrotropic activity the molecule actually has [9]. A study has shown that a recombinant version of HCG that lacks this amino acid sequence at the carboxy terminal has nearly the same activity level at the TSH receptor as TSH itself [10]. Normally in pregnancy, increased estrogen levels lead to increased thyroid binding globulin (TBG) production, and thus, the “total” thyroid hormone levels are increased, as the thyroid gland pushes more hormone out as more is bound to TBG. However, the measurement of “free” T3 and T4 will still be normal, and no symptoms of hyperthyroidism are seen. The symptoms that should prompt further investigation include sweating, heat intolerance, diarrhea, tremor, anxiety, palpitations, weight loss (especially in pregnancy, where the norm would be weight gain), etc. With the most common cause of this being Grave’s disease, a workup for TSH receptor stimulating antibodies should be undertaken, prior to suspecting trophoblastic tumors. Thyroid storm should be suspected with hyperthermia, new onset atrial fibrillation, confusion, coma, or severe restlessness, and should be managed with supportive measures and medications immediately. As with theca lutein cysts, the risk of hyperthyroidism and its sequelae is effectively eliminated once the beta-HCG stimulus resolves with the evacuation of the tumor.\n\nHyperemesis Gravidarum\n\nMorning sickness, or a mild amount of nausea/vomiting in pregnancy, is considered a normal effect of beta-HCG, but can pose dire risks for the mother when this becomes persistent. HG is characterized by extreme and persistent nausea and vomiting that can lead to dehydration, weight loss, and life-threatening electrolyte imbalances, and is considered a medical emergency, with an incidence of about 1.5%-3% worldwide [11]. This condition typically occurs before the 20th week of pregnancy, since the first trimester is when beta-HCG levels are the highest. Risks include a prior history of HG, family history of HG, twin gestations (higher HCG levels than a single pregnancy), and hydatidiform moles. Although generally a diagnosis of exclusion, loss of 5% of pre-pregnancy body weight combined with ketosis from dehydration and inability to consume calories precludes further testing and warrants hospitalization to stabilize the patient. Laboratory values generally show metabolic alkalosis resulting from stomach acid loss through continuous vomiting, and vitamin deficiencies become common with prolonged vomiting. Thus, management involves supportive measures with IV fluid administering to maintain hydration status and blood pressure stability, repletion of vitamins such as thiamine and pyridoxine to prevent Wernicke’s encephalopathy or peripheral neuropathy, and anti-emetics combined with small-portioned dry foods to attenuate emesis. Should the above management not prove sufficient, complications of severe HG can be seen in the form of anemia, hyponatremia and its sequelae, Mallory-Weiss tears from continuous vomiting, hypoglycemia, and malnutrition. These can pose risks to the fetus as well, in the event of a normal pregnancy, in the form of slow growth and failure to thrive. In our patient’s case, she had mild nausea and vomiting, and none of the other signs of HG, so further workup in this regard was unnecessary.\n\nPreeclampsia\n\nPreexisting hypertension can be exacerbated by pregnancy, and can lead to growth restriction for the fetus, along with a host of maternal complications. When a pregnant mother has no preexisting hypertension, but develops it after 20 weeks of gestation, this is known as gestational hypertension. If the mother is also found to have new onset proteinuria with signs of end organ damage, this now becomes categorized as preeclampsia. One mechanism by which preeclampsia occurs is through placental hypo-perfusion leading to a hypoxic state, causing constriction of spiral arteries. Although there are many ways this can occur, the invasion and overgrowth of trophoblastic tissue can compress spiral arteries recreating this same hypoxic environment, thus either directly causing, or exacerbating existing preeclampsia [11]. Risks for developing preeclampsia include prior history of preeclampsia, preexisting hypertension, gestational hypertension, kidney disease, tobacco use, advanced maternal age, obesity, multiple gestations, and diabetes mellitus. The treatment for preeclampsia without severe features is the management of blood pressure and delivery at term (37 weeks). Severe features of preeclampsia include systolic blood pressure greater than 160 mm Hg or diastolic greater than 110 mm Hg, thrombocytopenia, elevated liver enzymes with associated right upper quadrant pain, new-onset pulmonary edema, elevated creatinine, visual changes, or cerebral changes/deficits. One feared outcome is progression to full-blown eclampsia, which involves life-threatening seizures, so recognition and management of this condition is vital to positive maternal and fetal outcomes. The treatment for preeclampsia with severe features is strict management of blood pressure with plans for delivery at 34 weeks. Most, if not all, cases resolve with delivery. There has been evidence to show that giving low-dose aspirin starting at 12 to 16 weeks of gestation in high-risk patients can improve risks of developing preeclampsia [12]. In the case of our patient, she was normotensive and did not show any signs of end organ damage or proteinuria, so close monitoring was sufficient in this regard.\n\nChoriocarcinoma\n\nMalignant transformation of a complete mole can occur in 6%-32% of cases [4]. Half the occurrences of choriocarcinoma arise from a preexisting complete hydatidiform mole; spontaneous abortions make up 20% of the remaining cases and ectopic pregnancies account for about 2.5%-3% of cases. Normal pregnancies account for approximately 25%-30% of cases as well [4]. Therefore, a major risk factor is trophoblastic disease and, if recognized early, can be crucial to positive outcomes for the mother. Stage I disease is limited to the uterus, Stage II is spread to the cervix and vagina, Stage III is single-organ metastasis (most commonly lungs), and Stage IV is multi-organ metastasis (usually liver and brain). As this tumor is the result of chromosomal material of paternal origin, like most male-specific tumors, it is quite chemosensitive. While D&C can prove effective for moles, the presence of malignant tissue calls for a more thorough eradicative approach. For low-risk moles, generally Stage I, methotrexate has proven adequate. By inhibiting dihydrofolate reductase, methotrexate is able to inhibit DNA synthesis, and rapidly dividing cancer cells are unable to effectively do so any longer. A popular chemotherapeutic regimen for more advanced disease is the etoposide, methotrexate, actinomycin, cyclophosphamide, and vincristine (EMACO) combination regimen. A 1991 study aimed to demonstrate the efficacy of this regimen, and found that when compared to those undergoing a different regimen for trophoblastic disease, the EMACO regimen yielded an 82% remission rate, following the cohort to demonstrate an 85% survival rate [13]. For those acquiring drug resistance, it was shown that the addition of cisplatin could salvage 82% of the remaining subjects without surgery, whereas salvage surgery alone could save 87%, but came with its own risks. The toxicity and drug interactions of these chemotherapy agents are quite well known and predictable, and the benefits of using them to treat advanced choriocarcinoma almost always outweigh the risks of doing so. Our patient did not show signs of malignant transformation, and therefore did not require more advanced treatment. When there is a high index of suspicion for malignant transformation, it must be considered metastatic until proven otherwise. Choriocarcinoma has a tendency to spread to the lungs most commonly, and less so to the brain. In the case of our patient, though she had asthma to possibly explain her shortness of breath, a spread to the lungs of potential choriocarcinoma had to be ruled out, with the initial step being a chest X-ray. If there were truly metastases causing her dyspnea, they would be evident as classic “cannonball metastases”, which was not the case for our patient. The presence of findings on X-ray would then prompt an immediate high-resolution CT scan of the chest to localize the lesions and set up a treatment plan, and serves as a baseline to track therapeutic progress. CT scans are also important when staging the spread to less common regions of the body. Brain metastasis has been well-documented for this disease, and generally presents with new-onset headaches, visual changes, neurologic deficits, and seizures that prompt an imaging workup of the area. CT and MRI can be and have been used, depending on availability and stability of the patient. It is important to note that these imaging studies should be used as a pre-treatment baseline, with close follow-up and re-imaging to ensure eradication of malignant cells.\n\nTreatment\n\nThe centerpiece of treatment of molar pregnancy is removing the mole from the body in its entirety. The two methods utilized are uterine evacuation in the form of a D&C, or a complete hysterectomy, each with its pros and cons. A D&C is preferred in younger women who prefer to maintain their fertility, and is recommended for women not of advanced age, and who have partial moles. When the risk of progression to gestational trophoblastic neoplasia is increased, as in the case of age greater than 40 or in cases of a complete mole, then a hysterectomy is the preferred choice [14]. Although hysterectomy nearly eliminates the risk of local neoplasia, some women already have occult metastasis that goes undetected, and must be considered if symptoms arise after the uterus has been removed. This is supported by a study that looked at malignant transformation of moles and it was found that in complete moles removed by a D&C, there was a 55% recurrence rate due to retained tissue, with a 0% recurrence rate in those patients who underwent total abdominal hysterectomy [15]. After our conversation with our patient, a D&C was decided on, as the patient still wanted to preserve her fertility for some years, and did not want to undertake the risks of having an invasive surgery if she could avoid it. Medical management alone should not be used, as a study showed that nearly 26.2% of cases managed solely with medication required a surgical consult within the next five years, compared to only 3.8% of initial surgically managed patients [15].\n\nPrior to surgery, patients with various complications resulting from the molar pregnancy should have them effectively controlled. For instance, overt hyperthyroidism should prompt administration of a beta blocker such as propranolol to prevent surgery-induced thyroid storm. Preeclampsia with or without severe features should have tightly controlled blood pressure throughout the surgery, and magnesium sulfate should always be on hand in the case of eclampsia-related seizures. In the case of a partial mole, traces of fetal blood may be present within the normal portion of the placenta, and this could result in feto-maternal blood mixing; the clinician should take care to administer anti-D immunoglobulin should the mother be RhD negative (seen in this patient with a negative initial antibody screen) to prevent sensitization and alloimmunization in future pregnancies. With a D&C, disruption of the mole can cause quickly progressive hemorrhage, and this can be more so than that of a normal pregnancy. For this reason, oxytocin is given soon after the anesthesiologist sedates the patient, to constrict the spiral arteries and prevent bleeding; blood should be typed and cross-matched, ready to transfuse the patient if needed. This can be augmented with uterine massage transabdominally during the evacuation process. After the D&C is complete, a final check of the uterine cavity should be undertaken to ensure a complete removal of trophoblastic tissue, and the removed mass should be sent to pathology for examination. In the case of uncontrollable hemorrhage, one can consider immediately moving to hysterectomy, or less commonly, embolization of the uterine arteries. Hysterectomy is generally done laparoscopically to improve healing time, but runs the risk of injuring the ureters, as they are in close proximity to the surgeon’s workspace. With a transabdominal approach, symptomatic theca lutein cysts that can commonly be present can be drained or removed to prevent advancement to a torsion.\n\nFollow-up of the patient postoperatively to monitor beta-HCG levels is a crucial part of appropriately managing the patient. The beta-HCG level should return to baseline, while on contraception, over a period of some months, had the operation been successful at evacuating all traces of the trophoblastic tissue. The beta-HCG levels should be monitored weekly until the levels are undetectable or reach an acceptable plateau, with protocol described as the following: undetectable HCG levels for three consecutive weeks. If either of these criteria are met, then continued monitoring monthly is done for three months, and then no further if levels stay low; for a partial mole, monthly monitoring is done for one month and then done no further. For our particular patient, her prior medical history included migraines and a contraindication to estrogen-containing contraceptives. Intrauterine devices are relatively contraindicated, as they can worsen bleeding and place the patient at risk of uterine perforation, should the mole have invaded the uterine wall. As such, the patient was counseled on starting a progestin-only mini pill, supplemented by condom use, and followed the described protocol.\n\nOutcomes\n\nGTD with mole formation is a relatively rare occurrence, and has complications that warrant concern and close monitoring, but generally has a good prognosis with early intervention. When our patient was given her diagnosis of a complete hydatidiform mole, her biggest concern was preservation of her fertility, evidenced by her aversion to hysterectomy, and risk for other gestational complications in the future. A review between 1965 and 2013 by the New England Trophoblastic Disease Center [16], which followed 667 pregnancies in women who had been treated for molar pregnancy, found statistically significant outcomes listed in Table 2.\n\nTable 2 Outcomes following a molar pregnancy\nData is taken from [16].\n\nSignificant outcomes\t \t\nLive term births\t66.9%\t\nSpontaneous abortions\t18.3%\t\nPremature preterm deliveries\t6.6%\t\nOther abortion unspecified\t4.2%\t\nStillbirth\t1.5%\t\nRepeat molar pregnancy\t1.5%\t\nEctopic pregnancy\t1.0%\t\nFor our particular patient, other than her complete mole, her only true risk factor for any sort of gestational complications was her advanced maternal age, and as it stood, she had a very good chance of having a normal pregnancy with proper prenatal and antenatal care. Watchful management of the other listed complications was appropriate. A thorough staging workup for choriocarcinoma would not be required for most people, but extra precautions were taken with this patient who presented with shortness of breath, later found to be simple asthma exacerbation from the cold and dry winter air in the desert environment. Adding inhaled corticosteroids to her short-acting beta agonist inhaler helped curb these extra symptoms, which was a reassuring sign on her path to recovery.\n\nThe progression to choriocarcinoma from a complete mole lies between 6% and 32%, a wide and disconcerting range for those with GTD. However, for those diagnosed with malignant transformation, the prognosis still remains very good. The use of chemotherapy does not pose any increased risk of fetal malformation from baseline. For Stage I choriocarcinoma, single-agent chemotherapy cured 83% of patients in an analysis between 1985 and 2013 [12], with the other 17% also achieving complete remission with additional chemotherapy or surgery. In Stage II through IV choriocarcinoma, all patients were cured, but required surgery and additional chemotherapy from the base management algorithm. Recurrence rates of neoplastic disease are listed at 5%-10% of cases, with those at the higher end of the spectrum being due to large initial tumor burden, delayed care, and patients not adherent to therapy [17]. It is important to note that a PET scan should be considered in recurrent cases, to differentiate between new active tumors and the fibrotic plaques resulting from past tumors and chemotherapy induced fibrosis.\n\nOur patient showed strict compliance with treatment guidelines, and attended all appointments scheduled for her. She reported taking her progestin-only mini pill every day at the same time upon waking up, and continued to be watchful for any relapse of symptoms or new symptoms that arose. At her two-week follow-up, beta-HCG levels had reduced drastically, and showed a promising downward trend, reducing the likelihood of there being any remnant tissue or malignant tissue, though that risk was not zero. The patient was advised that after her beta-HCG levels stabilize, it was in her best interest to not try to become pregnant for one year, to allow the uterus and placenta to normalize, best increasing her chance for a normal pregnancy while reducing any of the negative outcomes listed in Table 2. It has also been recommended that a beta-HCG level should be checked six weeks postpartum in future pregnancies, for mothers who have had a history of GTD.\n\nConclusions\nMolar pregnancies are rare occurrences, but the index of suspicion should be high when a patient presents with unexplained vaginal bleeding after a positive serum pregnancy test, symptoms of hypothyroidism, hyperemesis gravidarum, dyspnea, or uterine size discrepancy given a particular gestational age. Suspected moles can be mostly ruled in with a transvaginal ultrasound; however, definitive diagnosis requires histopathological evaluation after an adequate biopsy. After diagnosis, surgical management is the cornerstone of treatment, either in the form of a D&C to evacuate the uterus of trophoblastic contents, or a hysterectomy. Fortunately, for our patient, the evacuation of the mole and subsequent beta-HCG testing while on contraception were without further complications.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Molecular Biology of the Cell: A Problems Approach Wilson JH Hunt T New York Garland Science 2002 https://books.google.co.in/books/about/Molecular_Biology_of_the_Cell.html?id=BFv6QwAACAAJ&redir_esc=y \n2 Management of molar pregnancy J Prenat Med Cavaliere A Ermito S Dinatale A Pedata R 15 17 3 2009 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279094/ 22439034 \n3 Pathology of molar pregnancy In Reproductive Health 3 2020 Vassilakos P Geneva Geneva Foundation for Medical Education and Research 1993 https://www.gfmer.ch/Books/Reproductive_health/Mole.html \n4 Diagnosis and treatment of gestational trophoblastic disease: ACOG Practice Bulletin No. 53 Gynecol Oncol Soper JT Mutch DG Schink JC for the American College of Obstetricians and Gynecologists 575 585 93 2004 15196847 \n5 The hydatidiform mole Cell Adh Migr Candelier JJ 226 235 10 2016 26421650 \n6 Prevalence and factors associated with hydatidiform mole among patients undergoing uterine evacuation at Mbarara Regional Referral Hospital Obstet Gynecol Int Mulisya O Roberts DJ Sengupta ES 9561413 2018 2018 https://www.hindawi.com/journals/ogi/2018/9561413/ 29805452 \n7 ABO blood-groups and the risk of gestational trophoblastic disease Tumori Parazzini F La Vecchia C Franceschi S Pampallona S Decarli A Mangili G Belloni C 123 126 71 1985 https://www.ncbi.nlm.nih.gov/pubmed/2988164 2988164 \n8 Risk factors for hydatidiform mole: is husband’s job a major risk factor? Asian Pac J Cancer Prev Shamshiri Milani H Abdollahi M Torbati S Asbaghi T Azargashb E 2657 2662 18 2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747385/ 29072060 \n9 Thyrotropic action of human chorionic gonadotropin Thyroid Yoshimura M Hershman JM 434 437 5 1995 https://www.ncbi.nlm.nih.gov/pubmed/8563483 \n10 Hyperthyroidism and pregnancy BMJ Marx H Amin P Lazarus JH 663 667 336 2008 18356235 \n11 Hyperemesis Gravidarum. StatPearls [Internet] Jennings LM Krywko D Treasure Island, FL StatPearls Publishing 2020 https://www.ncbi.nlm.nih.gov/books/NBK532917/ \n12 Molecular mechanisms for preeclampsia J Pregnancy Vitoratos N Hassiakos D Iavazzo C 298343 2012 2012 22523688 \n13 Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989 Br J Obstet Gynaecol Newlands ES Bagshawe KD Begent RH Rustin GJ Holden L 550 557 98 1991 1651757 \n14 Molecular genetic studies of complete hydatidiform moles Transl Pediatr Carey L Nash BM Wright DC 181 188 4 2015 26835372 \n15 Risk factors for complete molar pregnancy from a case-control study Am J Obstet Gynecol Berkowitz RS Cramer DW Bernstein MR Cassells S Driscoll SG Goldstein DP 1016 1020 152 1985 4025447 \n16 Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from the New England Trophoblastic Disease Center J Reprod Med Vargas R Barroilhet LM Esselen K Diver E Bernstein M Goldstein DP Berkowitz RS 188 194 59 2014 https://www.researchgate.net/publication/263295204_Subsequent_Pregnancy_Outcomes_After_Complete_and_Partial_Molar_Pregnancy_Recurrent_Molar_Pregnancy_and_Gestational_Trophoblastic_Neoplasia_An_Update_from_the_New_England_Trophoblastic_Disease_Center 24937955 \n17 Single-agent methotrexate chemotherapy for the treatment of nonmetastatic gestational trophoblastic tumors Am J Obstet Gynecol Lurain JR Elfstrand EP 574 579 172 1995 7856688\n\n",
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"issue": "12(9)",
"journal": "Cureus",
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"medline_ta": "Cureus",
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"pubdate": "2020-09-08",
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"title": "Hydatidiform Mole in a Patient With a Concern for Neoplasia: A Case Report.",
"title_normalized": "hydatidiform mole in a patient with a concern for neoplasia a case report"
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"literaturereference": "PRABHU IK AND ROSENBAUM A. HYDATIDIFORM MOLE IN A PATIENT WITH A CONCERN FOR NEOPLASIA: A CASE REPORT. CUREUS. 2020?12(9)",
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"abstract": "OBJECTIVE\nTo report a case of toxic epidermal necrolysis (TEN) associated with acetaminophen ingestion.\n\n\nCONCLUSIONS\nA seven-year-old girl developed TEN after acetaminophen ingestion. The diagnosis was based on clinical evaluation and skin biopsy. A later acetaminophen challenge, undertaken by an allergist who questioned the diagnosis, resulted in a similar skin reaction.\n\n\nCONCLUSIONS\nTEN is a severe disease with a high mortality rate. TEN may be either idiopathic or associated with several clinical conditions, such as viral infections, autoimmune disorders, malignancy, and drug hypersensitivity. Because of the rarity of its association with acetaminophen, the diagnosis in our patient was questioned by an allergist who performed an oral acetaminophen rechallenge test despite the potential risk. This caused a severe skin reaction that required rehospitalization.\n\n\nCONCLUSIONS\nTEN can be caused by over-the-counter medications such as acetaminophen. Rechallenge with the causative drug carries a risk of severe complications and should be avoided.",
"affiliations": "Department of Pediatrics, Schneider Children's Medical Center of Israel, Beilinson Campus, Petah Tiqva.",
"authors": "Halevi|A|A|;Ben-Amitai|D|D|;Garty|B Z|BZ|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "United States",
"delete": false,
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"issue": "34(1)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D002648:Child; D005260:Female; D005334:Fever; D006801:Humans; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "32-4",
"pmc": null,
"pmid": "10669183",
"pubdate": "2000-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic epidermal necrolysis associated with acetaminophen ingestion.",
"title_normalized": "toxic epidermal necrolysis associated with acetaminophen ingestion"
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}
],
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},
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"literaturereference": "HALEVI A, BEN-AMITAI D, GARTY BZ. TOXIC EPIDERMAL NECROLYSIS ASSOCIATED WITH ACETAMINOPHEN INGESTION. ANN PHARMACOTHER. 2000;JAN;34(1):32-4",
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{
"abstract": "A 32-year-old woman was diagnosed HIV positive with disseminated cryptococcal infection in May 2006. Her initial CD4 was 7 cells/µL and she had a right supraclavicular nodal mass, which was biopsied and shown to be consistent with cryptococcal lymphadenitis. She was treated for disseminated cryptococcal infection and was started on antiretroviral medications subsequently. Two years later, she developed a left supraclavicular mass. Her CD4 count was 320 cells/µL and HIV RNA level was undetectable. Investigations and biopsy results were consistent with a late presentation of cryptococcal immune reconstitution inflammatory syndrome (IRIS). She was treated with oral corticosteroids and her symptoms resolved completely. IRIS is a recognised complication of HIV treatment and occurs in a significant percentage of patients within the first 3 months of starting antiretroviral therapy. This case report illustrates the importance of recognising late presentations of IRIS. It is vital to differentiate true cryptococcal lymphadenitis from IRIS-induced cryptococcal lymphadenitis.",
"affiliations": "Department of GUM/HIV, Betsi Cadwaladr University Health Board, Bangor, UK.;Department of Genito-Urinary and HIV Medicine, Abertawe Bro Morgannwg University Health Board, Singleton Hospital, Swansea, South Wales, UK.",
"authors": "Sethupathi|Meenakshi|M|;Yoganathan|Kathir|K|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D019380:Anti-HIV Agents",
"country": "England",
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"issue": "2015()",
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"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000305:Adrenal Cortex Hormones; D000328:Adult; D019380:Anti-HIV Agents; D003453:Cryptococcosis; D005260:Female; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008199:Lymphadenitis; D009333:Neck",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25564633",
"pubdate": "2015-01-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17488505;17704683;15750393;21029993;18317001;20677939;23242412;22310819;12099747;16321643",
"title": "Late onset of cryptococcal cervical lymphadenitis following immune reconstitution inflammatory syndrome in a patient with AIDS.",
"title_normalized": "late onset of cryptococcal cervical lymphadenitis following immune reconstitution inflammatory syndrome in a patient with aids"
} | [
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{
"abstract": "Levetiracetam is an anti-epileptic drug commonly used in intensive care when seizure is suspected as a possible cause of coma. We propose to question the cofounding effect of Levetiracetam during the prognostication process in a case of anoxic coma. We report the story of a young woman presenting a comatose state following a hypoxic cardiac arrest. After a first EEG presenting an intermediate EEG pattern, a seizure suspicion led to prescribe Levetiracetam. The EEG showed then the appearance of burst suppression, which was compatible with a very severe pattern of post-anoxic coma. This aggravation was in fact related to an overdose of Levetiracetam (the only medication introduced recently) and was reversible after Levetiracetam cessation. The increased plasmatic dosages of Levetiracetam confirming this overdose could have been favoured by a moderate reduction of renal clearance, previously underestimated because of a low body-weight. This EEG dynamic was unexpected under Levetiracetam and could sign a functional instability after anoxia. Burst suppression is classically observed with high doses of anaesthetics, but is not expected after a minor anti-epileptic drug. This report proposes that Levetiracetam tolerance might not be straightforward after brain lesions and engages us to avoid confounding factors during the awakening prognostication, which is mainly based on the severity of the EEG. Hence, prognosis should not be decided on an isolated parameter, especially if the dynamic is atypical after a new prescription, even for well-known drugs. For any suspicion, the drug's dosage and replacement should be managed before any premature care's withdrawal.",
"affiliations": "Hospices Civils de Lyon, Hopital de la Croix Rousse, Service de Reanimation Médicale, Lyon, France.;Hospices Civils de Lyon, Hopital de la Croix Rousse, Service de Neurologie, Lyon, France, France; Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France.;Hospices Civils de Lyon, Hopital de la Croix Rousse, Service de Reanimation Médicale, Lyon, France; Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France.;Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France; Hospices Civils de Lyon, Hopital Pierre Wertheimer, Service des Explorations Fonctionnelles Neurologique, Bron, France.;Hospices Civils de Lyon, Hopital de la Croix Rousse, Service de Reanimation Médicale, Lyon, France; Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France. Electronic address: gobert.flo@gmail.com.",
"authors": "Bouchier|Baptiste|B|;Demarquay|Geneviève|G|;Guérin|Claude|C|;André-Obadia|Nathalie|N|;Gobert|Florent|F|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clineuro.2016.11.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-8467",
"issue": "152()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Awakening prognosis; Burst suppression; Levetiracetam; Overdose; Post anoxic coma",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D003128:Coma; D062787:Drug Overdose; D004569:Electroencephalography; D005260:Female; D006323:Heart Arrest; D006801:Humans; D000860:Hypoxia; D000077287:Levetiracetam; D010889:Piracetam",
"nlm_unique_id": "7502039",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "27842229",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Marked EEG worsening following Levetiracetam overdose: How a pharmacological issue can confound coma prognosis.",
"title_normalized": "marked eeg worsening following levetiracetam overdose how a pharmacological issue can confound coma prognosis"
} | [
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{
"abstract": "Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a newly recognized provisional entity included in mature B-cell neoplasm in the latest 2016 World Health Organization Classification. It has a self-limited growth potential with a high predilection for oral cavities and occurs in age-related or iatrogenic immunodeficiency with indolent clinical courses. However, it shares histological features with EBV-positive diffuse large B-cell lymphoma (DLBCL), and this often leads to diagnostic challenges and controversies in patients with an oral EBV-positive B-cell neoplasm. The aim of this study was to better characterize and comprehend the pathophysiology of DLBCL and EBVMCU in the oral cavity. We conducted clinicopathologic and recurrent gene mutation analysis of 49 cases (14 EBV positive, 35 EBV negative), including cases diagnosed as DLBCL or B-cell lymphoproliferative disorders with high-grade morphology in the oral cavity. All EBV-positive cases matched the criteria of EBVMCU, with significantly earlier clinical stages than the EBV-negative group (P=.0006). Besides, histological analysis showed that all EBV-positive cases presented polymorphous features, whereas 91.4% (32/35) of the EBV-negative cases showed diffuse and monotonous proliferation (P<.0001). Furthermore, EBV-positive cases presented favorable clinical outcomes without disease-related death or recurrence. Gene mutation analysis (MYD88, CD79A, CD79B, CARD11, and EZH2) revealed that 33.3% (9/27) of EBV-negative cases harbored at least 1 gene mutation, whereas no gene mutation was observed in the EBV-positive group (0/11). These results suggest that oral EBV-positive B-cell lymphoid proliferation with polymorphous features often fulfill the criteria for EBVMCU, with clinicopathologically and genetically distinctive properties.",
"affiliations": "Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.;Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Department of Analytical Information of Clinical Laboratory Medicine, Graduate School of Health Care Science, Bunkyo Gakuin University, 1-19-1, Mukougaoka, Bunkyo-ku, Tokyo 113-8668, Japan.;Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.;Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Institute of Education, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.;Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.;Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.;Division of Surgical Pathology, Tokyo Medical and Dental University Hospital, 1-5-45 Yushima, Bunkyo-ku Tokyo 113-8519, Japan.;Department of Clinical pathology, Japanese Red Cross Musashino Hospital, 1-26-1 Kyonan-cho, Musashino-City, Tokyo, 180-0023, Japan.;Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.;Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.;Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.;Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Electronic address: yamamoto.pth2@tmd.ac.jp.",
"authors": "Ohata|Yae|Y|;Tatsuzawa|Anna|A|;Ohyama|Yoshio|Y|;Ichikawa|Ayako|A|;Mochizuki|Yumi|Y|;Ishibashi|Sachiko|S|;Itakura|Yuri|Y|;Sakurai|Urara|U|;Sakamoto|Kei|K|;Ikeda|Tohru|T|;Kitagawa|Masanobu|M|;Yamamoto|Kouhei|K|",
"chemical_list": "D014408:Biomarkers, Tumor",
"country": "United States",
"delete": false,
"doi": "10.1016/j.humpath.2017.09.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0046-8177",
"issue": "69()",
"journal": "Human pathology",
"keywords": "Diffuse large B-cell lymphoma; EBV+ mucocutaneous ulcer; Epstein-Barr virus; Gene mutation; Lymphoproliferative disorders; Oral malignant lymphoma",
"medline_ta": "Hum Pathol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D049109:Cell Proliferation; D003937:Diagnosis, Differential; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms; D009154:Mutation; D060787:Neoplasm Grading; D019226:Oral Ulcer; D011237:Predictive Value of Tests",
"nlm_unique_id": "9421547",
"other_id": null,
"pages": "129-139",
"pmc": null,
"pmid": "28993276",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A distinctive subgroup of oral EBV+ B-cell neoplasm with polymorphous features is potentially identical to EBV+ mucocutaneous ulcer.",
"title_normalized": "a distinctive subgroup of oral ebv b cell neoplasm with polymorphous features is potentially identical to ebv mucocutaneous ulcer"
} | [
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{
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] |
{
"abstract": "An 80-year-old man with no personal or family history of bleeding, presented to hospital with extensive haematomas and skin bruising after using doxycycline. His basic lab workup was concerning for a coagulopathy with an elevated activated partial thromboplastin time and significant anaemia. Mixing studies and other factor levels were tested that led to the diagnosis of acquired haemophilia A with low factor VIII levels and high factor VIII antibodies. He was started on steroids, but his haemoglobin level continued to drop. Later, during his treatment, he was given multiple therapeutic agents, including cyclophosphamide, rituximab and recombinant factor VII (NovoSeven-R). Gradually factor VIII levels increased and haemoglobin stabilised. The hospital course was complicated by COVID-19 pneumonia leading to acute respiratory distress syndrome; the patient eventually expired due to respiratory failure.",
"affiliations": "Internal Medicine, HSHS Saint John's Hospital, Springfield, Illinois, USA ejazmohiudeenshah@gmail.com.;Haematology and Oncology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.;Haematology and Oncology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.;Haematology and Oncology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.",
"authors": "Shah|Ejaz|E|;Abro|Calvin|C|;Zaidi|Fawwad|F|;Goel|Ruchika|R|",
"chemical_list": "D004318:Doxycycline",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-244748",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(10)",
"journal": "BMJ case reports",
"keywords": "drugs and medicines; haematology (incl blood transfusion); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000086382:COVID-19; D004318:Doxycycline; D006467:Hemophilia A; D006801:Humans; D008297:Male; D010314:Partial Thromboplastin Time; D000086402:SARS-CoV-2",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34598965",
"pubdate": "2021-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Doxycycline-induced acquired haemophilia A.",
"title_normalized": "doxycycline induced acquired haemophilia a"
} | [
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{
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],
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"reaction": [
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Neutropenic sepsis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Renal failure",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Acquired haemophilia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Haematoma",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Coagulopathy",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Contusion",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
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{
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},
{
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],
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},
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"literaturereference": "Shah E, Abro C, Zaidi F, Goel R.. Doxycycline-induced acquired haemophilia A.. BMJ-Case-Rep. 2021;14:10",
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},
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}
] |
{
"abstract": "BACKGROUND\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe adverse drug reactions with high mortality.\n\n\nMETHODS\nTo present the clinical characteristics of SJS and TEN in Japan and evaluate the efficacy of treatments, we retrospectively analyzed cases of SJS and TEN treated in 2 university hospitals during 2000-2013.\n\n\nRESULTS\nFifty-two cases of SJS (21 males and 31 females; average age, 55.1 years) and 35 cases of TEN (17 males and 18 females; average age, 56.6 years) were included in this study. Twenty-eight cases of SJS (53.8%) and all cases of TEN were caused by drugs. Hepatitis was the most common organ involvement in both SJS and TEN. Renal dysfunction, intestinal disorder, and respiratory disorder were also involved in some cases. The major complication was pneumonia and sepsis. All cases except for 3 cases were treated systemically with corticosteroids. Steroid pulse therapy was performed in 88.6% of TEN. Plasmapheresis and/or immunoglobulin therapy was combined with steroid therapy mainly in TEN after 2007. The mortality rate was 6.9% and the rates for SJS and TEN were 1.9% and 14.3%, respectively. These were much lower than predicted mortality according to a severity-of-illness scoring system for TEN prognosis (SCORTEN) score. When comparing the mortality rate between 2000-2006 and 2007-2013, it was decreased from 4.5% to 0.0% in SJS and from 22.2% to 5.3% in TEN.\n\n\nCONCLUSIONS\nTreatment with steroid pulse therapy in combination with plasmapheresis and/or immunoglobulin therapy seems to have contributed to prognostic improvement in SJS/TEN.",
"affiliations": "Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan. Electronic address: yumiko@dream.design.co.jp.;Department of Dermatology, Yokohama City University Medical Center, Kanagawa, Japan.;Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.;Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.;Department of Dermatology, Yokohama City University Medical Center, Kanagawa, Japan.;Department of Dermatology, Yokohama City University Medical Center, Kanagawa, Japan.;Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan; Ai Dermatology and Allergy Clinic, Kanagawa, Japan.;Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.",
"authors": "Yamane|Yumiko|Y|;Matsukura|Setsuko|S|;Watanabe|Yuko|Y|;Yamaguchi|Yukie|Y|;Nakamura|Kazuko|K|;Kambara|Takeshi|T|;Ikezawa|Zenro|Z|;Aihara|Michiko|M|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1323-8930",
"issue": "65(1)",
"journal": "Allergology international : official journal of the Japanese Society of Allergology",
"keywords": "Cause; Mortality; Stevens–Johnson syndrome; Toxic epidermal necrolysis; Treatment",
"medline_ta": "Allergol Int",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009026:Mortality; D012189:Retrospective Studies; D012867:Skin; D013262:Stevens-Johnson Syndrome; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9616296",
"other_id": null,
"pages": "74-81",
"pmc": null,
"pmid": "26666483",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in 87 Japanese patients--Treatment and outcome.",
"title_normalized": "retrospective analysis of stevens johnson syndrome and toxic epidermal necrolysis in 87 japanese patients treatment and outcome"
} | [
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"abstract": "Gastric cancer with peritoneal carcinomatosis is a disease with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) can improve prognosis, although in most cases this should still be considered as a palliative treatment. Therefore, morbidity has to be avoided at all cost as quality of life is of utmost importance. We describe the case of a 64-year-old female with an adenocarcinoma of the stomach that was initially treated with a Billroth II gastrectomy, adjuvant chemotherapy and radiotherapy. During follow-up, the diagnosis of peritoneal carcinomatosis was made, and the patient was referred for CRS and HIPEC. Postoperatively, she developed rhabdomyolysis in both gastrocnemius muscles. Renal function remained within normal limits, but ultrasonography of the lower legs suggested the presence of bilateral abscesses. Drainage with pigtail catheters was necessary for more than 1 month, significantly impairing quality of life. The objective of this case report is to heighten awareness for this complication. Rhabdomyolysis is a rare complication of CRS and HIPEC, with a significant impact on quality of life. Prevention is necessary and can be achieved by adequate surgical positioning, using the altered lithotomy position, sufficient padding and by preventing hypovolemia.",
"affiliations": "Department of Surgical Oncology, University Hasselt, Diepenbeek, Belgium.",
"authors": "Bielen|Rob|R|;Verswijvel|Geert|G|;Van der Speeten|Kurt|K|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000346471cro-0006-0036Published online: January, 2013Rhabdomyolysis after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Case Report Bielen Rob aVerswijvel Geert bVan der Speeten Kurt ac*aDepartment of Surgical Oncology, University Hasselt, Diepenbeek, BelgiumbDepartment of Radiology, Ziekenhuis Oost-Limburg, Genk, University Hasselt, Diepenbeek, BelgiumcDepartment of Biomed Research Institute, Faculty of Medicine, University Hasselt, Diepenbeek, Belgium*Kurt Van der Speeten, Department of Surgical Oncology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, BE-3600 Genk (Belgium), E-Mail kurt.vanderspeeten@zol.beJan-Apr 2013 18 1 2013 18 1 2013 6 1 36 44 Copyright © 2013 by S. Karger AG, Basel2013This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No-Derivative-Works License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Gastric cancer with peritoneal carcinomatosis is a disease with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) can improve prognosis, although in most cases this should still be considered as a palliative treatment. Therefore, morbidity has to be avoided at all cost as quality of life is of utmost importance. We describe the case of a 64-year-old female with an adenocarcinoma of the stomach that was initially treated with a Billroth II gastrectomy, adjuvant chemotherapy and radiotherapy. During follow-up, the diagnosis of peritoneal carcinomatosis was made, and the patient was referred for CRS and HIPEC. Postoperatively, she developed rhabdomyolysis in both gastrocnemius muscles. Renal function remained within normal limits, but ultrasonography of the lower legs suggested the presence of bilateral abscesses. Drainage with pigtail catheters was necessary for more than 1 month, significantly impairing quality of life. The objective of this case report is to heighten awareness for this complication. Rhabdomyolysis is a rare complication of CRS and HIPEC, with a significant impact on quality of life. Prevention is necessary and can be achieved by adequate surgical positioning, using the altered lithotomy position, sufficient padding and by preventing hypovolemia.\n\nKey Words\nGastric cancerPeritoneal carcinomatosisCytoreductive surgeryHyperthermic intraperitoneal perioperative chemotherapyRhabdomyolysisCompartment syndrome\n==== Body\nBackground\nGastric cancer with peritoneal carcinomatosis (PC) has a poor prognosis. Median survival with systemic treatment is reported to be less than 3 months [1]. In the past, cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) improved prognosis of patients with isolated PC from other primary tumors [2–5]. In locally advanced gastric cancer with serosal or lymph node invasion, but without established PC, CRS + HIPEC was also associated with a better outcome according to three randomized controlled trials [6–8]. The same concept was then applied to gastric cancer with established PC. Several studies suggested that CRS and HIPEC could improve survival of these patients, with an acceptable morbidity and mortality [9, 10]. Patient selection is of utmost importance [11, 12]. Preoperative imaging and intraoperative staging systems estimating the extent of PC correlate with morbidity and mortality [13, 14]. Completeness of cytoreduction (CCR) and the experience of the surgical team also influence the outcome significantly, improving survival and lowering the risk of complications [15].\n\nComplications relate to both surgery and chemotherapy [16]. We report on a rare but important complication namely rhabdomyolysis. The reported incidence of rhabdomyolysis after surgery varies widely between 0.67% in laparoscopic nephrectomy and 37–77% in gastric bypass [17, 18]. The use of different diagnostic criteria is responsible for the wide variation between these data. In the first article, rhabdomyolysis was only diagnosed after patients’ complaints, whereas in the second article, creatinine kinase (CK) values were measured in all patients and rhabdomyolysis was defined as an increase of more than 5 times the upper limit. Nevertheless, body mass index is recognized as a significant risk factor [18]. Prolonged surgery and certain surgical positions are also identified risk factors for rhabdomyolysis [19]. The aim of this report is to heighten awareness for this complication.\n\nCase Description\nPresentation\nA 64-year-old female presented with an invasive adenocarcinoma of the stomach. She was treated with a Billroth II gastrectomy, followed by radiotherapy and chemotherapy. Pathology reported invasion of both lymphatic and blood vessels (T3N2M0). Adjuvant treatment was well tolerated. Six months later, the patient started complaining about diffuse abdominal pain. Initially, no focus was identified. Biochemistry remained within normal limits. Another 4 months later, a follow-up CT suggested peritoneal recurrence of the gastric carcinoma. PC was described caudal from the right hepatic lobe and anterior of the distal one-third of the sigmoid. Enlarged lymph nodes were demonstrated para-aortic. Chest X-ray was normal. A PET-CT was not executed because of the low sensitivity and specificity in gastric cancer, especially after gastrectomy [20].\n\nTreatment\nThe patient was referred for CRS and HIPEC after multidisciplinary consultation. She was placed in the modified lithotomy position and had intermittent compression stockings on both legs to improve venous return. Induction of anesthesia included the administration of propofol, fentanyl and rocuronium bromide intravenously. Anesthesia was maintained with target-controlled infusion of propofol. The peritoneal carcinomatosis index (PCI) according to Sugarbaker added up to a total score of 12 [21, 22]. A complete cytoreduction (CCR 0.1) was achieved. Then, HIPEC was administered by the open technique. The peritoneum was perfused with icodextrin 1.5% until a uniform intraperitoneal temperature of 41.5°C was managed. Subsequently, 78 mg of cisplatinum (50 mg/m2) and 23.4 mg of doxorubicin (15 mg/m2) were administered in three doses over a total of 90 min. During the operation, the patient stayed hemodynamically stable with a total blood loss of 900 ml. Fluid loss was compensated by 4,500 ml of crystalloid, 2,000 ml of colloid and 350 ml of whole blood transfusion. Diuresis remained above 1 ml/kg/h all the time. The total operating time was 10 h and the anesthetic time was 10 h and 50 min. The patient was transferred to the intensive care unit in a stable condition.\n\nPostoperative Course\nDuring the first 24 h postoperatively, the patient had a urine output of 1,500 ml. Biochemistry revealed an elevated serum CK of 2,175 U/l (normal range: 26–140 U/l) on day 0, which is not unusual after CRS and HIPEC. However, on postoperative day 1, CK levels further increased to a maximum of 9,079 U/l and urine testing revealed a myoglobinuria. The diagnosis of rhabdomyolysis was made. After removal of the peridural catheter on day 2, the patient started to complain of severe pain in both calves and paresthesias in her feet. Clinical examination of the lower legs demonstrated normal plantar and dorsiflexion, and normal arterial pulsations, excluding a compartment syndrome. Venous duplex ultrasonography excluded deep venous thrombosis but demonstrated hyperechoic areas within the muscles (fig. 1). Monitoring of the CK levels showed a gradual decline to 190 U/l on day 9. Renal function stayed within normal limits the whole time. Later on, the patient developed bilateral sterile abscesses in the gastrocnemius muscles as a complication of the rhabdomyolysis. The abscesses were punctured and drained with a pigtail catheter under the guidance of ultrasonography (fig. 2, fig. 3). Eventually the drains were removed, and the patient could be discharged after 1 month and 10 days. She was readmitted after 3 days with the same complaints, and a new ultrasonography-guided puncture was performed. Analgesics were administered if necessary, and after 8 more days in the hospital, the patient went home with the drains in situ. After 2 weeks, the catheters were permanently removed at the outpatient clinic.\n\nDiscussion\nGastric cancer with PC is a disease with a poor prognosis [1]. CRS and HIPEC can improve prognosis with acceptable mortality, morbidity and quality of life [9, 10, 23, 24]. In 2009, Glehen et al. [3] reported a multicenter cohort study of 1,290 patients with PC. CRS combined with HIPEC could achieve long-term survival in selected patients. However, they reported differences in outcome according to the primary tumor that caused PC. Gastric cancer had the poorest prognosis. In a subanalysis, Glehen et al. [9] investigated specifically those patients with PC from gastric cancer. They demonstrated a median survival of 9.2 months, which increased to 15 months in patients with CCR 0.1. In a phase III randomized clinical trial of patients with PC from gastric cancer, Yang et al. [10] reported medium survivals of 11.0 months in the CRS and HIPEC group, opposite to 6.5 months for CRS alone. In 2011, Gill et al. [24] reviewed all previous studies of CRS and HIPEC as a treatment for PC from gastric cancer. A total of ten studies were included, and analysis demonstrated a median survival of 7.9 months. Survival increased to 15 months for patients with CCR 0.1. Thus, it is possible to obtain a significant increase of survival. Patient selection is essential as CCR after CRS and HIPEC is the most important prognostic factor regardless of the origin of PC [11–13].\n\nHowever, at present, CRS combined with HIPEC should be considered as a palliative treatment in most patients with PC from gastric cancer. Next to survival, morbidity and quality of life become equally important in this setting. Morbidity is graded according to the National Common Terminology Criteria for Adverse Events (NCTCAE®) [25]. In a review of morbidity after CRS and HIPEC, Glockzin et al. [16] state that the incidence of major morbidity (grades III and IV) is relatively high, but comparable to the incidence of morbidity in any other major surgery. Several independent factors, such as CCR, PCI and experience of the surgical team, are correlated with morbidity and mortality. CCR 0.1 not only improves survival, but is also associated with a lower morbidity [9–11]. Low PCI scores increase the feasibility of CCR 0.1, with possibly less extensive surgery [14, 26]. The experience of the surgical team influences the risk of morbidity, as there is a long learning curve for CRS and HIPEC [27]. Postoperative morbidity lowers quality of life. When patients recover from CRS + HIPEC, quality of life will also restore, and after 3–4 months, most patients return to baseline or better functioning [28, 29]. However, postoperative complications can significantly decrease quality of life, and this must be avoided at all times.\n\nMost complications are surgery-related and/or a consequence of chemotherapy. In this case, we present a rare complication namely rhabdomyolysis of the lower legs. Rhabdomyolysis is defined as necrosis of skeletal muscle fibers with release of the fiber contents into the blood and urine [30]. There are many different etiologies for this condition: traumatic crush injury, hereditary muscle enzyme defects, several drugs and toxins, as well as metabolic endocrine disorders [31]. Another important etiology is prolonged immobilization, as in surgery. Persistent muscle hypoxemia due to unrelieved pressure on gravity-dependent body parts leads to a depletion of adenosine triphosphate (ATP) in the myocytes. Malfunction of a series of pumps and channels that regulate intracellular calcium levels, leads to an unregulated increase in intracellular calcium. This results in the activation of calcium-dependent neutral proteases, followed by destruction of myofibrillar, cytoskeletal and membrane proteins, ending in the disintegration of the myocytes [32]. The necrosis of muscle cells and loss of capillary wall integrity then results in transudation and exudation, ending in massive edema within the muscle compartment [33]. The edema increases the pressure within the compartment, affecting the vascular supply and forming a vicious cycle [21, 34, 35]. Further, when surgical procedures are terminated, ischemia-reperfusion injury and the following localized tissue edema can result in a continued low perfusion state in the local tissue bed [30, 33]. Additionally, a systemic hypovolemia is produced through the loss of intravascular fluid in local tissue beds further compromising perfusion. Finally, because of reperfusion, large quantities of myoglobin, potassium, phosphate, CK, lactate dehydrogenase and urate leak into the circulation, potentially leading to acute renal failure, cardiotoxicity or other complications [19, 33, 35]. This condition must not be confused with compartment syndrome. In compartment syndrome, high pressures within a muscle compartment compromise vascular supply [36, 37]. This leads to loss of peripheral arterial pulsations and neurological symptoms like paresthesias, muscular weakness or paralysis. A compartment syndrome can lead to rhabdomyolysis, and vice versa [19, 38]. However, compartment syndrome and rhabdomyolysis also exist separately. Further investigation is necessary to identify the factors that determine the exact relationship between rhabdomyolysis and compartment syndrome.\n\nRhabdomyolysis has been described as a complication of renal, neurosurgical and bariatric surgery [17, 18, 38–42]. Several risk factors are reported: obesity, prolonged duration of surgery, surgical positioning, hypovolemia, diabetes and hypertension. Firstly, morbid obesity is a major risk factor, as a body mass index of more than 30% of the ideal already increases the risk of developing rhabdomyolysis [41]. The extra weight puts substantial pressure on the muscle mass [42]. Other mechanisms related to the metabolic derangement could also be involved [18, 42]. Secondly, prolonged duration of surgery is correlated with a higher incidence of rhabdomyolysis. In 1986, a study of Harris et al. [43] demonstrated that skeletal muscle tolerates ischemia for 2 h. Thereafter, ultrastructural ischemic changes occur. After 4–6 h, these changes become irreversible [44]. Thirdly, surgical positioning is also important. Various case reports in multiple disciplines describe rhabdomyolysis after prolonged surgery in different positions [17–19, 38, 41, 45]. They all indicate a correlation between surgical position, surgical length and the risk of rhabdomyolysis. Accordingly, prolonged pressure on particular muscle groups leads to rhabdomyolysis. Finally, diabetes and hypertension may increase the risk of rhabdomyolysis by leading to chronic microcirculation abnormalities [18, 38]. This leads to a higher susceptibility to perfusion problems and is a predisposing factor for rhabdomyolysis.\n\nThe outcome of rhabdomyolysis is correlated to an early diagnosis [46, 47]. A high level of awareness is crucial. Treatment is focused on preserving renal function. Because of the tendency to develop hypovolemia, aggressive fluid replacement is essential [33, 39]. Urine output should be monitored by placing a urinary catheter. Then, intravenous fluids are administered by a rate of 500–1,000 ml/h to ensure a urine output greater then 150–300 ml/h [47, 48]. However, if oliguria persists, fluid overload should also be avoided. The exact composition of the fluid regimen is still under discussion. In animal studies, urinary alkalinization by using sodium bicarbonate has positive effects [49]. Empirically, the administration of mannitol is also defendable as it induces osmotic diuresis as well as renal vasodilatation and is involved in free radical scavenging, although there is a risk of acidifying the urine [50]. However, clinical superiority has not been shown for these therapies when compared to the administration of normal saline solution [51]. Another point of importance is the prevention or treatment of electrolyte disorders. Particularly the control of hyperkalemia is important to prevent cardiotoxicity. Potassium can be removed from the body by kaliuresis (loop diuretics) and intestinal potassium binders [33]. In rare cases, when the kidneys no longer respond to these supportive measures, temporary dialysis can be necessary. If a compartment syndrome is present, a decompressive fasciotomy is necessary [48].\n\nAs discussed above, CRS and HIPEC is in most cases a palliative treatment for PC from gastric cancer. Therefore, prevention of complications is important. Not only because they decrease the prognosis, but also because they lower the quality of life in patients with a shortened life expectancy. There are several hypothetical methods to prevent rhabdomyolysis in this specific setting. However, morbid obesity, diabetes and hypertension cannot be changed rapidly. Hypovolemia and surgical positioning are the only two modifiable risk factors. Hypovolemia can simply be prevented by monitoring fluid loss during the operation and replacing this loss sufficiently. To reduce the risk of rhabdomyolysis by surgical positioning, various methods are proposed. Firstly, generous padding of all pressure points effectively lowers the risk of rhabdomyolysis, if properly executed [40, 45, 52]. Secondly, the modified lithotomy position increases the risk of rhabdomyolysis and compartment syndrome of the lower legs. Therefore, this position should not be used if possible. Nevertheless, if necessary, an altered lithotomy position is proposed, with support at the feet instead of the knees or lower legs by the use of St. Mark's leg holders, thereby effectively lowering the compartment pressure [37]. Another benefit of this altered position is the impossibility of compressing the lower popliteal veins. Finally, although intermittent pneumatic stockings lower pressure in the muscle compartment, in prolonged surgery one should consider not to use them during the whole operating time [53], as they eventually become a source of friction and pressure themselves.\n\nConclusion\nThis report presents a case of rhabdomyolysis after treatment for PC from gastric cancer with CRS and HIPEC. In most cases, this is a palliative treatment, thus it is essential that quality of life is secured. Therefore, all morbidity should be prevented. Rhabdomyolysis is a rare complication of CRS and HIPEC, but it can significantly decrease quality of life. Prevention is necessary and can be achieved by adequate surgical positioning, using the altered lithotomy position, sufficient padding and by preventing hypovolemia.\n\nDisclosure Statement\nThe authors declare that they have no competing interests.\n\nFig. 1 Ultrasound image of the proximal gastrocnemius muscles in the axial plane: collection with hyper- and hypoechoic areas (arrows), suggesting abscess formation.\n\nFig. 2 Ultrasound image of an 18-gauge Chiba® puncture needle within the proximal gastrocnemius muscles in the axial plane. Ultrasonography-guided puncture of the abscess was followed by insertion of an 8F-pigtail catheter to drain the collection. This procedure was performed in both legs.\n\nFig. 3 8F-pigtail catheters draining the sterile abscesses in the proximal gastrocnemius muscles.\n==== Refs\nReferences\n1 Sadeghi B Arvieux C Glehen O Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE I multicentric prospective study Cancer 2000 88 358 363 10640968 \n2 Verwaal VJ van Ruth S de Bree E van Slooten GW van Tinteren H Boot H Zoetmulder F Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer J Clin Oncol 2003 21 3737 3743 14551293 \n3 Glehen O Gilly FN Boutitie F Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy Cancer 2010 116 5608 5618 20737573 \n4 Portilla G Barrios P Rufian S Management of peritoneal surface malignancy with cytoreductive surgery and perioperative intraperitoneal chemotherapy Eur J Surg Oncol 2006 32 628 631 16682169 \n5 Kusamara S Younan R Baratti D Costanzo P Favaro M Gavazzi C Deraco M Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion: analysis of morbidity and mortality in 209 peritoneal surface malignancies treated with closed abdomen technique Cancer 2006 106 1144 1153 16456817 \n6 Yonemura Y de Aretxabala X Fujimura T Intraoperative chemothermic peritoneal perfusion as an adjuvant to gastric cancer: final results of a randomized controlled study Hepatogastroenterology 2001 48 1176 1182 11490827 \n7 Yu W Whang I Chung HY Averbach A Sugarbaker PH Indications for early postoperative intraperitoneal chemotherapy of advanced gastric cancer: results of a prospective randomized trial World J Surg 2001 25 985 990 11571980 \n8 Fujimoto S Takahashi M Mutou T Kobayashi K Toyosawa T Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in patients with advanced gastric carcinoma Cancer 1999 85 529 534 10091726 \n9 Glehen O Gilly FN Arvieux C Peritoneal carcinomatosis from gastric cancer: a multi-institutional study of 159 patients treated by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy Ann Surg Oncol 2010 17 2370 2377 20336386 \n10 Yang XJ Huang CQ Suo T Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial Ann Surg Oncol 2011 18 1575 1581 21431408 \n11 Piso P Glockzin G von Breitenbuch P Patient selection for a curative approach to carcinomatosis Cancer 2009 15 236 242 \n12 Saxena A Yan TD Morris DL Critical assessment of preoperative and operative risk factors for complications after iterative peritonectomy procedures Eur J Surg Oncol 2010 36 309 314 19615849 \n13 Cotte E Passot G Gilly FN Glehen O Selection of patients and staging of peritoneal surface malignancies World J Gastrointest Oncol 2010 2 31 35 21160814 \n14 Verwaal VJ Van Tinteren H Ruth SV Zoetmulder AN Toxicity of cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy J Surg Oncol 2004 85 61 67 14755505 \n15 Kerscher AG Mallalieu J Pitroff A Kerscher F Esquivel J Morbidity and mortality of 109 consecutive cytoreductive procedures with hyperthermic intraperitoneal chemotherapy (HIPEC) performed at a community hospital World J Surg 2010 34 62 69 20020294 \n16 Glockzin G Schlitt HJ Piso P Peritoneal carcinomatosis: patient selection, perioperative complications and quality of life related to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy W J Surg Oncol 2009 7 5 \n17 Glassman DT Merriam WG Trabulsi EJ Byrne D Gomella L Rhabdomyolysis after laparoscopic nephrectomy JSLS 2007 11 432 437 18237506 \n18 Dornas de Oliveira L Diniz MT Diniz MD Savassi-Rocha AL Camargos ST Cardoso F Rhabdomyolysis after bariatric surgery by Roux-en-Y gastric bypass: a prospective study Obes Surg 2009 19 1102 1107 19096900 \n19 Alterman I Sidi A Azamfirei L Copotoiu S Ezri T Rhabdomyolysis: another complication after prolonged surgery J Clin Anesth 2007 19 64 66 17321931 \n20 Ha TK Choi YY Song SY Kwon SJ F18-fluorodeoxyglucose-positron emission tomography and computed tomography is not accurate in preoperative staging of gastric cancer J Korean Surg Soc 2011 81 104 110 22066108 \n21 Portilla AG Shigeki K Dario B Marcello D The intraoperative staging systems in the management of peritoneal surface malignancy J Surg Oncol 2008 98 228 231 18726882 \n22 Elias D Souadka A Fayard F Mauguen A Dumont F Honore C Goere D Variation in the peritoneal cancer index scores between surgeons and according to when they are determined (before or after cytoreductive surgery) Eur J Surg Oncol 2012 1 6 \n23 Yang XJ Li Y Yonemura Y Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy to treat gastric cancer with ascites and/or peritoneal carcinomatosis: Results from a Chinese center J Surg Oncol 2010 101 457 464 20401915 \n24 Gill RS Al-Adra D Nagendran J Campbell S Shi X Haase E Schiller D Treatment of gastric cancer with peritoneal carcinomatosis by cytoreductive surgery and HIPEC: a systematic review of survival, mortality and morbidity J Surg Oncol 2011 104 692 698 21713780 \n25 National Cancer Institute: Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, DHHS. May 29, 2009 NIH publication # 09–7473.\n26 Casado-Adam A Alderman R Stuart A Chang D Sugarbaker PH Gastrointestinal complications in 147 consecutive patients with peritoneal surface malignancy treated by cytoreductive surgery and perioperative intraperitoneal chemotherapy J Surg Oncol 2011 2011 468698 \n27 Smeenk RM Verwaal VJ Zoetmulder FA Learning curve of combined modality treatment in peritoneal surface disease Br J Surg 2007 94 1408 1414 17631678 \n28 Piso P Glockzin G Von Breitenbuch P Popp FC Dahlke MH Schlitt HJ Nissan A Quality of life after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies J Surg Oncol 2009 100 317 320 19697438 \n29 McQuellon RP Russel GB Shen P Stewart JH Saunders W Levine EA Survival and health outcomes after cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for disseminated peritoneal cancer of appendiceal origin Ann Surg Oncol 2008 15 125 133 18030535 \n30 Guis S Mattei JP Cozzone PJ Bendahan D Pathophysiology and clinical presentations of rhabdomyolysis Joint Bone Spine 2005 72 382 391 16214072 \n31 Allison RC Bedsole DL The other medical causes of rhabdomyolisis Am J Med Sci 2003 326 79 88 12920439 \n32 Wrogemann K Pena SD Mitochondrial calcium overload: a general mechanism for cell-necrosis in muscle diseases Lancet 1976 1 672 674 73643 \n33 Bosch X Poch E Grau JM Rhabdomyolisis and acute kidney injury N Engl J Med 2009 361 62 72 19571284 \n34 Chung JH Ahn KR Park JH Lower leg compartment syndrome following prolonged orthopedic surgery in the lithotomy position Korean J Anesthesiol 2010 59 S49 S52 21286459 \n35 Khan FY Rhabdomyolysis: a review of the literature Neth J Med 2009 67 272 283 19841484 \n36 Mubarak SJ Pedowitz RA Hargens AR Compartment syndromes Curr Orthop 1989 3 36 40 11537166 \n37 Zappa J Sugarbaker PH Compartment syndrome of the leg associated with lithotomy position for cytoreductive surgery J Surg Oncol 2007 96 619 623 17786971 \n38 Filis D Daskalakis M Askoxylakis I Metaxari M Melissas J Rhabdomyolysis following laparoscopic gastric bypass Obes Surg 2005 15 1496 1500 16354534 \n39 Dakwar E Rifkin SI Volcan IJ Goodrich JA Uribe JS Rhabdomyolysis and acute renal failure following minimally invasive spine surgery J Neurosurg Spine 2011 14 785 788 21417696 \n40 Faintuch J de Cleva R Pajecki D Garrido AB Cecconello I Rhabdomyolysis after gastric bypass: severity and outcome patterns Obes Surg 2006 16 1209 1213 16989706 \n41 Torres-Villalobos G Kimura E Mosqueda JL Garcia-Garcia E Dominguez-Cherit G Herrera MF Pressure-induced rhabdomyolysis after bariatric surgery Obes Surg 2003 13 297 301 12740143 \n42 Lagandré S Arnalsteen L Vallet B Predictive factors for rhabdomyolysis after bariatric surgery Obes Surg 2006 16 1365 1370 17059748 \n43 Harris K Walker PM Mickle DA Metabolic response of skeletal muscle to ischemia Am J Physiol 1986 250 2 Pt 2 213 220 \n44 Blaisdell FW The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review Cardiovasc Surg 2002 10 620 630 12453699 \n45 De Freitas Carvalho DA Valezi AC Macedo de Brito E Lacerdo de Souza JC Masson AC Matsuo T Rhabdomyolysis after bariatric surgery Obes Surg 2006 16 740 744 16756735 \n46 Reisiger KE Landman J Kibel A Clayman RV Laparoscopic renal surgery and the risk of rhabdomyolysis: diagnosis and treatment J Urol 2005 66 suppl 5A 29 35 \n47 Ettinger J Marcilio de Souza CA dos Santos-Filho PV Azaro E Mello CA Fahel E Batista PB Rhabdomyolysis: diagnosis and treatment in bariatric surgery Obes Surg 2007 17 525 532 17608266 \n48 Vanholder R Sever MS Erek E Lameire N Rhabdomyolysis J Am Soc Neph 2000 11 1553 1561 \n49 Zager RA Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury Lab Invest 1989 60 619 629 2716281 \n50 Better OS Stein JH Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis N Eng J Med 1990 322 825 829 \n51 Brown CV Rhee P Chan L Evans K Demetriades D Velmahos GC Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? J Trauma 2004 56 1191 1196 15211124 \n52 Ettinger J dos Santos-Filho PV Azaro E Melo CA Fahel E Batista PB Prevention of rhabdomyolysis in bariatric surgery Obes Surg 2005 15 874 879 15978162 \n53 Pfeffer SD Halliwill JR Warner MA Effects of the lithotomy position and external compression on the lower leg muscle compartment pressure Anes 2001 95 632 636\n\n",
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"keywords": "Compartment syndrome; Cytoreductive surgery; Gastric cancer; Hyperthermic intraperitoneal perioperative chemotherapy; Peritoneal carcinomatosis; Rhabdomyolysis",
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{
"abstract": "OBJECTIVE\nSertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants.\n\n\nMETHODS\nPregnant women with moderate untreated depression were recruited in 2016-2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed.\n\n\nRESULTS\nNine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers', measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants.\n\n\nCONCLUSIONS\nPlacental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment.\n\n\nBACKGROUND\nThe trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.",
"affiliations": "Division of Paediatrics at the Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden. essi.heinonen@ki.se.;Division of Paediatrics at the Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.;Psychiatry South West, Stockholm Healthcare Region, Stockholm, Sweden.;Division of Paediatrics at the Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.;Department of Clinical Sciences, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden.;Division of Clinical Pharmacology at the Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.;Division of Clinical Pharmacology at the Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.;Division of Paediatrics at the Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.",
"authors": "Heinonen|E|E|http://orcid.org/0000-0003-2107-0561;Blennow|M|M|;Blomdahl-Wetterholm|M|M|;Hovstadius|M|M|;Nasiell|J|J|;Pohanka|A|A|;Gustafsson|L L|LL|;Wide|K|K|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-021-03122-z",
"fulltext": "\n==== Front\nEur J Clin Pharmacol\nEur J Clin Pharmacol\nEuropean Journal of Clinical Pharmacology\n0031-6970\n1432-1041\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n33751155\n3122\n10.1007/s00228-021-03122-z\nClinical Trial\nSertraline concentrations in pregnant women are steady and the drug transfer to their infants is low\nhttp://orcid.org/0000-0003-2107-0561\nHeinonen E. essi.heinonen@ki.se\n\n12\nBlennow M. mats.blennow@ki.se\n\n12\nBlomdahl-Wetterholm M. margareta.blomdahl-wetterholm@sll.se\n\n3\nHovstadius M. malin@hovstadius.com\n\n1\nNasiell J. josefine.nasiell@ki.se\n\n45\nPohanka A. anton.pohanka@sll.se\n\n67\nGustafsson L. L. lars-l.gustafsson@ki.se\n\n67\nWide K. katarina.wide@ki.se\n\n18\n1 grid.4714.6 0000 0004 1937 0626 Division of Paediatrics at the Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden\n2 grid.24381.3c 0000 0000 9241 5705 Department of Paediatrics and Newborn Medicine, Karolinska University Hospital, Stockholm, Sweden\n3 grid.425979.4 0000 0001 2326 2191 Psychiatry South West, Stockholm Healthcare Region, Stockholm, Sweden\n4 grid.4714.6 0000 0004 1937 0626 Department of Clinical Sciences, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden\n5 grid.412154.7 0000 0004 0636 5158 Department of Obstetrics and Gynaecology, Danderyd Hospital, Stockholm, Sweden\n6 grid.4714.6 0000 0004 1937 0626 Division of Clinical Pharmacology at the Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden\n7 grid.24381.3c 0000 0000 9241 5705 Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden\n8 grid.24381.3c 0000 0000 9241 5705 Department of Paediatrics and Emergency Paediatrics, Karolinska University Hospital, Stockholm, Sweden\n22 3 2021\n22 3 2021\n2021\n77 9 13231331\n24 11 2020\n9 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This 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/.\nPurpose\n\nSertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants.\n\nMethod\n\nPregnant women with moderate untreated depression were recruited in 2016–2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed.\n\nResults\n\nNine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers’, measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants.\n\nConclusion\n\nPlacental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment.\n\nTrial registration\n\nThe trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1007/s00228-021-03122-z.\n\nKeywords\n\nAntenatal depression\nInfant\nPharmacokinetics\nPregnancy\nSelective serotonin reuptake inhibitors\nTherapeutic drug monitoring\nhttp://dx.doi.org/10.13039/501100004359 Vetenskapsrådet 521-2012-3466 http://dx.doi.org/10.13039/501100004348 Stockholms Läns Landsting 533069 571301 Lilla Barnets Fond (SE)http://dx.doi.org/10.13039/501100013495 Märta och Gunnar V. Philipsons Stiftelse European Society of Pediatric Researchhttp://dx.doi.org/10.13039/501100008352 Stiftelsen Samariten http://dx.doi.org/10.13039/501100004047 Karolinska Institutet Karolinska Universitetssjukhusetissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nIntroduction\n\nSertraline is one of the most commonly used selective serotonin reuptake inhibitors (SSRI) during pregnancy, and generally proven safe for this use [1–6]. Plasma sertraline concentrations are shown to both increase and decrease during pregnancy [7–9]. No clear association has been found between the dose of sertraline or the plasma sertraline concentration and the clinical effect [10–15]. Plasma sertraline concentrations seem to vary up to 10-fold between individuals, but with a low intraindividual variation, with a recommended therapeutic range of 10–50 ng/mL [12, 16, 17]. The inter- and intraindividual variations seem similar in pregnant and non-pregnant populations.\n\nSertraline and desmethylsertraline are weak basic compounds. Sertraline is over 98% protein bound in plasma, binding to both albumin and alfa 1-acid-glycoprotein (AAP), but most likely mainly to AAP [18–20]. The levels of both albumin and AAP decrease during pregnancy, potentially affecting the sertraline plasma concentrations [21]. Multiple Cytochrome P450 (CYP) enzymes in the liver metabolize sertraline to its main weakly active metabolite N-desmethylsertraline [22]. The activity of these enzymes is genetically coded [23]. Current consensus is that CYP2C19 has a major role in sertraline metabolism and that the genetic differences in its expression cause interindividual variability in sertraline concentrations. The importance of CYP2B6, CYP3A4, CYP2C9, and CYP2D6 for the disposition of sertraline in vivo is not yet clear [22, 24–26]. Pregnancy induces changes in metabolic enzyme activity, with the activity of CYP2C19 being slightly down-regulated, and the activities of the other potentially important enzymes being up-regulated [7–9, 21]. As the pharmacokinetics change during pregnancy, therapeutic drug monitoring (TDM) might be a way to improve both safety and efficacy of the treatment [7, 12, 16, 17].\n\nThe infant albumin level at birth is slightly higher than the maternal, whereas the level of AAP is only a third of the mothers [27]. In previous studies, the placental penetration of sertraline to infant serum has seemed low, with infant-mother ratios at around 0.3–1.0 reported [25, 28–32]. Transient neonatal effects such as jitteriness, hypoglycemia, and respiratory disorders are described after intrauterine SSRI exposure [33, 34].\n\nDesigning a randomized controlled trial, we aimed to clarify several aspects of the effects of antidepressant treatment on the pregnant mother and her infant. In this pharmacokinetic part of the study, we aimed to clarify the variability in plasma sertraline concentrations during pregnancy and demonstrate whether TDM would improve the safety and efficacy of the treatment. In the infant, we aimed to measure the plasma levels of sertraline and relate these to the maternal concentrations and potential clinical symptoms in the new born.\n\nMaterials and methods\n\nClinical design and methods\n\nThis study is part of a double-blind randomized controlled trial examining the effects of sertraline and depression in pregnancy on the short- and long-term outcomes in the infants, the MAGDALENA study. The study design is fully described in the study protocol publication [35], and details on the recruitment, randomization, and follow-up are presented in the online supplement. All patients had an untreated moderate major depressive disorder at inclusion. Women with psychiatric or somatic comorbidities or any chronical drug treatment were excluded from the study. All included women were offered a 12-week program of Internet-based cognitive behavior therapy (I-CBT) with pregnancy-adapted treatment modules developed by our team [36]. Additionally, the women were either randomized to sertraline or placebo with the daily dose starting at one capsule á 25 mg. The treatment effect was followed up by the Montgomery Åsberg Depression Scale (MADRS) at the follow-up visits with the study midwife [37, 38]. The dose was increased in steps of one capsule when lacking treatment response, up to a dose of four capsules (100 mg of sertraline vs placebo). If patients in the placebo arm did not improve despite the I-CBT treatment, they were unblinded and switched to treatment with sertraline.\n\nThis pharmacology part of the study describes the sixteen included mother-infant-pairs, focusing on the nine mothers who in the end received treatment with sertraline (Suppl.Fig.1). Plasma sertraline and desmethylsertraline concentrations in the mothers were measured once in the second trimester around week 21 (range 17–25) of pregnancy and once in the third trimester around week 30 (range 26–36) of pregnancy, the morning after the delivery and 1-month postpartum. The infant concentrations are measured in cord blood and at 48 h of age together with the routine neonatal screening (Table 2, Fig. 1). All concentrations are steady-state total plasma concentrations. The babies were monitored with the modified Neonatal Abstinence Scale (NAS) according to Finnegan [39] during their first 48 h of life, and their plasma glucose concentrations (p-glucose) were measured at 6 and 48 h of age. Fig. 1 a, b Boxplots of the penetration ratios of sertraline (a) and desmethylsertraline (b). a) Penetration ratio of sertraline into cord blood (CB/MP, 5 mother-infant pairs): median 0.33; IQ-range 0.24–0.58; range: 0.14–1.17, and infant plasma (IP/MP, 5 mother-infant pairs): median 0.25; IQ-range 0.23–0.26; range 0.16–0.49. b) Penetration ratio of desmethylsertraline into cord blood (CB/MP, 5 mother-infant pairs): median 0.29; IQ-range 0.28–0.36; range: 0.24–1.42, and infant plasma (IP/MP, 5 mother-infant pairs); median 0.34, IQ-range 0.31–0.37; range 0.31–0.46\n\nLaboratory methods\n\nFour milliliters of venous blood was collected from the women at each visit and from the umbilical cord at delivery into sodium heparin tubes. From the infants, 0.5 mL venous blood was collected at 48 h of age into lithium heparin capillary tubes. The drug analytical laboratory method and its performance are described in detail in the online supplement.\n\nStatistical analysis\n\nPlasma concentrations originally presented in molar units (nmol/L) were converted to mass units (ng/mL) by multiplying the molar unit with the molecular weights of sertraline, 306.2 g/mol, and desmethylsertraline, 292.2 g/mol, to achieve the concentrations in ng/L and dividing by 1000 to achieve the concentrations in ng/mL [40]. A concentration-by-dose (C/D) ratio in (ng/mL)/(mg/day) was calculated by dividing the achieved concentration by the daily dose of sertraline in milligrams. Alteration ratios (AR) were used to analyze the difference between maternal plasma concentrations in the pregnant and the non-pregnant state, in accordance with previous studies [41]. Alteration ratios were calculated for the measuring points in pregnancy and at delivery by dividing these dose-adjusted concentrations with their non-pregnant reference, measured 1-month postpartum. Due to the nature of these analyses, the data were analyzed per protocol, and women were moved between treatment groups when treatment regime changed. To explore the foetal exposure, correlations was calculated between the concentration in maternal plasma and the ones in cord blood and infant plasma. The penetration ratio into cord blood (CB) and infant plasma (IP) was calculated by dividing the concentration in cord blood or infant plasma with the concentration in maternal plasma (MP), reflecting the penetration ratio into the infant.\n\nData is presented as medians, interquartile (IQ) ranges between the first(Q1) and the third(Q3) quartiles as well as ranges between min and max values. Correlations were computed to assess the relationship between the drug concentrations in maternal plasma and the infant. Because of the linearity of this correlation (Supp. Fig. 3), Pearson’s correlation coefficients were calculated. When searching for statistical significance in the decreased sertraline concentrations during pregnancy compared to postpartum, the non-parametric Wilcoxon’s signed rank test was used due to the small sample size. The non-parametric Spearman’s correlation test was used to study the correlation between the sertraline concentration and the treatment effect in the pregnant women (Section 2.2 of the online supplement). Statistical analyses were conducted with SPSS (version 26, IBM, Armonk, NY, USA).\n\nResults\n\nPatient characteristics\n\nThe study cohort consisted of 16 women recruited between May 2016 and March 2019. Ten women were randomized to sertraline and six to placebo treatment. In the end, nine women with two or more available sertraline plasma concentrations are included in the analysis (Table 2, Table 3, Supplemental Fig. 2). The randomization procedure and the flowchart of the study are described in detail in the online supplement (Supplemental Fig. 1). In two cases, infant drug concentrations are missing or lacking informed consent from the other parent, leading to seven mother-infant-pairs being analyzed for placental cross-over (Fig. 1, Supplemental Fig. 3).\n\nConcomitant medications are presented in supplementary Table 1. The only concomitant psychotropic drug was promethazine, a first-generation antihistamine used temporarily by three women in the study. Temporary use of promethazine during pregnancy for pregnancy-related nausea and anxiety is common.\n\nSertraline and desmethylsertraline plasma concentrations during pregnancy\n\nThe repeated concentration measures of sertraline and desmethylsertraline show an up to 10-fold interindividual variation (Table 2). The intraindividual dose-adjusted measures seem fairly consistent over the course of pregnancy with an increase postpartum, visualized in the line graph in supplemental Figure 2 (Table 2, Supplemental Fig. 2). The median dose-adjusted sertraline concentration increased with 67% from 0.15 to 0.25 (ng/mL)/(mg/day) from the second trimester to postpartum, but the variation was large, and the increase was not statistically significant (p = 0,345) (Table 2). The increase over time in the non-dose-adjusted concentrations might be related to the study design with increased dosage during pregnancy in most patients. We studied the correlation between plasma sertraline concentrations and treatment effect measured with a change in MADRS, without finding any significant correlations. This is further described in the online supplement, Section 2.2.\n\nAlteration ratios\n\nWe calculated alteration ratios between pregnant and non-pregnant state on the 8 patients with available non-pregnant reference concentrations measured 1-month postpartum. The median alteration ratio for sertraline during pregnancy is 0.83 and for desmethylsertraline 0.82, with an almost 10-fold variation in both (Table 3).\n\nInfant sertraline exposure\n\nThe median concentration of sertraline in maternal plasma at delivery (n = 8) was 14.38 ng/mL (range 3.64–24.17), and the median concentrations in the infants were 4.28 ng/mL (range 1.22–6.12) in cord blood (n = 5) and 4.59 ng/mL (range 1.25–7.04) in infant plasma at 48 h of age (n = 5). The median concentration of desmethylsertraline in maternal plasma at delivery (n = 8) was 33.60 ng/mL (range 7.01–31.36). Median concentrations in the infants were 9.93 ng/mL (range 4.96–17.23) in cord blood (n = 5) and 17.52 ng/mL (range 9.93–20.44) in infant plasma at 48 h of age (n = 5). We confirmed the concentrations being generally lower in the infants than in their mothers by calculating penetration ratios into cord blood (CB) and infant plasma (IP) (Fig. 1). Figure 1 also show a decreased ratio of sertraline and an increased ratio of desmethylsertraline between the samples measured from cord blood and in infant plasma at 48 h of age, indicating clearance of sertraline and conversion into desmethylsertraline within the first 48 h of life.\n\nThe correlations between the sertraline and desmethylsertraline concentrations in maternal plasma and the infant are fairly linear, as presented in supplemental Fig. 3. The Pearson correlation coefficients for these correlations were r = 0.70 (p = 0.19) for the correlation of sertraline concentration between maternal plasma and cord blood, r = 0.64 (p = 0.24) for sertraline concentration between maternal and infant plasma, r = 0.78 (p = 0.12) for desmethylsertraline concentration between maternal plasma and cord blood, and r = 0.83 (p = 0.08) for desmethylsertraline concentration between maternal and infant plasma.\n\nNeonatal outcomes\n\nAll infants are healthy at birth, with all 5' and 10' APGAR scores being 9 or 10 (Table 1). No baby showed any signs of severe withdrawal symptoms, classified as NAS > 8 points. One baby in the placebo group shows signs of moderate abstinence (NAS 7 points), and two babies in the sertraline treatment group show signs of mild abstinence (NAS 4 points), but none required any treatment for this (Table 1). One baby in the sertraline treatment group presented with a single low p-glucose of 2.5 mmol/L before the second feed but did not require any additional treatment apart from extra feeding. No other babies signs of hypoglycemia. One baby in the sertraline group was born preterm at 33 weeks of gestation and was the only baby who needed neonatal care. This baby did not have any complications from the premature birth. One baby in the placebo group was small for gestational age. All other babies were appropriate weight for gestational age. Two babies in the sertraline group and one in the placebo group experienced mild respiratory disorders with no need of neonatal care or respiratory support with continuous positive airway pressure (CPAP) after the initial 20 min in life. One baby in the sertraline group experienced transient jitteriness at 1 week of age with a normal EEG at check-up. Table 1 Patient characteristics and delivery outcomes\n\nPatient\tAssignedtreatment\tMaximal dose of Sertraline (mg)\tMaternal age (years)\tGA (w+d)\tDelivery mode\tInfant sex\tInfant weight (g)\tWeight percentile\tAPGAR\tNAS\t\n1\tSertraline\t50\t26\t33 + 2\tVaginal\tBoy\t2021\t43\t9.9.10\t4\t\n2\tSertraline\t50\t31\t39 + 4\tVaginal instrumental\tGirl\t3510\t59\t9.10.10\t2\t\n3\tSertraline a\t50\t31\t38 + 5\tVaginal\tBoy\t3420\t50\t10.10.10\tNA\t\n4\tSertraline\t50\t32\t39 + 3\tVaginal\tGirl\t3610\t68\t9.10.10\t4\t\n5\tSertraline\t100\t32\t37 + 0\tVaginal\tBoy\t3400\t74\t9.10.10\tNA\t\n6\tSertraline\t75\t32\t37 + 3\tVaginal\tBoy\t3330\t62\t7.9.9\t3\t\n7\tSertraline\t75\t32\t37 + 6\tPlanned CS\tGirl\t2890\t32\t9.10.10\t0\t\n8\tSertraline\t75\t32\t39 + 0\tPlanned CS\tBoy\t3510\t53\t9.10.10\t2\t\n9\tSertraline d\t75\t36\t38 + 3\tVaginal\tNA\tNA\tNA\tNA\tNA\t\n10\tSertraline b\t75\t39\t39 + 2\tVaginal\tBoy\t3150\t24\t6.9.10\tNA\t\n11\tPlacebo\t0\t24\t38 + 4\tVaginal\tGirl\t3300\t52\t9.10.10\tNA\t\n12\tPlacebo c\t75\t28\t37 + 4\tVaginal\tGirl\t3140\t55\t7.9.10\t2\t\n13\tPlacebo\t0\t29\t42 + 3\tVaginal\tGirl\t3380\t38\t9.10.10\t7\t\n14\tPlacebo\t0\t33\t39 + 5\tVaginal\tGirl\t2732\t6\t9.10.10\t0\t\nGA gestational age at delivery in weeks + days. CS cesarean section. NAS modified neonatal abstinence scale according to Finnegan in Swedish [39]. Data of all included patients apart from the two early dropouts from the placebo group is presented. NA not available\n\naTreatment discontinued in 2nd trimester. bTreatment discontinued in 3rd trimester. cRandomized to placebo but active treatment from 2nd trimester. dLacking informed consent for infant data\n\nDiscussion\n\nThis study on sertraline concentrations in pregnant women and their infants demonstrates an over 10-fold interindividual variability in sertraline and its metabolite plasma concentrations across the course of the pregnancy (Table 2), supporting previous studies from both pregnant and non-pregnant populations [7, 12, 17]. The intraindividual variability during pregnancy is low, presented in supplemental Fig. 2. We found an overrepresentation of lower concentrations, with only a few notably higher concentrations as reported in non-pregnant populations, adding to the varying results from studies in pregnant women [7, 12, 17, 42]. This variability is probably due to genetic differences in drug metabolic capacity, mainly caused by the polymorphism of the CYP2C19-enzyme [22, 26]. We also observe an up to 10-fold variation in the alteration ratios between pregnant and non-pregnant state, with the median ratio just below 1 (Table 3). This supports the findings of a recent study and suggests a genetic variation in the pregnancy-induced changes of the drug metabolizing enzymes as well [41]. However, it might also be explained by altered levels of protein binding during pregnancy [21]. The median drug-adjusted sertraline plasma concentration increased by 67% from the second trimester to postpartum (Table 2, Supplemental Fig. 2). However, probably due to sample size, this was not statistically significant. Based on these findings, together with results from previous studies, it seems wise to monitor plasma sertraline concentrations during and after pregnancy [7, 12, 25, 43]. Table 2 Sertraline and desmethylsertraline plasma concentrations\n\n\tN\tDose\n(mg)\tMeasured concentration\n(ng/mL)\tDose-adjusted concentration (ng/mL)/(mg/day)\t\nMedian (range)\tMedian (Q1–Q3)\tRange\tMedian (Q1–Q3)\tRange\t\nSertraline\t\n2nd trimester\t7\t50 (50–50)\t7.65 (5.81–12.09)\t3.98–17.14\t0.15 (0.12–0.24)\t0.08–0.34\t\n3rd trimester\t9\t50 (50–75)\t9.49 (7.34–17.14)\t1.53–20.81\t0.19 (0.12–0.23)\t0.03–0.38\t\nAt delivery\t8\t75 (50–100)\t14.38 (7.65–18.67)\t3.64–24.17\t0.19 (0.15–0.25)\t0.07–0.32\t\nPostpartum\t8\t75 (50–75)\t17.9 (8.87–19.35)\t6.12–52.02\t0.25 (0.17–0.29)\t0.12–0.69\t\nDesmethylsertraline\t\n2nd trimester\t7\t50 (50–50)\t24.25 (22.65–32.29)\t15.78–10.52\t0.49 (0.45–0.65)\t0.32–0.88\t\n3rd trimester\t9\t50 (50–75)\t35.06 (28.05–55.52)\t10.52–61.36\t0.70 (0.47–0.74)\t0.21–1.11\t\nAt delivery\t8\t75 (50–100)\t33.60 (22.95–46.75)\t7.01–61.36\t0.46 (0.37–0.62)\t0.14–0.82\t\nPostpartum\t6\t75 (50–75)\t45.29 (28.56–78.89)\t16.95–87.66\t0.69 (0.43–1.05)\t0.34–1.17\t\nSertraline dose presented as median and range (min-max) and measured and dose-adjusted sertraline and desmethylsertraline plasma concentrations presented as medians, interquartile ranges (Q1–Q3) and ranges (min-max)\n\nTable 3 Alteration ratios\n\nAlteration ratio, median (min-max)\t2nd trimester\t3rd trimester\tDelivery\t\nSertraline\t0.88 (0.49–1.37)\t0.69 (0.17–1.23)\t0.85 (0.21–2.08)\t\nDesmethylsertraline\t0.94 (0.47–1.38)\t0.89 (0.62–1.44)\t0.72 (0.25–1.22)\t\nAlteration ratios between pregnant and the non-pregnant state measured 1-month postpartum for sertraline and desmethylsertraline, presented as a median (min-max) of the 8 women with sufficient data\n\nMedian plasma concentrations of sertraline in the infants were found to be around a third of the mother’s, suggesting a low placental passage of sertraline. This is in line with findings from a handful earlier studies and is reassuring regarding the safety of sertraline during pregnancy [29–32]. We also found a linearity in this correlation not previously described, presented in the online supplement. The low infant levels might be explained by sertraline mostly being bound to AAP, present in the infant at levels around a third of the mother’s. The very high proportion of protein-bound sertraline and its metabolite probably also explains why the sertraline concentration in the infant is low even though the placental permeability for the free form of the drug is markedly increased at the end of the pregnancy. Our results also suggest that in the infant, sertraline is effectively cleared and converted to desmethylsertraline (Fig. 1), which is in line with one previous study showing a total clearance of sertraline at five days of age [31].\n\nPrevious studies have shown that both maternal major depression and exposure to SSRIs are associated to increased risks for intrauterine growth restriction, prematurity, and neonatal adaptation problems including jitteriness, respiratory problems, and hypoglycemia [30, 33, 44]. In the present study, none of the nine exposed infants had any signs of asphyxia, intrauterine growth restriction, or poor neonatal adaptation. One infant exposed to sertraline experienced transient jitteriness at 1 week of age and two infants in the sertraline group and one in the placebo group experienced a transient need of respiratory support with CPAP, for less than 20 min. Group sizes were too small to determine whether any of these outcomes are significant. Large postpartum hemorrhage when using SSRI is a known complication [45, 46], and in this small sample, we found a tendency towards increased postpartum hemorrhage in the women treated with sertraline, presented in Section 2.5 of the online supplement.\n\nThe main strength of our study is that the indication for the treatment was well-based by the study psychiatrist and same in all patients, which is often not the case in naturalistic studies. As per protocol, the patients also did not have any significant concomitant medications. The greatest limitation of our study turned out to be the sample size, and none of the results is statistically significant. However, previous studies have encountered the same limitation, and increasing the sample sizes to achieve significant results is our common challenge.\n\nAs sertraline is highly protein bound, it would have been of great interest to also measure the concentrations of the free drug. This would have had potential to increase our knowledge about the pregnancy changes of sertraline concentrations and the transfer of sertraline to the infant.\n\nConsidering SSRIs being such a common treatment during pregnancy, it is a shame that studying its effects is so complicated, with small sample sizes limiting clinical studies and register-based studies struggling with confounding, especially confounding by the severity of the underlying disease. In the online supplement, we are discussing the challenges of RCT:s in this field. We hope that our finding of infant plasma concentrations being just a third of the maternal concentration can bring further assurance to the safety of the use of sertraline during pregnancy. It is also assuring for the safety of the treatment that the repeated measures of maternal concentrations are reasonably stable across the course of the pregnancy.\n\nConclusions\n\nIn our small cohort, sertraline concentrations during pregnancy do seem lower than the ones postpartum, probably indicating an increased metabolism during pregnancy. However, this is not true for all of the women, supporting the role of genetic differences. Therapeutic drug monitoring during pregnancy can increase the safety and efficacy of the treatment on group level, finding the poor metabolizers at risk for elevated drug concentrations with potential to cause adverse effects, as well as the women with low concentrations as a reason to lack of treatment effect. In our study, the infant plasma concentrations were low, and no serious adverse events were found in the included infants. Therefore, based on our material together with previous studies in the field covering the long-term effects [5, 6], it seems as if sertraline is safe to use for moderate depression during pregnancy when indicated. Further, collecting novel un-confounded data through randomized trials in this field is very difficult, why register based studies have an important role in future.\n\nSupplementary Information\n\nESM 1 (PDF 730 kb)\n\nAcknowledgements\n\nOur special gratitude goes to Eva-Marie Nordenadler, the psychiatry nurse responsible for all treatment evaluations, gynecologist Barbara Szymanska von Schultz and all our study midwives for supporting the included women throughout the study and making sure the samples were taken at given times. The study psychologists Viktor Kaldo and Erik Forssell who developed the I-CBT treatment protocol, and psychologists Mikaela Bergmark and Sandra Frööjd who monitored the patients during the I-CBT treatment. We are of course also grateful for the cooperation within the whole MAGDALENA study group including the safety and monitoring board consisting of experts in the various specialities that this study involves; all its members have contributed to achieving these results. We would like to acknowledge M Bendix, ML Dahl and C Rück for input on the study protocol at an early phase of the project. We also like to acknowledge all women, their babies and their families who participate in the MAGDALENA study and the numerous midwives, obstetricians, and staff at all recruiting Antenatal Clinics and Maternity Wards and Delivery Units in Stockholm Healthcare Region.\n\nData and material availability\n\nIndividual data are protected by the General data protection Regulation in EU (GDPR). All data is stored and accessible in a data repository at the University.\n\nCode availability\n\nNot applicable\n\nAuthors’ contributions\n\nEH, KW, and LLG wrote this manuscript. EH and LLG also wrote the study protocol article for the MAGDALENA study. KW was the principal investigator for this study, and JN, LLG and MB were members of the governing study board. MB was the main applicant and receiver of the initial funding decision from the Swedish Research Council and acted as a sponsor for the study. MB is also a senior researcher with full responsibility for the study design and participation in the completion of the manuscript.\n\nJN, KW, and MB conceived the study protocol and KW wrote the initial draft of it. MH was the study midwife at the end of the study, who collected and organized all data in the end. M.B-W was the study psychiatrist responsible for the psychiatric assessment regarding inclusion in the study as well as for the clinical decisions about pharmacotherapy during the study period. EH and KW designed the data collection forms for the infant outcomes and performed clinical examinations after delivery and made sure that the infant samples were collected. AP and LLG were responsible for the laboratory analyses of plasma sertraline and metabolite concentrations.\n\nAll authors have in different ways been involved in various degrees in the development of study design and take responsibility for the final study design.\n\nFunding\n\nOpen access funding provided by Karolinska Institute. This work was supported by the Swedish Research Council (DNR 521-2012-3466), the regional agreement on medical training and clinical research between Karolinska Institutet and Stockholm City Council (ALF, project number 533069 years 2015–2017 and project number 573301 years 2018–2020), Lilla Barnets Fond, Märta Philipssons stiftelse, European Society of Pediatric Research, Stiftelsen Samariten and funds from both Karolinska Institutet (awarded LLG) and the neonatology department at Karolinska University Hospital (awarded EWH). The funding agencies did not have any part in the design, data collection, and analysis or reporting of this trial.\n\nDeclarations\n\nEthics approval\n\nThe study was approved by the regional ethical review board in Stockholm (dnr.2014/952-31).\n\nConsent to participate\n\nInformed consent to participate was obtained from all participants included in the study for both themselves and their infants. For the infants informed consent to participate was also obtained from the other parent.\n\nConsent to publish\n\nInformed consent to publish the results was obtained from all participants included in the study and from the other parent to publish the results regarding the infants.\n\nCompeting interests\n\nThe authors declare no competing interests.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nChange history\n\n3/25/2021\n\nSupplementary Materials update.\n==== Refs\nReferences\n\n1. Molenaar NM Bais B Lambregtse-Van Den Berg MP Mulder CL Howell EA Fox NS Rommel A-S Bergink V Kamperman AM The international prevalence of antidepressant use before, during, and after pregnancy: a systematic review and meta-analysis of timing, type of prescriptions and geographical variability J Affect Disord 2020 264 82 89 10.1016/j.jad.2019.12.014 31846905\n2. Reefhuis J Devine O Friedman JM Louik C Honein MA National Birth Defects Prevention S Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports BMJ 2015 351 h3190 10.1136/bmj.h3190 26156519\n3. Reis M Kallen B Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data Psychol Med 2010 40 10 1723 1733 10.1017/S0033291709992194 20047705\n4. Womersley K Ripullone K Agius M What are the risks associated with different selective serotonin re-uptake inhibitors (SSRIs) to treat depression and anxiety in pregnancy? An evaluation of current evidence Psychiatr Danub 2017 29 Suppl 3 629 644 28953843\n5. Sujan AC Rickert ME Oberg AS Quinn PD Hernandez-Diaz S Almqvist C Lichtenstein P Larsson H D'Onofrio BM Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring JAMA 2017 317 15 1553 1562 10.1001/jama.2017.3413 28418479\n6. Brown HK Ray JG Wilton AS Lunsky Y Gomes T Vigod SN Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children JAMA 2017 317 15 1544 1552 10.1001/jama.2017.3415 28418480\n7. Westin AA Brekke M Molden E Skogvoll E Spigset O Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: changes in drug disposition PLoS One 2017 12 7 e0181082 10.1371/journal.pone.0181082 28708853\n8. Sit DK Perel JM Helsel JC Wisner KL Changes in antidepressant metabolism and dosing across pregnancy and early postpartum J Clin Psychiatry 2008 69 4 652 658 10.4088/jcp.v69n0419 18426260\n9. Freeman MP Nolan PE Jr Davis MF Anthony M Fried K Fankhauser M Woosley RL Moreno F Pharmacokinetics of sertraline across pregnancy and postpartum J Clin Psychopharmacol 2008 28 6 646 653 10.1097/JCP.0b013e31818d2048 19011433\n10. Ruhé HG Huyser J Swinkels JA Schene AH Dose escalation for insufficient response to standard-dose selective serotonin reuptake inhibitors in major depressive disorder Br J Psychiatry 2006 189 4 309 316 10.1192/bjp.bp.105.018325 17012653\n11. DeVane CL Liston HL Markowitz JS Clinical pharmacokinetics of sertraline Clin Pharmacokinet 2002 41 15 1247 1266 10.2165/00003088-200241150-00002 12452737\n12. Reis M Åberg-Wistedt A Ågren H Höglund P Åkerblad A-C Bengtsson F Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression Hum Psychopharmacol Clin Exp 2004 19 5 283 291 10.1002/hup.599\n13. Jakubovski E Varigonda AL Freemantle N Taylor MJ Bloch MH Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder Am J Psychiatr 2016 173 2 174 183 10.1176/appi.ajp.2015.15030331 26552940\n14. Baker CB Tweedie R Duval S Woods SW Evidence that the SSRI dose response in treating major depression should be reassessed: a meta-analysis Depress Anxiety 2003 17 1 1 9 10.1002/da.10079 12577272\n15. Hieronymus F Nilsson S Eriksson E A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors Transl Psychiatry 2016 6 6 e834 e834 10.1038/tp.2016.104 27271860\n16. Baumann P The AGNP-TDM Expert Group Consensus Guidelines: Focus on therapeutic monitoring of antidepressants Pharmacol Mood Disord 2005 7 3 231 247 10.31887/dcns.2005.7.3/pbaumann\n17. Lundmark J Reis M Bengtsson F Therapeutic drug monitoring of sertraline : variability factors as displayed in a clinical setting Ther Drug Monit 2000 22 4 446 454 10.1097/00007691-200008000-00014 10942186\n18. Murdoch D McTavish D Sertraline Drugs 1992 44 4 604 624 10.2165/00003495-199244040-00007 1281075\n19. Ronfeld RASG Tremaine LM Distribution and pharmacokinetics of the selective 5-HT uptake blocker sertraline in man, rat and dog Psychopharmacology 1988 96 Suppl 269\n20. Huang Z Ung T Effect of alpha-1-acid glycoprotein binding on pharmacokinetics and pharmacodynamics Curr Drug Metab 2013 14 2 226 238 23092311\n21. Jeong H Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes Expert Opin Drug Metab Toxicol 2010 6 6 689 699 10.1517/17425251003677755 20367533\n22. Huddart R Hicks JK Ramsey LB Strawn JR Smith DM Bobonis Babilonia M Altman RB Klein TE PharmGKB summary: sertraline pathway, pharmacokinetics Pharmacogenet Genomics 2020 30 2 26 33 10.1097/FPC.0000000000000392 31851125\n23. Zhou Y Ingelman-Sundberg M Lauschke VM Worldwide distribution of cytochrome P450 alleles: a meta-analysis of population-scale sequencing projects Clin Pharmacol Ther 2017 102 4 688 700 10.1002/cpt.690 28378927\n24. Obach RS Cox LM Tremaine LM Sertraline is metabolized by multiple cytochrome p450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study Drug Metab Dispos 2005 33 2 262 270 10.1124/dmd.104.002428 15547048\n25. Pogliani L Falvella FS Cattaneo D Pileri P Moscatiello AF Cheli S Baldelli S Fabiano V Cetin I Clementi E Zuccotti G Pharmacokinetics and pharmacogenetics of selective serotonin reuptake inhibitors during pregnancy: an observational study Ther Drug Monit 2017 39 2 197 201 10.1097/ftd.0000000000000370 28045861\n26. Saiz-Rodriguez M Belmonte C Roman M Ochoa D Koller D Talegon M Ovejero-Benito MC Lopez-Rodriguez R Cabaleiro T Abad-Santos F Effect of polymorphisms on the pharmacokinetics, pharmacodynamics and safety of sertraline in healthy volunteers Basic Clin Pharmacol Toxicol 2018 122 5 501 511 10.1111/bcpt.12938 29136336\n27. Ewing G Tatarchuk Y Appleby D Schwartz N Kim D Placental transfer of antidepressant medications: implications for postnatal adaptation syndrome Clin Pharmacokinet 2015 54 4 359 370 10.1007/s40262-014-0233-3 25711391\n28. Colombo A, Giordano F, Giorgetti F, Di Bernardo I, Bosi MF, Varinelli A, Cafaro R, Pileri P, Cetin I, Clementi E, Viganò CA, Dell'Osso B (2020) Correlation between pharmacokinetics and pharmacogenetics of selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors and maternal and neonatal outcomes: results from a naturalistic study in patients with affec. Hum Psychopharmacol Clin Exp. 10.1002/hup.2772\n29. Hendrick V Stowe ZN Altshuler LL Hwang S Lee E Haynes D Placental passage of antidepressant medications Am J Psychiatr 2003 160 5 993 996 10.1176/appi.ajp.160.5.993 12727706\n30. Paulzen M Goecke TW Stickeler E Grunder G Schoretsanitis G Sertraline in pregnancy - Therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood J Affect Disord 2017 212 1 6 10.1016/j.jad.2017.01.019 28129551\n31. Rampono J Proud S Hackett LP Kristensen JH Ilett KF A pilot study of newer antidepressant concentrations in cord and maternal serum and possible effects in the neonate Int J Neuropsychopharmacol 2004 7 3 329 334 10.1017/s1461145704004286 15035694\n32. Rampono J Simmer K Ilett KF Hackett LP Doherty DA Elliot R Kok CH Coenen A Forman T Placental transfer of SSRI and SNRI antidepressants and effects on the neonate Pharmacopsychiatry 2009 42 3 95 100 10.1055/s-0028-1103296 19452377\n33. Norby U Forsberg L Wide K Sjors G Winbladh B Kallen K Neonatal morbidity after maternal use of antidepressant drugs during pregnancy Pediatrics 2016 138 5 e20160181 10.1542/peds.2016-0181 27940758\n34. Moses-Kolko EL Bogen D Perel J Bregar A Uhl K Levin B Wisner KL Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications JAMA 2005 293 19 2372 2383 10.1001/jama.293.19.2372 15900008\n35. Heinonen E Szymanska-von Schultz B Kaldo V Nasiell J Andersson E Bergmark M Blomdahl-Wetterholm M Forsberg L Forsell E Forsgren A Froojd S Goldman A Nordenadler EM Sklivanioti M Blennow M Wide K Gustafsson LL MAGDALENA: study protocol of a randomised, placebo-controlled trial on cognitive development at 2 years of age in children exposed to SSRI in utero BMJ Open 2018 8 8 e023281 10.1136/bmjopen-2018-023281 30082365\n36. Forsell E Bendix M Hollandare F Szymanska von Schultz B Nasiell J Blomdahl-Wetterholm M Eriksson C Kvarned S Lindau van der Linden J Soderberg E Jokinen J Wide K Kaldo V Internet delivered cognitive behavior therapy for antenatal depression: a randomised controlled trial J Affect Disord 2017 221 56 64 10.1016/j.jad.2017.06.013 28628768\n37. First, M. B., & Gibbon, M. (2004). The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II). In M. J. Hilsenroth & D. L. Segal (Eds.), Comprehensive handbook of psychological assessment, Vol. 2. Personality assessment (p. 134–143). John Wiley & Sons Inc.\n38. Montgomery SA Asberg M A new depression scale designed to be sensitive to change Br J Psychiatry 1979 134 382 389 10.1192/bjp.134.4.382 444788\n39. Forsberg L Naver L Gustafsson LL Wide K Neonatal adaptation in infants prenatally exposed to antidepressants--clinical monitoring using Neonatal Abstinence Score PLoS One 2014 9 11 e111327 10.1371/journal.pone.0111327 25365553\n40. National Center for Biotechnology Information (2020) PubChem Compound Summary for CID 68617 SRS, 2020 from https://pubchem.ncbi.nlm.nih.gov/compound/Sertraline\n41. Schoretsanitis G Spigset O Stingl JC Deligiannidis KM Paulzen M Westin AA The impact of pregnancy on the pharmacokinetics of antidepressants: a systematic critical review and meta-analysis Expert Opin Drug Metab Toxicol 2020 16 5 431 440 10.1080/17425255.2020.1750598 32238008\n42. Deligiannidis KM Byatt N Freeman MP Pharmacotherapy for mood disorders in pregnancy: a review of pharmacokinetic changes and clinical recommendations for therapeutic drug monitoring J Clin Psychopharmacol 2014 34 2 244 255 10.1097/JCP.0000000000000087 24525634\n43. Svensson M, Reimers A, Reis M (2020) [Pharmacokinetics of antidepressants during pregnancy]. Lakartidningen 117\n44. Källén B Neonate characteristics after maternal use of antidepressants in late pregnancy Arch Pediatr Adolesc Med 2004 158 4 312 316 10.1001/archpedi.158.4.312 15066868\n45. Lindqvist PG Nasiell J Gustafsson LL Nordstrom L Selective serotonin reuptake inhibitor use during pregnancy increases the risk of postpartum hemorrhage and anemia: a hospital-based cohort study J Thromb Haemost 2014 12 12 1986 1992 10.1111/jth.12757 25322909\n46. Skalkidou A, Sundstrom-Poromaa I, Wikman A, Hesselman S, Wikstrom AK, Elenis E. SSRI use during pregnancy and risk for postpartum haemorrhage: a national register-based cohort study in Sweden. BJOG 2020;127:1366–1373.\n\n",
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"abstract": "Metformin-associated lactic acidosis (MALA) is a rare but serious complication of metformin use, associated with high mortality. MALA can occur any time a patient on metformin suffers disruption in renal function resulting in the accumulation of metformin. A 63-year-old man with a history of non-insulin-dependent type 2 diabetes mellitus, alcohol abuse, and hypothyroidism was brought to the emergency department with altered mental status, nausea, vomiting, and abdominal pain. He was found to be in respiratory distress, was hypotensive and hypoglycemic (48 mg/dL), and required emergent intubation. Blood work was significant for pH<6.69, undetectable bicarbonate, anion gap 37.2 mEq/L, lactate >12 mmol/L, creatinine 15.95 mg/dL, blood urea nitrogen (BUN) 112 mg/dL, glomerular filtration rate (GFR), 3 ml/min/1.73sqm, and potassium 7 mmol/L. He suffered cardiac arrest, underwent cardiopulmonary resuscitation (CPR), and was admitted to the intensive care unit (ICU) where he required multiple vasopressors, bicarbonate infusion, and bicarbonate pushes. He was started on continuous renal replacement therapy with a high flux membrane. A high dose of pre- and post- filter fluids was used to improve conductive clearance. His pH corrected to normal in less than 24 hours, and hemodialysis was initiated the following day for a total of four days. Head/chest/abdomen/pelvis CT, urine, and blood cultures did not reveal any pathology that would explain lactic acidosis. The patient's dose of metformin was 1 gr twice daily and sitagliptin, 100 mg daily. Blood metformin that had been tested on admission was 29 mcg/ml (therapeutic range, 1-2 mcg/ml). Methanol, ethanol, ethylene glycol, propylene glycol, and isopropanol levels were negative. He had been started on lisinopril 5 mg and amitriptyline 25 mg four weeks prior to admission and had normal creatinine at that time. He was discharged to an acute rehabilitation facility on day seven of hospitalization. MALA generally presents with nausea, vomiting, and fatigue-often mimicking sepsis. It is possible that our patient progressively developed alcoholic ketoacidosis and acute renal failure from dehydration and excessive drinking in the setting of newly started Angiotensin-converting-enzyme (ACE) inhibitor. Recommendations for the optimal treatment of MALA mostly depend on expert opinion and case reports. Treatment is restricted to supportive measures, although hemodialysis may offer a protective effect. Our case demonstrates that even in extreme cases of MALA, prompt and adequate supportive measures can produce a favorable outcome.",
"affiliations": "Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA.;Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA.;Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA.;Internal Medicine, Community Medical Center, Toms River, USA.;Critical Care Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA.",
"authors": "Sendil|Selin|S|;Yarlagadda|Keerthi|K|;Lawal|Halimat|H|;Nookala|Vinod|V|;Shingala|Hiren|H|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.9119\nEmergency Medicine\nInternal Medicine\nNephrology\nMetformin Associated Lactic Acidosis in the Intensive Care Unit: A Rare Condition Mimicking Sepsis\nMuacevic Alexander Adler John R Sendil Selin 1 Yarlagadda Keerthi 1 Lawal Halimat 1 Nookala Vinod 2 Shingala Hiren 3 \n1 \nInternal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA \n\n2 \nInternal Medicine, Community Medical Center, Toms River, USA \n\n3 \nCritical Care Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA \n\nSelin Sendil sendils@upmc.edu\n10 7 2020 \n7 2020 \n12 7 e911926 6 2020 10 7 2020 Copyright © 2020, Sendil et al.2020Sendil et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/36360-metformin-associated-lactic-acidosis-in-the-intensive-care-unit-a-rare-condition-mimicking-sepsisMetformin-associated lactic acidosis (MALA) is a rare but serious complication of metformin use, associated with high mortality. MALA can occur any time a patient on metformin suffers disruption in renal function resulting in the accumulation of metformin.\n\nA 63-year-old man with a history of non-insulin-dependent type 2 diabetes mellitus, alcohol abuse, and hypothyroidism was brought to the emergency department with altered mental status, nausea, vomiting, and abdominal pain. He was found to be in respiratory distress, was hypotensive and hypoglycemic (48 mg/dL), and required emergent intubation. Blood work was significant for pH<6.69, undetectable bicarbonate, anion gap 37.2 mEq/L, lactate >12 mmol/L, creatinine 15.95 mg/dL, blood urea nitrogen (BUN) 112 mg/dL, glomerular filtration rate (GFR), 3 ml/min/1.73sqm, and potassium 7 mmol/L. He suffered cardiac arrest, underwent cardiopulmonary resuscitation (CPR), and was admitted to the intensive care unit (ICU) where he required multiple vasopressors, bicarbonate infusion, and bicarbonate pushes. He was started on continuous renal replacement therapy with a high flux membrane. A high dose of pre- and post- filter fluids was used to improve conductive clearance. His pH corrected to normal in less than 24 hours, and hemodialysis was initiated the following day for a total of four days. Head/chest/abdomen/pelvis CT, urine, and blood cultures did not reveal any pathology that would explain lactic acidosis. The patient’s dose of metformin was 1 gr twice daily and sitagliptin, 100 mg daily. Blood metformin that had been tested on admission was 29 mcg/ml (therapeutic range, 1-2 mcg/ml). Methanol, ethanol, ethylene glycol, propylene glycol, and isopropanol levels were negative. He had been started on lisinopril 5 mg and amitriptyline 25 mg four weeks prior to admission and had normal creatinine at that time. He was discharged to an acute rehabilitation facility on day seven of hospitalization.\n\nMALA generally presents with nausea, vomiting, and fatigue-often mimicking sepsis. It is possible that our patient progressively developed alcoholic ketoacidosis and acute renal failure from dehydration and excessive drinking in the setting of newly started Angiotensin-converting-enzyme (ACE) inhibitor. Recommendations for the optimal treatment of MALA mostly depend on expert opinion and case reports. Treatment is restricted to supportive measures, although hemodialysis may offer a protective effect. Our case demonstrates that even in extreme cases of MALA, prompt and adequate supportive measures can produce a favorable outcome.\n\nmetformin associated lactic acidosismalametforminrenal failurecrrtThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nMetformin-associated lactic acidosis (MALA) is a rare but potentially fatal complication of metformin use with a 30-50% mortality rate [1]. MALA can occur any time a patient on metformin suffers a disruption in renal function resulting in an accumulation of metformin. Here, we present a case of a 63-year-old male with non-insulin-dependent type II diabetes mellitus (NIDDM) on metformin who developed severe lactic acidosis, profound acidemia, significant electrolyte abnormalities, and ultimately cardiac arrest in the setting of acute kidney injury (AKI). \n\nCase presentation\nA 63-year-old Caucasian male with a past medical history of NIDDM, alcohol use disorder, anxiety, and hypothyroidism was brought to the emergency department (ED) via emergency medical services (EMS) with altered mental status. He had reportedly been having nausea, vomiting, and abdominal pain for one week, and also developed progressively worsening change in vision for about 48 hours. Initially, EMS found his blood glucose 48 mg/dL and administered intravenous (IV) dextrose. Upon arrival at the ED, he was found to be in respiratory distress with labored breathing and respiratory rate of 22/minute. His heart rate was 63 beats per minute, blood pressure 47/33 mmHg, temperature 92.6 °F (rectal temperature). The patient required emergent intubation in the ED. His initial blood work was significant for pH<6.69 (could not be calculated by our institution's blood gas analyzer), undetectable bicarbonate (could not be calculated by our institution's blood gas analyzer), anion gap 37.2 mEq/L, lactate >12 mmol/L, creatinine 15.95 mg/dL, blood urea nitrogen (BUN) 112 mg/dL, glomerular filtration rate (GFR) 3 ml/min/1.73sqm, phosphorus 17.7 mmol/L, potassium 7 mmol/L (Table 1).\n\nTable 1 The patient's BMP from a month ago and the BMP obtained in the ED\nBMP was unremarkable a month ago when started on lisinopril.\n\nBMP: basic metabolic panel; BUN: blood urea nitrogen; GFR: glomerular filtration rate; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ED: emergency department\n\nParameters\tBMP a month prior to presentation\tBMP after initial stabilization\t\nSodium (mmol/L)\t140\t131\t\nPotassium (mmol/L)\t4.4\t7\t\nChloride (mmol/L)\t105\t89\t\nCO2 (mmol/L)\t25.9\t4.8\t\nAnion Gap (mEq/L)\t9.1\t37.2\t\nBUN (mg/dL)\t14\t112\t\nCreatinine (mg/dL)\t0.81\t15.95\t\nGFR (ml/min/1.73sqm)\t>90\t3\t\nPhosphorus (mg/dL)\t \t17.7\t\nGlucose (mg/dL)\t119\t138\t\nCalcium (mg/dL)\t9.3\t7.8\t\nALP (U/L)\t123\t72\t\nALT (U/L)\t14\t17\t\nAST (U/L)\t16\t21\t\nTotal Bilirubin (mg/dL)\t0.3\t0.3\t\nTotal Protein (g/dL)\t6.7\t5.1\t\nAlbumin (g/dL)\t3.9\t3\t\nHis white blood cell count (WBC) was 9.5 K/µL, neutrophils 50%, band 6% (Table 2), activated partial thromboplastin time 79.3 seconds, and international normalized ratio 1.1. He developed cardiac arrest in the ED, received brief cardiopulmonary resuscitation (CPR) with a return of spontaneous circulation (ROSC), and was admitted to the intensive care unit (ICU). He required multiple vasopressors and bicarbonate infusion in addition to several bicarbonate pushes. He was started on continuous renal replacement therapy (CRRT) with a high flux membrane. High dose of pre- and post- filter fluids was used to improve conductive clearance. CRRT was chosen over hemodialysis due to hemodynamic instability. His pH corrected to normal levels with CRRT in less than 24 hours (Table 3). He was transitioned to hemodialysis the following day. His lactic acid and bicarbonate levels improved to normal levels in 48 hours. \n\nTable 2 The patient's CBC on presentation\nCBC: complete blood count; WBC: white blood cell; RBC: red blood cell; MCV: mean corpuscular volume; RDW: the red cell distribution width\n\nParameters\tValues\t\nWBC (K/uL)\t9.5\t\nRBC (M/uL)\t3.91\t\nHemoglobin (g/dL)\t11.6\t\nHematocrit (%)\t39\t\nMCV (FL)\t99.8\t\nPlatelet Count (K/uL)\t318\t\nRDW (%)\t16.3\t\nNeutrophils (%)\t49.5\t\nBand (%)\t5.7\t\nLymphocytes (%)\t33.3\t\nMonocytes (%)\t1\t\nMetamyelocytes %)\t8.6\t\nMyelocytes (%)\t1.9\t\nAnisocytosis\t1+\t\nTable 3 The patient's initial ABG and the much-improved ABG on CRRT in less than 24 hours\nABG: arterial blood gas\n\nParameters\tABG on presentation (intubated)\tABG after 24 hours on CRRT (intubated)\t\npH Art\t<6.69\t7.42\t\npCO2\n\t40.4\t34.7\t\npO2\n\t138\t94\t\nHCO3\n\tcould not calculate\t22.9\t\nBase Excess\tcould not calculate\t1\t\nThe patient's urine and blood cultures did not grow any microorganism. Chest x-ray (CXR) did not show any acute cardiopulmonary process. His head computed tomography (CT) did not show any acute abnormality. CT chest abdomen pelvis did not reveal any acute pathology that can explain the patient's severe lactic acidosis. The patient was on metformin 1 gram twice daily and sitagliptin 100 mg daily at home prior to this hospitalization. A blood metformin level was sent on admission and came back as 29 mcg/ml (therapeutic range 1-2 mcg/ml). Methanol, ethanol, ethylene glycol, propylene glycol, and isopropanol levels came back negative (Table 4).\n\nTable 4 Toxicology panel showing significantly elevated blood levels of metformin\nToxicology panel\tValues\tReference range\t\nMetformin\t29\t1-2 mcg/mL\t\nSalicylate\t<2.5\t<2.5\t\nAcetaminophen\t<10\t<10\t\nDesipramine\t<5\tTherapeutic range changes\t\nImipramine\t<5\tTherapeutic range changes\t\nAmitriptyline\t18\tTherapeutic range changes\t\nDoxepin\t<5\tTherapeutic range changes\t\nDoxepin Total\t<5\tTherapeutic range changes\t\nNordoxepine\t<5\tTherapeutic range changes\t\nTotal Amitriptyline and Nortriptyline\t31\t100 - 250 mcg/L\t\nDesmethylclomipramine\t<5\t150 - 350 mcg/L\t\nTotal Clomipramine\tNone detected\tUnknown\t\nMethanol\t<0.01\t<0.01\t\nEthylene glycol\t20\t \t\nIsopropanol\t<0.01\t<0.01\t\nAcetone\t140\t <100 = negative, >150 = acetone metabolic imbalance\t\nA review of the patient's electronic medical records revealed that he was started on lisinopril 5 mg daily and amitriptyline 25 mg daily four weeks prior to this admission and had normal kidney function (BUN, creatinine, GFR) at that time. His renal function normalized within four days, and he did not need hemodialysis after that. He was ultimately discharged to an acute rehabilitation facility on day seven of hospitalization.\n\nDiscussion\nMetformin is a widely used biguanide anti-diabetic medication with multiple mechanisms of action, which decreases insulin resistance and hepatic glucose output; it enhances peripheral glucose uptake with net effects of decreasing fasting and post-prandial blood glucose [2]. These overall benefits make it the first-line drug as it does not cause hypoglycemia as often as the most other classes of oral anti-diabetic medications. Although generally considered as safe, metformin's most serious but rare side effect is MALA. The mechanism of MALA is complex. Metformin promotes the conversion of glucose to lactate in the splanchnic bed of the small intestine and also inhibits mitochondrial respiratory chain complex 1, leading to decreased hepatic gluconeogenesis from lactate, pyruvate, and alanine resulting in additional lactate and substrate for lactate production. In the absence of acute overdose, metformin-associated lactic acidosis rarely develops in patients without comorbidities such as renal or hepatic insufficiency or acute infection. However, in the rare circumstance when metformin-associated lactic acidosis develops, mortality is high [1,3]. Higher mortality was associated with increased age, lower arterial pH, elevated prothrombin time, and need for mechanical ventilation and vasoactive medications [4].\n\nMALA can occur any time a patient on metformin suffers disruption in renal function resulting in the accumulation of metformin. MALA generally presents with nausea, vomiting, and fatigue, mimicking sepsis [5]. Reportedly, the patient was complaining of nausea, vomiting, and abdominal pain for a few days prior to presentation. Interestingly, he was also complaining of \"tunnel vision\" to his family. In this case, the patient was found to have a severe anion gap metabolic acidosis with a massively elevated lactic acid despite an acceptable blood pressure, benign abdominal examination, and lack of fever. It is not necessarily due to impaired tissue perfusion, but rather to interference with ATP production. In our patient, the elevation in lactic acid was due, in part, to the accumulation from hepatic gluconeogenesis inhibition and, more importantly, accumulation of NADH (from oxidative phosphorylation inhibition) which results in shunting of pyruvate to lactate (in lieu of acetyl-CoA). It is possible that our patient progressively developed alcoholic ketoacidosis and acute renal failure from dehydration and excessive drinking in the setting of a newly started angiotensin-converting-enzyme (ACE) inhibitor. This could have been the initial insult, but since ethylene glycol toxicity could not be ruled out without levels, he was also treated with fomepizole. If presentation delayed enough, ethylene glycol level might actually be normal given that it is not ethylene glycol itself, which causes toxicity but rather its metabolites glycolic acid and oxalic acid. However, given the history, AKI, and renal failure from dehydration may be more likely. The report of vision changes brought to mind methanol toxicity. However, renal failure is not common. As suspected, blood metformin levels sent during the initial presentation came back significantly elevated at 29 mcg/ml (therapeutic range: 1-2 mcg/ml).\n\nRecommendations for the optimal treatment of MALA mostly depend on expert opinion and case reports. Initial treatment is restricted to supportive measures, although hemodialysis may offer a protective effect [1,5,6]. Metformin is exclusively renally cleared. While metformin is not typically considered a \"dialyzable\" drug due to its high volume of distribution, there is no other alternative [6]. In our patient, we chose to proceed with CRRT due to significant hemodynamic instability requiring multiple vasopressors at the maximum doses. However, as soon as his hemodynamics improved, he was switched to hemodialysis. Ultimately, in less than 24 hours, his pH improved to normal physiologic limits. Our case demonstrates that even in extreme cases of MALA, prompt and adequate supportive measures can produce a favorable outcome.\n\nConclusions\nAlthough rare, MALA can be encountered in the ICU and continues to be a life-threatening condition. In view of current literature, recommendations for the optimal treatment of MALA depend on expert opinion and case reports. Treatment is restricted mostly to supportive measures, although hemodialysis may possess a protective effect. Our case demonstrates that even in extreme cases of MALA, with the prompt and adequate supportive measures, a favorable outcome is possible. More studies with larger patient populations are needed to reach definitive and data-driven recommendations on the treatment of MALA.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Metformin-associated lactic acidosis in an intensive care unit Crit Care Peters N Jay N Barraud D Cravoisy A Nace L Bollaert PE Gibo S 149 12 2008 18495050 \n2 Re-evaluation of a biguanide, metformin: mechanism of action and tolerability Pharmacol Res Sirtori CR Pasik C 187 228 30 1994 7862618 \n3 Lactic acidosis in metformin treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations Drug Saf Lalau JD Race JM 377 384 20 1999 10230584 \n4 Metformin-associated lactic acidosis: a prognostic and therapeutic study Crit Care Med Seidowsky A Nseir S Houdret N Fourrier F 2191 2196 37 2009 19487945 \n5 Metformin-associated lactic acidosis: a case report Drug Saf Case Rep Umeda T Minami T Bartolomei K Summerhill E 8 5 2018 29427160 \n6 Extracorporeal treatment for metformin poisoning: systematic review and recommendations from the Extracorporeal Treatments in Poisoning Workgroup Crit Care Med Calello D Liu KD Wiegand TJ 1716 1730 43 2015 25860205\n\n",
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{
"abstract": "BACKGROUND\nDespite the widespread use of oral or topical acyclovir, allergic contact dermatitis caused by it has been rarely reported, with fewer than 20 case studies published in the English literature to date.\n\n\nMETHODS\nA diagnosis of allergic contact dermatitis from acyclovir cream was established in a 62-year-old female patient who had been continuously using acyclovir cream for 3 weeks after systemic therapy for herpes zoster with acyclovir, and in a 35-year-old female patient, who had undergone liver transplantation in 2008 and subsequently developed a severe form of herpes zoster treated orally with 4 g/day acyclovir and prolonged topical administration of acyclovir cream. In both cases, patch tests were performed with extended European Baseline Series, with the excipients of acyclovir cream (propylene glycol, sodium lauryl sulfate, cetostearyl alcohol, dimethyl sulfoxide) and commercial cream containing acyclovir 2%. Positive reactions were obtained only with the commercial cream with acyclovir 2%. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Allergic contact dermatitis caused by acyclovir is rarely reported and frequently misdiagnosed, despite the wide use of oral or topical acyclovir. Allergic contact dermatitis due to acyclovir applied topically is a clinical problem with which health care providers should be familiar, and which prompts patch testing in suspected patients. Knowledge and education focused on allergens are important to clinicians in daily practice.",
"affiliations": "Department of Dermatology, Nicolina Medical Center, Iasi, Romania; Department of Dermato-Physiology, Apollonia University, Iasi, Romania.;\"Gr. T. Popa\" University of Medicine and Pharmacy, Iasi, Romania.;\"Gr. T. Popa\" University of Medicine and Pharmacy, Iasi, Romania.;Department of Histology, University of Medicine and Pharmacy of Tirgu Mures, Tirgu Mures, Romania.;Department of Pathology, University of Medicine and Pharmacy of Tirgu Mures, Tirgu Mures, Romania.",
"authors": "Chiriac|Anca|A|;Chiriac|Anca E|AE|;Pinteala|Tudor|T|;Moldovan|Cosmin|C|;Stolnicu|Simona|S|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2016.07.083",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "52(2)",
"journal": "The Journal of emergency medicine",
"keywords": "acyclovir; allergic contact dermatitis; topical treatment",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000212:Acyclovir; D000287:Administration, Topical; D000328:Adult; D000998:Antiviral Agents; D017449:Dermatitis, Allergic Contact; D004636:Emergency Service, Hospital; D005260:Female; D014645:Herpesvirus 3, Human; D006801:Humans; D016031:Liver Transplantation; D008875:Middle Aged; D063465:Skin Cream",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "e37-e39",
"pmc": null,
"pmid": "27658557",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Allergic Contact Dermatitis from Topical Acyclovir: Case Series.",
"title_normalized": "allergic contact dermatitis from topical acyclovir case series"
} | [
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{
"abstract": "BACKGROUND\nThere is a major unmet need for effective treatments in patients with squamous cell carcinoma of the lung. LUX-Lung 8 compared afatinib (an irreversible ErbB family blocker) with erlotinib (a reversible EGFR tyrosine kinase inhibitor), as second-line treatment for patients with advanced squamous cell carcinoma of the lung.\n\n\nMETHODS\nWe did this open-label, phase 3 randomised controlled trial at 183 cancer centres in 23 countries worldwide. We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum-based-chemotherapy. Participants were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. The randomisation was done centrally with an interactive voice or web-based response system and stratified by ethnic origin (eastern Asian vs non-eastern Asian). Clinicians and patients were not masked to treatment allocation. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). The key secondary endpoint was overall survival. This trial is registered with ClinicalTrials.gov, NCT01523587.\n\n\nRESULTS\n795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). Median follow-up at the time of the primary analysis of progression-free survival was 6·7 months (IQR 3·1-10·2), at which point enrolment was not complete. Progression free-survival at the primary analysis was significantly longer with afatinib than with erlotinib (median 2·4 months [95% CI 1·9-2·9] vs 1·9 months [1·9-2·2]; hazard ratio [HR] 0·82 [95% CI 0·68-1·00], p=0·0427). At the time of the primary analysis of overall survival (median follow-up 18·4 months [IQR 13·8-22·4]), overall survival was significantly greater in the afatinib group than in the erloinib group (median 7·9 months [95% CI 7·2-8·7] vs 6·8 months [5·9-7·8]; HR 0·81 [95% CI 0·69-0·95], p=0·0077), as were progression-free survival (median 2·6 months [95% CI 2·0-2·9] vs 1·9 months [1·9-2·1]; HR 0·81 [95% CI 0·69-0·96], p=0·0103) and disease control (201 [51%] of 398 patients vs 157 [40%] of 397; p=0·0020). The proportion of patients with an objective response did not differ significantly between groups (22 [6%] vs 11 [3%]; p=0·0551). Tumour shrinkage occurred in 103 (26%) of 398 patients versus 90 (23%) of 397 patients. Adverse event profiles were similar in each group: 224 (57%) of 392 patients in the afatinib group versus 227 (57%) of 395 in the erlotinib group had grade 3 or higher adverse events. We recorded higher incidences of treatment-related grade 3 diarrhoea with afatinib (39 [10%] vs nine [2%]), of grade 3 stomatitis with afatinib (16 [4%] vs none), and of grade 3 rash or acne with erlotinib (23 [6%] vs 41 [10%]).\n\n\nCONCLUSIONS\nThe significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib, along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung.\n\n\nBACKGROUND\nBoehringer Ingelheim.",
"affiliations": "Gustave Roussy Cancer Campus and University Paris-Sud, Paris, France. Electronic address: Jean-Charles.Soria@gustaveroussy.fr.;Medical Oncology Department, Vall d' Hebron University Hospital, Vall d' Hebron Institute of Oncology, Barcelona, Spain.;Hospital Carlos Haya, Malaga, Spain.;Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Athens School of Medicine, Athens, Greece.;Chungbuk National University College of Medicine, Cheongju, South Korea.;Ege University Faculty of Medicine, Izmir, Turkey.;Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece.;First Hospital Affiliated to Jilin University, Jilin, China.;Hospital Lozano Blesa, Zaragoza, Spain.;Izmir Chest Diseases Research Hospital, Izmir, Turkey.;Istituto Nazionale Tumori \"Fondazione G Pascale\"-IRCCS, Naples, Italy.;Department of Medicine, Ulsan University Hospital, Ulsan, South Korea.;University Hospital, Bologna, Italy.;Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA.;Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA.;Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA.;Division of Medical Oncology, University of Ottawa, Ottawa, ON, Canada.",
"authors": "Soria|Jean-Charles|JC|;Felip|Enriqueta|E|;Cobo|Manuel|M|;Lu|Shun|S|;Syrigos|Konstantinos|K|;Lee|Ki Hyeong|KH|;Göker|Erdem|E|;Georgoulias|Vassilis|V|;Li|Wei|W|;Isla|Dolores|D|;Guclu|Salih Z|SZ|;Morabito|Alessandro|A|;Min|Young J|YJ|;Ardizzoni|Andrea|A|;Gadgeel|Shirish M|SM|;Wang|Bushi|B|;Chand|Vikram K|VK|;Goss|Glenwood D|GD|;|||",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "16(8)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "897-907",
"pmc": null,
"pmid": "26156651",
"pubdate": "2015-08",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial.",
"title_normalized": "afatinib versus erlotinib as second line treatment of patients with advanced squamous cell carcinoma of the lung lux lung 8 an open label randomised controlled phase 3 trial"
} | [
{
"companynumb": "CA-ASTELLAS-2014US013849",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
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}
],
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"reactionmeddrapt": "Dehydration",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SORIA J-C, FELIP E, COBO M, LU S, SYRIGOS K, LEE K ET AL.. AFATINIB VERSUS ERLOTINIB AS SECOND-LINE TREATMENT OF PATIENTS WITH ADVANCED SQUAMOUS CELL CARCINOMA OF THE LUNG (LUX-LUNG 8): AN OPEN-LABEL RANDOMISED CONTROLLED PHASE 3 TRIAL.. THE LANCET ONCOLOGY. 2015;1-11",
"literaturereference_normalized": "afatinib versus erlotinib as second line treatment of patients with advanced squamous cell carcinoma of the lung lux lung 8 an open label randomised controlled phase 3 trial",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "CA",
"receiptdate": "20160913",
"receivedate": "20150728",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 11318277,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20161109"
}
] |
{
"abstract": "Background: The incidence of myocarditis in patients with coronavirus disease 2019 (COVID-19) remains unknown; however, increasing evidence links COVID-19 to cardiovascular complications such as arrhythmias, heart failure, cardiogenic shock, fulminant myocarditis, and cardiac death. We present a case of suspected COVID-19-induced myopericarditis and discuss the diagnostic implications, pathophysiology, and management. Case Report: A 72-year-old female was admitted to the hospital with acute on chronic respiratory failure in the setting of COVID-19. The next day, she developed pressure-like retrosternal chest pain. Laboratory findings revealed elevated cardiac enzymes and inflammatory markers consistent with myocardial injury. Electrocardiogram revealed diffuse ST segment elevations without reciprocal changes, concerning for myopericarditis. Transthoracic echocardiography showed new findings of severely reduced left ventricular (LV) systolic function, with an estimated ejection fraction (EF) of 20%. Her hospital course was further complicated by cardiogenic shock that required treatment in the intensive care unit with vasopressors and inotropes. During the next few days, she had almost full recovery of her LV function, with EF improving to 50%. However, her clinical status deteriorated, likely the result of a bowel obstruction. She was transitioned to comfort care at the request of her family, and she died shortly after. Conclusion: This case highlights diagnostic and therapeutic challenges that physicians may encounter when managing acute cardiac injury in the setting of COVID-19. The multiple mechanisms of COVID-19-related myocardial injury may influence the approach to diagnosis and treatment.",
"affiliations": "Department of Hospital Medicine, Ochsner Clinic Foundation, New Orleans, LA.;Department of Hospital Medicine, Ochsner Clinic Foundation, New Orleans, LA.;The University of Queensland Faculty of Medicine, Ochsner Clinical School, New Orleans, LA.;The University of Queensland Faculty of Medicine, Ochsner Clinical School, New Orleans, LA.;The University of Queensland Faculty of Medicine, Ochsner Clinical School, New Orleans, LA.;The University of Queensland Faculty of Medicine, Ochsner Clinical School, New Orleans, LA.",
"authors": "Okor|Ivana|I|;Sleem|Amber|A|;Zhang|Alice|A|;Kadakia|Rikin|R|;Bob-Manuel|Tamunoinemi|T|;Krim|Selim R|SR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.31486/toj.20.0090",
"fulltext": "\n==== Front\nOchsner J\nOchsner J\nTOJ\nochjnl\nThe Ochsner Journal\n1524-5012\n1524-5012\nAcademic Division of Ochsner Clinic Foundation\n\n10.31486/toj.20.0090\ntoj.20.0090\nCase Reports and Clinical Observations\nSuspected COVID-19–Induced Myopericarditis\nOkor, I\nCOVID-19–Induced Myopericarditis\nOkor Ivana DO 1\nSleem Amber DO 1\nZhang Alice MD 2\nKadakia Rikin MD 23\nBob-Manuel Tamunoinemi MD 23\nKrim Selim R. MD 23\n1 Department of Hospital Medicine, Ochsner Clinic Foundation, New Orleans, LA\n2 The University of Queensland Faculty of Medicine, Ochsner Clinical School, New Orleans, LA\n3 Department of Cardiology, John Ochsner Heart and Vascular Institute, Ochsner Clinic Foundation, New Orleans, LA\nAddress correspondence to Selim R. Krim, MD, Department of Cardiology, John Ochsner Heart and Vascular Institute, Ochsner Clinic Foundation, 1514 Jefferson Hwy., New Orleans, LA 70121. Tel: (504) 842-3717. Email: selim.krim@ochsner.org\nSummer 2021\nSummer 2021\n21 2 181186\n©2021 by the author(s); Creative Commons Attribution License (CC BY)\n2021\nhttps://creativecommons.org/licenses/by/4.0/ ©2021 by the author(s); licensee Ochsner Journal, Ochsner Clinic Foundation, New Orleans, LA. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (creativecommons.org/licenses/by/4.0/legalcode) that permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.\n\nBackground: The incidence of myocarditis in patients with coronavirus disease 2019 (COVID-19) remains unknown; however, increasing evidence links COVID-19 to cardiovascular complications such as arrhythmias, heart failure, cardiogenic shock, fulminant myocarditis, and cardiac death. We present a case of suspected COVID-19–induced myopericarditis and discuss the diagnostic implications, pathophysiology, and management.\n\nCase Report: A 72-year-old female was admitted to the hospital with acute on chronic respiratory failure in the setting of COVID-19. The next day, she developed pressure-like retrosternal chest pain. Laboratory findings revealed elevated cardiac enzymes and inflammatory markers consistent with myocardial injury. Electrocardiogram revealed diffuse ST segment elevations without reciprocal changes, concerning for myopericarditis. Transthoracic echocardiography showed new findings of severely reduced left ventricular (LV) systolic function, with an estimated ejection fraction (EF) of 20%. Her hospital course was further complicated by cardiogenic shock that required treatment in the intensive care unit with vasopressors and inotropes. During the next few days, she had almost full recovery of her LV function, with EF improving to 50%. However, her clinical status deteriorated, likely the result of a bowel obstruction. She was transitioned to comfort care at the request of her family, and she died shortly after.\n\nConclusion: This case highlights diagnostic and therapeutic challenges that physicians may encounter when managing acute cardiac injury in the setting of COVID-19. The multiple mechanisms of COVID-19–related myocardial injury may influence the approach to diagnosis and treatment.\n\nKeywords:\n\nCardiomyopathies\nCOVID-19\nmyocarditis\npericarditis\nTakotsubo cardiomyopathy\n==== Body\nINTRODUCTION\n\nAs of September 2020, coronavirus disease 2019 (COVID-19) had affected more than 30 million people globally.1 COVID-19–related cardiovascular complications such as tachyarrhythmia, heart failure, cardiogenic shock, fulminant myocarditis, and cardiac death have been reported.2 The pathophysiologic mechanisms responsible for COVID-19–induced myocarditis remain under investigation. We present a case of suspected COVID-19–induced myopericarditis and discuss the diagnostic implications, pathophysiology, and management.\n\nCASE REPORT\n\nA 72-year-old female with a medical history of systemic hypertension, chronic obstructive pulmonary disease (COPD) on 2 L of oxygen (O2) via nasal cannula presented to the emergency department (ED) with worsening shortness of breath after being diagnosed 1 week earlier with COVID-19. On arrival in the ED, she was afebrile but tachycardic, with a heart rate of 132/min. Blood pressure was 145/80 mmHg, and O2 saturation was 98% on 15 L non-rebreather mask. Initial laboratory tests revealed a normal leukocyte count but elevated acute phase reactant markers, including C-reactive protein (CRP) of 35.1 mg/L (reference range, 0-8.2 mg/L), D-dimer of 0.51 mg/L FEU (reference range, <0.5 mg/L FEU), and lactate dehydrogenase (LDH) of 379 U/L (reference range, 110-260 U/L).\n\nThe patient was admitted for hypoxic respiratory failure. Initial therapy included 500 mg oral azithromycin and 1 g intravenous (IV) ceftriaxone daily. She also received 1 dose of 125 mg IV methylprednisolone, followed by 40 mg of oral prednisone daily.\n\nOn hospital day 2, she developed a pressure-like retrosternal chest discomfort that radiated to her shoulders. Electrocardiogram (ECG) showed diffuse T wave inversions in the inferior and anterolateral leads with prolonged QTc 660 ms (Figure 1). Serial cardiac enzymes showed up-trending of high-intensity troponin markers from 0.01 to 1.0 ng/mL. Because of acute ECG changes and elevated cardiac enzymes, the patient was empirically treated with oral aspirin 325 mg, ticagrelor 180 mg, and a heparin infusion (initial bolus 60 U/kg, followed by 12 U/kg/h).\n\nFigure 1. Initial electrocardiogram with normal sinus rhythm shows T wave inversions in inferior and anterolateral leads with prolonged QTc.\n\nOn hospital day 3, transthoracic echocardiography (TTE) showed new findings of severely reduced left ventricular (LV) systolic function, with an estimated ejection fraction (EF) of 20%. The patient had multiple LV wall abnormalities including akinetic inferolateral and apical anterior walls and hypokinetic basal and septal walls. A small pericardial effusion was also noted (Figure 2). The following differential diagnoses were entertained: acute coronary syndrome, myopericarditis, and stress-induced cardiomyopathy.\n\nFigure 2. Initial echocardiogram in (A) 4-chamber view shows multiple segmental abnormalities and an ejection fraction of 20%. (B) Parasternal long axis view shows multiple segmental abnormalities, trace effusion, and low ejection fraction of 20%.\n\nOn hospital day 4, the patient became markedly agitated, disoriented, and confused. Physical examination revealed normal heart sounds without murmurs, gallops, or rubs, but the patient was noted to have jugular vein distention, decreased breath sounds, lower extremity swelling, and cool extremities. Laboratory tests revealed leukocytosis with a white blood cell count of 30 K/uL (reference range, 3.9-12.7 K/uL), elevated lactic acid at 4.2 mmol/L (reference range, 0.5-2.2 mmol/L), increased CRP of 71.9 mg/L, ferritin of 394 ng/mL (reference range, 20-300 ng/mL), LDH of 591 U/L, and B-type natriuretic peptide of 2,336 pg/mL (reference range, 0-99 pg/mL). Meanwhile, cardiac troponin had trended down from 1.0 to 0.2 ng/mL. Computed tomography scan of the head without contrast was negative for ischemia or intracranial hemorrhage. Repeat ECG noted new diffuse ST elevations, most prominent in the anterolateral and inferior leads and with persistent ST elevation in the inferior leads (Figure 3). Central venous catheter was placed and showed low cardiac output with a significantly reduced mixed venous O2 saturation of 28%. Coronary angiography was not performed because of the patient's infectious state and clinical instability.\n\nFigure 3. Follow-up electrocardiogram shows ST elevations.\n\nBecause of the patient's hypotension, low output state, and congestion, she was transferred to the intensive care unit (ICU) and treated with dobutamine infusion at an initial rate of 2.5 μg/kg/min (up-titrated to 5 μg/kg/min), inhaled nitric oxide at 10 ppm, norepinephrine infusion (0.02-3.0 μg/kg/min), and furosemide 20 mg/h infusion. Heparin infusion and ticagrelor were discontinued because of low suspicion for acute coronary syndrome at that point. The patient's antibiotic regimen was also adjusted, and IV vancomycin 1,250 mg every 24 hours and piperacillin/tazobactam 4.5 g every 8 hours were added (Table 1). Her ICU course was further complicated by tachyarrhythmias, including atrial fibrillation with rapid ventricular response and ventricular tachycardia, which resolved after the addition of amiodarone infusion (150 mg to start, followed by 1 mg/min continuous infusion).\n\nTable 1. Medication Details\n\nMedication\tDose and Frequency\tMethod of Administration\tStart Day\tEnd Day\t\nCeftriaxone\t1 g every 24 h\tIntravenous\tDay 1\tDay 4\t\nAzithromycin\t500 mg once, then 250 mg daily\tOral\tDay 1\tDay 4\t\nMethylprednisolone\t125 mg once\tIntravenous\tDay 1\tDay 1\t\nPrednisone\t40 mg every 24 h\tOral\tDay 2\tDay 4\t\nAspirin\t325 mg once\tOral\tDay 2\tDay 2\t\nTicagrelor\t180 mg once, then 90 mg every 12 h\tOral\tDay 2\tDay 4\t\nHeparin\t60 U/kg to start, followed by 12 U/kg/h continuous infusion\tIntravenous\tDay 2\tDay 4\t\nDobutamine\t2.5 μg/kg/min to start, followed by 5.0 μg/kg/min continuous infusion\tIntravenous\tDay 4\tDay 12\t\nInhaled nitric oxide\t10 ppm\tInhalation\tDay 4\tDay 6\t\nNorepinephrine\t0.02-3.0 μg/kg/min\tIntravenous\tDay 4\tDay 8\t\nFurosemide\t20 mg/h continuous infusion\tIntravenous\tDay 4\tDay 12\t\nVancomycin\t1,250 mg every 24 h\tIntravenous\tDay 4\tDay 6\t\nPiperacillin/tazobactam\t4.5 g every 8 h\tIntravenous\tDay 4\tDay 6\t\nAmiodarone\t150 mg to start, followed by 1 mg/min continuous infusion\tIntravenous\tDay 5\tDay 5\t\nColchicine\t0.6 mg daily\tOral\tDay 8\tDay 14\t\n\nOn hospital day 6, the patient's hemodynamic status had improved. Her vasopressor requirements decreased, and she was successfully weaned off nitric oxide. Bedside TTE revealed apical wall hypokinesis but an improved LV systolic function with an EF of 35% to 40%. All antibiotics were discontinued because of the absence of evidence for bacterial infection.\n\nOn hospital day 8, the patient had been weaned off nor-epinephrine and was started on colchicine 0.6 mg daily for myopericarditis. On examination, she was alert and able to answer yes/no questions but had frequent episodes of delirium.\n\nRepeat ECG on day 9 showed almost full recovery of her LV function, with EF improved to 50%. Moderate circumferential pericardial effusion without tamponade physiology was noted (Figure 4).\n\nFigure 4. Follow-up echocardiogram in (A) 4-chamber view and (B) parasternal long axis view shows improved ejection fraction of 50%, moderate pericardial effusion, and recovery of segmental wall motion abnormalities.\n\nOn hospital day 12, the patient's cardiogenic shock had resolved, and she had been weaned off dobutamine. On examination, she was afebrile with a stable blood pressure of 145/65 mmHg, heart rate of 65/min, and O2 saturation of 98% on 2 L of O2 via nasal cannula. Because of the patient's significantly improved clinical status, she was transferred out of the ICU.\n\nOn hospital day 14, her clinical status deteriorated again, with worsening mentation and significant abdominal pain. Abdominal x-ray revealed signs of bowel obstruction. The patient's family was contacted, and the decision was made not to pursue further intervention. The patient was transitioned to comfort care and died shortly afterward. Table 2 presents a timeline summary of the case.\n\nTable 2. Summary of Patient's Hospital Course\n\nDay 1\tDay 2\tDays 3-5\tDays 6-7\tDay 8\tDay 9\tDays 10-12\tDay 14\t\nPatient admitted for hypoxic respiratory failure due to COVID-19.\tPatient develops chest pain with troponin peak of 1.0 ng/mL. T wave inversions on ECG.\tTTE shows EF of 20%. Diffuse ST elevations on ECG. Patient has altered mental status and signs of cardiogenic shock. Patient on vasopressor and inotropic support. Admitted to ICU.\tPatient improves. Weaned from hemodynamic support. TTE shows EF of 35% to 40%.\tWeaned from all vasopressor support. Started on colchicine.\tTTE shows EF of 50%.\tCardiogenic shock resolved. Patient stepped down to floor.\tClinical status deteriorated; signs of bowel obstruction. Patient transitioned to comfort care.\t\nECG, electrocardiogram; EF, ejection fraction; ICU, intensive care unit; TTE, transthoracic echocardiography.\n\nDISCUSSION\n\nDuring her hospitalization, a patient with acute on chronic respiratory failure in the setting of COVID-19 developed suspected acute myopericarditis with severe LV dysfunction. Although the incidence of myocarditis in patients with COVID-19 remains unknown, increasing evidence links COVID-19 to cardiovascular complications such as arrhythmias, heart failure, cardiogenic shock, fulminant myocarditis, and cardiac death.2\n\nMyopericarditis presents with a variety of symptoms ranging from dyspnea and chest pain to cardiogenic shock, as observed in our case. Cardiac biomarkers troponin I and troponin T may be elevated in cases of myocarditis.3 Incidentally, elevated serum cardiac biomarkers have been recognized in patients with COVID-19, with significantly higher values in patients admitted to the ICU.4 The significance of elevated troponins, however, requires careful consideration, as elevated troponins are a nonspecific marker of myocardial injury. ECG findings with myocarditis are also nonsensitive and nonspecific, with findings such as T wave inversions, nonspecific ST segment changes, and ST elevations mimicking myocardial ischemia as observed in our case (Figure 2). In the presence of elevated cardiac biomarkers and ST elevations on ECG, acute coronary syndrome should always be ruled out. In our patient, however, the diffuse ST elevations with absence of reciprocal changes on ECG, in addition to the presence of elevated CRP, leukocytosis, and pericardial effusion on TTE, was more supportive of myopericarditis. Because of the health care risk associated with the COVID-19 pandemic and the clinical instability of this patient, endomyocardial biopsy, cardiac magnetic resonance imaging, and diagnostic coronary angiogram were not performed.\n\nAnother potential etiology was stress-induced cardiomyopathy, also known as Takotsubo cardiomyopathy.5 This clinical syndrome is characterized by LV dysfunction attributable to significant emotional or physical stress. Takotsubo cardiomyopathy is also characterized by apical ballooning or apical hypokinesia, akinesia, or dyskinesia, with basal hyperkinesis in the absence of major coronary disease on angiography.5 In our case, the TTE showed diffuse wall motion abnormalities, including basal segments, a finding that is atypical in Takotsubo cardiomyopathy.5 Nevertheless, in the absence of angiographic evidence, Takotsubo cardiomyopathy could not entirely be ruled out.\n\nSeveral mechanisms have been suggested in the pathogenesis of COVID-19–related myocardial injury. One is via direct myocardial lysis, where the virus gains entry into the cardiac myocyte by binding to the angiotensin-converting enzyme-2 (ACE2) receptor, leading to changes in the ACE2 pathway with consequent myocardial injury.2,5 Alternatively, elevated proinflammatory cytokines, commonly observed in patients with COVID-19, may trigger an exaggerated response from the immune system, leading to myocardial injury.2,6 Myocardial injury can also result from the body's inability to match the myocardial O2 demands in the setting of increased metabolism caused by systemic infection from COVID-19 and hypoxemia from pneumonitis/pneumonia/acute respiratory distress syndrome.2 Finally, given the high-stress state associated with an acute illness such as COVID-19, catecholamine surge and systemic inflammation may lead to plaque destabilization, rupture, and, eventually, acute coronary syndrome.5\n\nGiven the multiple mechanisms of myocardial injury in patients with COVID-19, consideration of targeted therapeutic options is essential. Data published in October 2020 suggest some benefit with the use of corticosteroids in COVID-19 patients with myocarditis.7 Our patient was treated with steroids in the context of acute respiratory failure and COPD exacerbation, in addition to colchicine for myopericarditis. Colchicine is a well-known anti-inflammatory drug used in the treatment of pericarditis.8,9 A 2019 paper by Tardif et al showed that colchicine is beneficial in reducing adverse cardiovascular events.10 The use of glucocorticoids and colchicine in COVID-19 patients with myopericarditis may have some benefit.\n\nCONCLUSION\n\nThis case highlights the diagnostic and therapeutic challenges that physicians may encounter when managing acute cardiac injury in the setting of COVID-19. We believe it is essential to recognize that the multiple mechanisms of COVID-19–related myocardial injury may influence the approach to diagnosis and treatment. Also, further evidence is needed to determine the utility of immunomodulatory agents and glucocorticoid therapy for patients with suspected COVID-19 myocarditis.\n\nACKNOWLEDGMENTS\n\nThe authors have no financial or proprietary interest in the subject matter of this article.\n\nThis article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care and Medical Knowledge.\n==== Refs\nREFERENCES\n\n1. Coronavirus disease (COVID-19) pandemic. World Health Organization. September 2020. Accessed September 25, 2020. www.who.int/emergencies/diseases/novel-coronavirus-2019\n2. Guzik TJ , Mohiddin SA , Dimarco A , COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res. 2020;116 (10 ):1666-1687. doi: 10.1093/cvr/cvaa106 32352535\n3. Blauwet LA , Cooper LT . Myocarditis. Prog Cardiovasc Dis. 2010;52 (4 ):274-288. doi: 10.1016/j.pcad.2009.11.006 20109598\n4. Wang D , Hu B , Hu C , Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323 (11 ):1061-1069. doi: 10.1001/jama.2020.1585 32031570\n5. de Chazal HM , Del Buono MG , Keyser-Marcus L , et al. Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72 (16 ):1955-1971. doi: 10.1016/j.jacc.2018.07.072 30309474\n6. Libby P . The heart in COVID-19: primary target or secondary bystander? JACC Basic Transl Sci. 2020;5 (5 ):537-542. doi: 10.1016/j.jacbts.2020.04.001 32292847\n7. Kow CS , Hasan SS . Glucocorticoid versus immunoglobulin in the treatment of COVID-19-associated fulminant myocarditis. Infection. 2020;48 (5 ):805-806. doi: 10.1007/s15010-020-01441-4 32388676\n8. Imazio M , Brucato A , Adler Y . A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2014;370 (8 ):781. doi: 10.1056/NEJMc1315351\n9. Imazio M , Belli R , Brucato A , Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicenter, double-blind, placebo-controlled, randomised trial. Lancet. 2014;383 (9936 ):2232-2237. doi: 10.1016/S0140-6736(13)62709-9 24694983\n10. Tardif JC , Kouz S , Waters DD , Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381 (26 ):2497-2505. doi: 10.1056/NEJMoa1912388 31733140\n\n",
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"issn_linking": "1524-5012",
"issue": "21(2)",
"journal": "The Ochsner journal",
"keywords": "COVID-19; Cardiomyopathies; Takotsubo cardiomyopathy; myocarditis; pericarditis",
"medline_ta": "Ochsner J",
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"pages": "181-186",
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"pubdate": "2021",
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"references": "24694983;32031570;30309474;32388676;32292847;20109598;32352535;31733140;24552333",
"title": "Suspected COVID-19-Induced Myopericarditis.",
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}
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},
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"literaturereference": "OKOR I, SLEEM A, ZHANG A, KADAKIA R, BOB?MANUEL T, KRIM S. SUSPECTED COVID?19?INDUCED MYOPERICARDITIS. OCHSNER JOURNAL. 2021?21 (2):181?186. DOI:10.31486/TOJ.20.0090",
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},
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] |
{
"abstract": "Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiological syndrome characterized by seizures, altered level of consciousness, visual disturbance, and hyperintense lesions on magnetic resonance imaging most commonly in the posterior regions. PRES is typically associated with a number of complex clinical conditions including: Preeclampsia/eclampsia, allogeneic bone marrow transplantation, solid organ transplantation, autoimmune diseases, and high-dose anti-neoplastic therapy. We herein describe a case of recurrent PRES in a 29-year-old lady of refractory anaplastic large-cell lymphoma who was on second-line chemotherapy with Ifosfamide-Carboplatin-etoposide regimen. We have also tried to illustrate the pathogenesis, radiological features, and management of PRES. Although reversible in most cases, PRES may be recurrent even in chemotherapy--induced cases and result in fatal outcomes despite appropriate intervention. This is the first--reported case of recurrent PRES with such a fatal outcome, as a complication of anti-neoplastic systemic therapy.",
"affiliations": "Department of Radiation Oncology, Institute Rotary Cancer Hospital, AIIMS, New Delhi, India.",
"authors": "Roy|Soumyajit|S|;Gandhi|Ajeet K|AK|;Jana|Manisha|M|;Julka|Pramod K|PK|",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; D016190:Carboplatin; D007069:Ifosfamide",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.136668",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "10(2)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D059248:Chemoradiotherapy; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007069:Ifosfamide; D017728:Lymphoma, Large-Cell, Anaplastic; D054038:Posterior Leukoencephalopathy Syndrome; D011239:Prednisolone; D016879:Salvage Therapy; D014750:Vincristine",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "393-6",
"pmc": null,
"pmid": "25022403",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Recurrent posterior reversible encephalopathy syndrome after chemotherapy in hematologic malignancy-posterior reversible encephalopathy syndrome can strike twice!!!",
"title_normalized": "recurrent posterior reversible encephalopathy syndrome after chemotherapy in hematologic malignancy posterior reversible encephalopathy syndrome can strike twice"
} | [
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],
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"abstract": "Gag protein of human immunodeficiency virus (HIV) has been reported to play a crucial role in establishing infection, viral replication, and disease progression; thus, gag might be related to treatment response. The objective of this study was to investigate molecular genotypes of the gag gene, particularly the important functional binding domains in relation to treatment outcomes.\nHIV-infected children enrolled and treated at Vietnam National Children's Hospital were recruited in the study. A total of 25 gag sequences were generated and used to construct phylogenetic trees and aligned with a reference sequence comparing 17 functional domains.\nWe found that all patients in a treatment failure (TF) group belonged to one cluster of the phylogenetic tree. In addition, the rate of mutations was significantly higher in TF compared with a treatment success (TS) group, specifically the PIP2 recognition motif, and the nucleocapsid basic and zinc motif 2 domains [median and (interquartile range (IQR): 12.5 (6.25-12.5) versus 50 (25-50), p < 0.01; 0 (0-0) versus 0 (0-21.43), p = 0.03 and 0 (0-7.14) versus 7.14 (7.14-7.14), p = 0.04, respectively]. When analyzing gag sequences at different time points in seven patients, we did not observe a consistent mutation pattern related to treatment response.\nGag mutations in certain domains might be associated with increased viral load; therefore, studying the molecular genotype of the gag gene might be beneficial in monitoring treatment response in HIV-infected children.",
"affiliations": "Laboratory Centre, Hanoi University of Public Health, 1 Duc Thang, North Tu Liem, Hanoi, Vietnam.;Vietnam National Children's Hospital, Hanoi, Vietnam.;Hanoi University of Public Health, Hanoi, Vietnam.;Dinh Tien Hoang Institute of Medicine, Hanoi, Vietnam.;Vietnam National Children's Hospital, Hanoi, Vietnam.;Vietnam National Children's Hospital, Hanoi, Vietnam.;Training and Research Academic Collaboration (TRAC), Sweden, Vietnam.;Training and Research Academic Collaboration (TRAC), Sweden, Vietnam.",
"authors": "Dang|Linh Vu Phuong|LVP|https://orcid.org/0000-0001-6886-2713;Pham|Hung Viet|HV|;Dinh|Thanh Thi|TT|;Vu|Phuong Thi|PT|;Nguyen|Lam Van|LV|;Le|Hai Thanh|HT|;Larsson|Mattias|M|;Olson|Linus|L|https://orcid.org/0000-0003-0046-6348",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2049936120958536",
"fulltext": "\n==== Front\nTher Adv Infect Dis\nTher Adv Infect Dis\nTAI\nsptai\nTherapeutic Advances in Infectious Disease\n2049-9361 2049-937X SAGE Publications Sage UK: London, England \n\n10.1177/2049936120958536\n10.1177_2049936120958536\nOriginal Research\nMolecular genotypes of gag sequences in HIV-1 infected children treated with antiretroviral therapy in Vietnam\nhttps://orcid.org/0000-0001-6886-2713Dang Linh Vu Phuong Laboratory Centre, Hanoi University of Public Health, 1 Duc Thang, North Tu Liem, Hanoi, Vietnam\n Pham Hung Viet Vietnam National Children’s Hospital, Hanoi, Vietnam\n Dinh Thanh Thi Hanoi University of Public Health, Hanoi, Vietnam\n Vu Phuong Thi Dinh Tien Hoang Institute of Medicine, Hanoi, Vietnam\n Nguyen Lam Van Vietnam National Children’s Hospital, Hanoi, Vietnam\n Le Hai Thanh Vietnam National Children’s Hospital, Hanoi, Vietnam\n Larsson Mattias Training and Research Academic Collaboration (TRAC), Sweden, Vietnam\nDepartment of Global Public Health, Karolinska Institutet, Stockholm, Sweden\n https://orcid.org/0000-0003-0046-6348Olson Linus Training and Research Academic Collaboration (TRAC), Sweden, Vietnam\nDepartment of Global Public Health, Karolinska Institutet, Stockholm, Sweden\nDepartment of Woman’s and Child’s Health, Karolinska Institutet, Stockholm, Sweden\n dvpl@huph.edu.vn; phuonglinh.j@gmail.com\n17 9 2020 \nJan-Dec 2020 \n7 204993612095853625 2 2020 18 8 2020 © The Author(s), 20202020SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background:\nGag protein of human immunodeficiency virus (HIV) has been reported to play a crucial role in establishing infection, viral replication, and disease progression; thus, gag might be related to treatment response. The objective of this study was to investigate molecular genotypes of the gag gene, particularly the important functional binding domains in relation to treatment outcomes.\n\nMethods:\nHIV-infected children enrolled and treated at Vietnam National Children’s Hospital were recruited in the study. A total of 25 gag sequences were generated and used to construct phylogenetic trees and aligned with a reference sequence comparing 17 functional domains.\n\nResults:\nWe found that all patients in a treatment failure (TF) group belonged to one cluster of the phylogenetic tree. In addition, the rate of mutations was significantly higher in TF compared with a treatment success (TS) group, specifically the PIP2 recognition motif, and the nucleocapsid basic and zinc motif 2 domains [median and (interquartile range (IQR): 12.5 (6.25–12.5) versus 50 (25–50), p < 0.01; 0 (0–0) versus 0 (0–21.43), p = 0.03 and 0 (0–7.14) versus 7.14 (7.14–7.14), p = 0.04, respectively]. When analyzing gag sequences at different time points in seven patients, we did not observe a consistent mutation pattern related to treatment response.\n\nConclusion:\nGag mutations in certain domains might be associated with increased viral load; therefore, studying the molecular genotype of the gag gene might be beneficial in monitoring treatment response in HIV-infected children.\n\nARTCD4 T cell countsgag mutationHIV-1HIV viral loadtreatment failurenational foundation for science and technology developmenthttps://doi.org/10.13039/100007224Training and Research Academic Collaboration (TRAC) – Sweden – Vietnamcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nHuman immunodeficiency virus (HIV) disease progression following infection varies greatly between individuals. While certain patients remain asymptomatic for long periods of time without treatment, known as long-term non-progressors (LTNPs),1,2 the majority of patients follow a similar pattern of disease progression, with an increased viral load followed by viral suppression and the acquired immunodeficiency syndrome (AIDS) stage, during which the viral load is increased again. The duration of disease progression is dependent on a numbers of factors, in which HIV virus evolution and immune response are considered to be among the most important elements.3,4 Generally, children infected with HIV encounter faster rates of disease progression compared with that of their adult counterparts.5,6 Faster disease progression could be due to immature development of the immune system of children, and the substantial rate of evolution of the HIV virus in pediatric populations.3,5\n\nAnalyses of the HIV genome has revealed evidence of genomic instability, ranging from single-nucleotide polymorphisms (SNPs) to sequence deletions in HIV-1 genes encoding structural, regulatory, and accessory proteins such as gag (structural) and nef (accessory) in HIV-infected children.7,8 Diverse polymorphisms in the gag gene have been shown to be associated with disease progression,9 whereas studies analyzing the HIV genome in long-term non-progressors LTNPs or “elite controllers” have reported no significant defects of the amino acid sequence of gag,10 suggesting a role of genetic variability of gag in disease progression.\n\nGag protein, after being translated, is able to find and bind specifically to viral genomic RNA and bring this compound to the host cell membrane, facilitating viral budding from the membrane forming a new virion.11,12 Many studies have emphasized the irreplaceable role of gag protein in the process of viral assembly, binding, and maturation of new virions.13,14 Structurally, the gag polyprotein is stratified into four different big domains, including the N terminus matrix (MA), capsid (CA), nucleocapsid (NC), and the C terminus P6 domains, which are further divided into smaller domains with different functions in the HIV cycle process. The MA domain, which contains basic myristoylation, PIP (PCNA-interacting protein) 2 recognition motif, trimer interface 1, trimer interface 2, and nuclear localization 2 domains, is required for plasma membrane targeting, binding, and viral assembly.15 The CA domain, which is responsible for development of a structural core, consists of NTD-NTD interface 2, NTD-NTD interface 3, cyclophilin A binding, MHR (major homology region), and dimerization domains. In addition, two important domains called nucleocapsid and zinc motif 2 belonging to the NC domain containing Zinc motif 1, have been shown to participate in recognition and interaction during viral replication. The last domain, P6, includes Vpr binding 1, ALIX interaction, and Vpr binding 2 domains and has been shown to be involved in processing viral particles.16,17 When these domains are mutated, viral replication, and, subsequently, disease progression might be significantly affected.18,19 With the current study, we investigated the molecular pattern of these functional domains in HIV-infected children.\n\nResearch methods and design\nSetting\nThe study has a retrospective design. The study subjects were selected from outpatients diagnosed and treated at National Children’s Hospital, Hanoi, Vietnam. The treatment was first-line ART containing one non-nucleoside reverse transcriptase inhibitor (Nevirapine) and two nucleoside reverse transcriptase inhibitors (Stavudine or Zidovudine and Lamivudine).\n\nStudy population and sampling strategy\nPatients were taken from a previous study20; 86 patients were included, with full informed consent signed by the parents or responsible person. Ethical permission for the current research has also been approved by the ethical committee of Hanoi University of Public Health with the registration number 261/2015/YTCC-HD3.\n\nIn the study, 24 blood samples of patients were collected, and RNA was extracted and sequencing. The blood samples were used to determine CD4 T cell counts, CD4 T cell percentage, and HIV viral load. We later followed up patients but only managed to obtain seven samples after 24 months of following up for further analysis. The ID number of each patient, and status regarding treatment response, are included in supplemental data.\n\nLaboratory methods\nPeripheral CD4 T-cell counts were analyzed by Flow Cytometry (Sysmex Partec, Münster, Germany) and biannual quantification of viral load using the Cobas Taqman HIV-1 test (detection limit, 40 copies/ml).\n\nViral RNA was extracted from plasma samples (280 µl) by QIAamp Viral RNA Mini Kit (Qiagen, Hilden, Germany) and was used to synthesize cDNA using First-Strand Synthesis System for reverse-transcriptase (RT)–PCR (Invitrogen, Carlsbad, CA, USA) using random primers. A PCR was implemented to retrieve gag regions. The PCR mixtures and cycling conditions were described previously.21 For the gag region, primers used to amplify HXB2 positions 796-2381 were F2NST (5′-GCGGAGGCTAGAAGGAGAGAGATGG -3′) and SP3AS (5′-CCTCCAATTCCCCCTATCATTTTTGG-3′).22 First-round PCRs were conducted in 50 µl reaction containing 25 µl of master mix consisting of 10 × PCR Gold buffer (Applied Biosystems Inc., Foster City, CA, USA), a 40 µM concentration of each deoxynucleoside triphosphate (dNTP), 1.5 mM MgCl2, 0.75 U of AmpliTaq Gold DNA polymerase (Applied Biosystems Inc.); 2 µl of 0.4 µM concentration of each primer; and 5–10 µl of DNA template. The cycling conditions for the first round were 1 cycle at 95°C for 10 min; 30 cycles of 95°C for 10 s, the annealing temperature at 68°C for 30 s, and extension at 72°C for 1min; and a final extension at 72°C for 5 min. The second-round PCRs contained similar final concentrations in the PCR mixtures, but with 1 µl of the pooled first-round products with similar cycling conditions.\n\nThe final PCR products obtained were purified and directly sequenced using Big Dye terminator reaction kits and a capillary sequencer (Applied Biosystems 3100). The sequences obtained were aligned with reference sequence HXB2, with relevant subtypes and circulating recombinant forms (CRF01-AE), using Bioedit software and blast in NCBI and Mega 5.0 software. The gag gene sequence was further analyzed using the MAFFT version 7 program (https://mafft.cbrc.jp/alignment/server/). A total of 17 important functional domains were aligned with the HXB2 strain in the Los Alamos HIV database, including basic myristylation, PIP2 recognition motif, trimer interface 1, trimer interface 2, nuclear localization 2, NTD-NTD interface 1, NTD-NTD interface 2, NTD-NTD interface 3, cyclophilin A binding, MHR, dimerization, interaction domain, zinc motif 1, nucleocapsid basic domain, zinc motif 2, Vpr binding 1, and ALIX interaction.8\n\nData analysis\nData were collected and managed by excel and analyzed by Stata 12.0.20 (Stata Corp LLC, College Station, TX, USA) for descriptive statistics and statistical inference. The descriptive statistic was used to summarize the variables of different groups, whereas the statistical inference was used to compare different variables between TF and TS groups. Since the data were not normally distributed, the descriptive statistics were median with interquartile range (IQR) and N (number) and % (percentage); whereas Mann–Whitney test and multiple comparison were used to compare different variables between treatment success (TS) and treatment failure (TF) groups.\n\nResults\nCharacteristics of HIV-infected subjects\nAs can be seen from Table 1, the total participants were 25, in which 16 participants were male and 9 were female. The median age of HIV-infected children was 4.7 in the TS group (IQR 3.1–6.8), and 5.8 in the TF group (3.7–7.8). The median CD4 T cell count was not significantly different between TS and TF groups [594 (270–976) versus 523 (162–884), respectively]. Nevertheless, the median HIV viral load was significantly lower in the TS, compared with the TF group 400 (400–400) versus 5021,000 (42,000–10,000,000), respectively (p < 0.01). There were higher numbers of boys than girls in the TS group, whereas the TF group had opposite gender proportions; 80% of the patients in the TS group suffered from opportunistic infections, and all patients in the TF group had opportunistic infections, the majority of which were at clinical stage 2 and 3 (Table 1). There were six patients with a viral load of >1000 copies/ml and thus belonging to the TF group (the ID of patients include 1053, 1065, 1072, 1082, 1087, and 1145). The remaining patients belonged to the TS group (data not shown).\n\nTable 1. The general and clinical characteristics of HIV infected children in current study.\n\nCharacteristics\tTS\tTF\tp value (Mann–Whitney)\t\n\tMedian\tIQR\tMedian\tIQR\t\nAge\t4.7\t3.1\t6.8\t5.8\t3.9\t7.8\t0.52\t\nCD4 T cell counts\t594\t270\t976\t523\t162\t884\t0.84\t\nCD4 T cell percentage\t23.2\t15.8\t26.7\t17.7\t8\t27.4\t0.96\t\nHIV viral load\t400\t400\t400\t5021000\t42000\t10,000,000\t<0.01\t\nCharacteristics\t\t\t\tTS\tTF\t\n\t\t\t\t\nn\n\t%\t\nn\n\t%\t\nSex\t\t\tMale\t14\t64\t1\t14.3\t\n\t\t\tFemale\t9\t36\t5\t85.7\t\nOpportunistic infection\t\t\t20\t87\t6\t100\t\nClinical stage of HIV infection\t\t\t\n1\n\t4\t16\t\t\t\n\t\t\t\n2\n\t11\t44\t5\t83.3\t\n\t\t\t\n3\n\t4\t16\t1\t16.7\t\n\t\t\t\n4\n\t1\t4\t\t\t\nHIV, human immunodeficiency virus; IQR, Interquartile range; N, number; TF, treatment failure; TS, treatment success.\n\nGenetic analysis of the gag gene in HIV-infected subjects\nPhylogenetic analysis of the gag gene showed that all HIV from patients belonged to genotype CRF01_AE (data not shown). The result showed that all the patients in the TF group belonged to cluster 1 of the phylogenetic tree. Specifically, patients 1053, 1082, and 1145 belonged to cluster 1.1, whereas patients 1072, 1065, and 1087 belonged to cluster 1.2 (Figure 1). Three patients belonging to cluster 1.1 had high HIV viral load and low CD4 T cell counts, while patients belonging to cluster 1.2 had high CD4 T cell counts despite high HIV viral load.\n\nFigure 1. Phylogenetic tree based on gag gene in HIV-1 infected participants in the study.\n\nHIV-1, human immunodeficiency virus-1.\n\nStratifying into different functional domains of gag protein, we found that TF patients encountered a higher frequency of mutations compared with TS patients (supplemental Figure). While the majority of functional domains did not differ significantly between TS and TF patients, the median rate of mutations in the PIP2 recognition motif in the TF group was significantly higher compared with the TS group [50 (25–50) versus 12.5 (6.25–12.5), p < 0.01]. Similarly, nucleocapsid basic domain and zinc motif 2 also carried higher levels of mutations in TF compared with TS patients [0 (0–0) versus 0 (0–21.43), p = 0.03 and 0 (0–7.14) versus 7.14 (7.14–25), p = 0.04, respectively] (Table 2). When using multiple comparison, only PIP2 recognition motif and Nucleocapsid basic domain showed the significant different between two groups (p < 0.01 and p = 0.03, respectively).\n\nTable 2. The percentage of difference between different gag functional domain sequence of HIV-infected participant in the current study compared with the referenced sequence.\n\nFunctional domains\tTS\tTF\tp value (Mann-Whitney)\tMultiple comparison\t\n\tMedian\tIQR\tMedian\tIQR\t\nBasic domain\t12.50\t6.25\t12.50\t12.50\t6.25\t12.50\t0.66\t0.95\t\nPIP2 recognition motif\t12.50\t6.25\t12.50\t50.00\t25.00\t50.00\t<0.01\t<0.01\t\nTrimer interface 1\t16.67\t16.67\t16.67\t16.67\t16.67\t16.67\t0.94\t0.97\t\nTrimer interface 2\t16.67\t16.67\t16.67\t16.67\t16.67\t16.67\t0.45\t0.43\t\nNuclear localization 2\t66.67\t66.67\t66.67\t66.67\t66.67\t66.67\t0.6\t1.0\t\nNTD-NTD interface 1\t0\t0\t0\t0\t0\t0\tNA\tNA\t\nNTD-NTD interface 2\t0\t0\t0\t0\t0\t0\tNA\tNA\t\nNTD-NTD interface 3\t20.00\t20.00\t20.00\t20.00\t20.00\t20.00\t0.3\t0.08\t\nCyclophilin A binding\t10.00\t10.00\t10.00\t10.00\t10.00\t20.00\t0.63\t0.83\t\nMHR\t0\t0\t0\t0\t0\t4.76\t0.37\t0.56\t\nDimerization\t9.09\t9.09\t9.09\t9.09\t0\t9.09\t0.12\t0.20\t\nInteraction domain\t14.29\t14.29\t28.57\t21.43\t14.29\t28.57\t0.42\t0.21\t\nZinc motif 1\t7.14\t7.14\t7.14\t21.43\t7.14\t42.86\t0.08\t0.45\t\nNucleocapsid basic domain\t0\t0\t0\t0\t0\t21.43\t0.03\t0.03\t\nZinc motif 2\t0\t0\t7.14\t7.14\t7.14\t25.00\t0.04\t0.13\t\nALIX interaction\t85.71\t71.43\t85.71\t85.71\t57.14\t85.71\t0.83\t0.97\t\nVpr binding 1\t20.00\t20.00\t20.00\t20.00\t20.00\t20.00\t0.58\tNA\t\nThe data is presented as the difference between different Gag functional domains in comparison to the reference sequence.\n\nHIV, human immunodeficiency virus; IQR, Interquartile range; MHR, major homology region; NA, Not applicable; TF, treatment failure; TS, treatment success.\n\nFigure 2 represents the sequencing of seven patients with different time points. Regardless of the treatment response, all the sequences showed high levels of homogeneity compared with reference sequences. The trimer interface 2, and the NTD-NTD interface 3 domain sequences collected at different time points were highly homogenous, with only one amino acid substitution in both sequences, compared with the reference sequence. The results were similar for nuclear localization 2 domain, except for patients 1032, in which one amino acid was different between sequences taken at two different time points (Figure 2).\n\nFigure 2. Mutations in the gag gene in HIV-1 infected participant in the study. The gag sequence of the same patients was analyzed at two different time points (L1 and L2, in which L1 was taken prior to treatment initiation while L2 was taken after 24 h of the treatment initiation). The two sequences at different time points were aligned with each other and aligned with the referenced sequence.\n\nHIV-1, human immunodeficiency virus-1.\n\nThe cyclophilin A binding domain of patient 1058 showed one amino acid difference in both sequences compared with the reference gene, while patient 1082 was found to have one amino acid substitution within sequences taken at different time points. The zinc motif one domain showed one amino acid substitution in patients 1015; six amino acid substitutions in patients 1077, and one amino acid substitution in patient 1087, compared with sequences of the same patient taken at earlier time points. Both patients 1015 and 1087 had one amino acid insertion and one amino acid substitution in both sequences in comparison with the reference gene (Figure 2).\n\nDiscussion\nIn this study, we analyzed sequences of the gag gene in HIV-infected children in relation to treatment response. Consistent with most of findings concerning the HIV genome in South East Asia, our results confirmed presence of the subtype CRF01_AE in all patients in the present study.23 Extensive studies have been conducted to investigate the association between HIV subtype and disease progression; however, the results have been inconsistent.24 Saina et al. indicated that patients could be either rapid or slow progressors regardless of subtype distribution.25\n\nIn the present study, we found that, even though all patients were found to carry the subtype CRF01_AE, phylogenic cluster analysis reveal that participants belong to different clusters of the phylogenic tree. In addition, Louwagie has suggested that the subtype A has the most diversity of gag gene among other subtypes26; thus, we might speculate that the subtype CRF01_AE might encounter high levels of diversity. Since all children in the study were infected with HIV vertically, the HIV genotype reflected directly the genotype of their mother, suggesting the variety of complex recombinant forms of HIV in Vietnam. Interestingly, TF patients with high CD4 T cell counts and high viral load belonged to one cluster, whereas TF patients with low CD4 T cell counts and high HIV viral load belonged to another cluster. High viral load might be the result of the increase of viral replication, infectivity, viral fitness or/and immune-escape mutations. The results might implicate that HIV virus in these patients underwent similar mutations in the gag gene, leading to increased viral replication. Two patients (1053 and 1087) on the same cluster were shown to have developed reverse transcriptase inhibitor (RTI)-resistance mutations, which are the most dominant lamivudine-resistant mutations found among HIV infected children in Vietnam.20 The M184V/I mutation has been found to be associated with increased viral load in several studies,27,28 and immunological recovery despite virological failure has previously been reported in patients with an M184V escape mutation that confers lamivudine resistance.29 The mutation M184V/I has been shown to affect other mutations in different genes,30 and it might be speculated that M184V/I might be associated with certain mutations in the gag gene facilitating increased viral load. Similarly, other mutations in the gag gene might result in lower viral load. The causal relationship between gag mutations and CD4 T cell counts has not been fully established. Therefore, the low CD4 T cell counts in the TF group belonging to a lower cluster of the tree might not reflect a direct consequence of profound viral replication as the result of gag mutations. Nevertheless, these patients might already suffer from low CD4 T cell counts prior to elevation of viral load as the result of gag mutations. Other clusters containing patients with high CD4 T cell counts despite high levels of viral load might be an interesting group to study. However, we have not found consistent mutations in this group, suggesting complexity of mutations and interaction between these mutations for the establishment of viral replication in different settings with CD4 T cell counts.\n\nSaina et al. found no significant between-group differences in the amino acid variations, insertions, or deletions of gag sequences, and proposed that gag sequence variations are not as important as HLA in influencing disease progression.25 Inconsistent with this finding, we did observe a significant difference in rate of mutations in the gag gene of the TF group in comparison with those of the TS group, particularly with regard to the PIP2 recognition motif and nucleocapsid basic domains. The PIP2 recognition motif is involved in the assemblance of HIV at the plasma membrane of infected cells, and several studies emphasize the importance of the PIP2 recognition motif for the production of infectious virions,31 and, without the PIP2 recognition motif, membrane binding would not occur.32,33 Unfortunately, we could not find the established association between mutation of the PIP2 recognition motif and increased viral replication. Nevertheless, given the role of this domain, it is reasonable that high levels of mutations might be associated with increased HIV replication or infectivity in patients. Monde et al. pointed out that the PIP2 domain is crucial for Gag binding to the plasma membrane and the release of virus from the cell line. The adapted mutant virus (74LR) displayed accelerated replication kinetics compared with wild-type virus, which is probably due to increased virus infectivity.34 We did not observe the 74LR mutation in our patient, suggesting that another mechanism might be involved in our cohort.\n\nThe nucleocapsid domain, on the other hand, is required for RNA binding activity and thus affects virus assembly.35,36 Several studies have pointed out the crucial role of the nucleocapsid domain for RNA packaging and recombination, and show that mutations at the nucleocapsid domain lead to inefficient package of viral RNA. However, in our data, mutations at this domain were observed in patients with high viral load, suggesting that these mutations might be associated with viral packaging and thus viral assembly. Regarding the mutations observed in the zinc finger motif domain, and consistent with our finding, Mark-Danieli et al. also identified a relationship between zinc finger mutants and increased RNA-binding specificities, and showed that the N17K mutant led to a 7- to 9-fold increase in RNA packaging.37 Compared with the N17K mutant virus, E21K and N27K mutant viruses were not significantly superior to the WT virus in transduction efficiency. The domain has proven necessary for different steps of the HIV life cycle, and deletions of the domain might result in defective viral formation. The different mutations in the domain were found to yield different outcomes regarding viral development.37,38 We found that HIV mutations in these domains might be associated with increased HIV replication, and, thus, might enhance infectivity. Through evolution, certain mutants became associated with increased infectivity and others became associated with decreased viral stability. Understanding the interaction between these mutations is a complex issue in need of further research.\n\nOverall, our results also confirmed that TF patients had higher levels of mutation in the gag gene in comparison to TS patients, which is consistent with the finding that patients with disease progression tend to have diverse polymorphisms in the gag gene,9 while LTNPs or “elite controllers” showed limited mutations in the gag gene.10 In addition, TF patients in the study also showed high levels of viral load, suggesting that gag mutations and viral load might have a certain association. The association between these two factors should be studied further in order to answer the question of how and why increased gag mutations might lead to increased pace of disease progression.\n\nOur study has several limitations. First, we accessed mutations of gag sequences at only one time point and the number of patients was limited. Secondly, we were able to access only seven patients at different time points. However, given the diversity in the gag gene, our cases contribute to the understanding of mutations within the gag gene in relation to treatment response. Thirdly, in our setting, we could assess only the most prominent clone of HIV virus as this might represent the minority effect of HIV to disease progression, thus careful interpretation of the data should be taken into consideration. And finally, our results present observation only, therefore it is difficult to draw any evidence-based conclusions from the results.\n\nConclusion\nIn conclusion, Gag mutations in certain domains might be associated with increased viral load; therefore studying the molecular genotype of the gag gene might be beneficial in monitoring treatment response in HIV-infected children.\n\nSupplemental Material\nSupplementary_data_1 – Supplemental material for Molecular genotypes of gag sequences in HIV-1 infected children treated with antiretroviral therapy in Vietnam\nClick here for additional data file.\n\nSupplemental material, Supplementary_data_1 for Molecular genotypes of gag sequences in HIV-1 infected children treated with antiretroviral therapy in Vietnam by Linh Vu Phuong Dang, Hung Viet Pham, Thanh Thi Dinh, Phuong Thi Vu, Lam Van Nguyen, Hai Thanh Le, Mattias Larsson and Linus Olson in Therapeutic Advances in Infectious Disease\n\n We would like to express our appreciation to the National Foundation for Science and Technology Development, Ministry of Science and Technology (grant number 106-YS.02-2014.22.), for financial support. We thank our students Nguyen Manh Tien, Nguyen Huu The Tung, Tran Thi Anh, Nguyen Anh Dung for valuable contributions. We would also like to thank The Swedish Foundation for International Cooperation in Research and Higher Education, STINT (through the TRAC Collaboration Sweden-Vietnam) for the support.\n\nAuthor contributions: Linh Vu Phuong Dang: Conception and designing study; writing manuscript\n\nHung Viet Pham: performing experiment\n\nThanh Thi Dinh: literature search; administrative, technical and logistic support, performing analysis\n\nPhuong Thi Vu: analysis and interpretation of the data\n\nLam Van Nguyen: sample and data collection\n\nHai Thanh Le: Provision of data and sample of patients\n\nLinus Olson: Writing manuscript, critical revision of the manuscript\n\nConflict of interest statement: All authors were involved in the research and the writing of the manuscript and have approved the final version for this publication. We declare no conflict of interests.\n\nFunding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Nafosted, National Foundation for Science and Technology Development, Training and Research Academic Collaboration (TRAC) – Sweden – Vietnam\n\nORCID iDs: Linh Vu Phuong Dang \nhttps://orcid.org/0000-0001-6886-2713\n\nLinus Olson \nhttps://orcid.org/0000-0003-0046-6348\n\nSupplemental material: Supplemental material for this article is available online.\n==== Refs\nReferences\n1 \nGurdasani D Iles L Dillon DG , et al\nA systematic review of definitions of extreme phenotypes of HIV control and progression\n. AIDS \n2014 ; 28 : 149 –162\n.24149086 \n2 \nPoropatich K Sullivan DJ Jr. \nHuman immunodeficiency virus type 1 long-term non-progressors: the viral, genetic and immunological basis for disease non-progression\n. 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Clin Diagn Lab Immunol \n2003 ; 10 : 979 –981\n.14607855 \n31 \nMucksch F Laketa V Muller B , et al\nSynchronized HIV assembly by tunable PIP2 changes reveals PIP2 requirement for stable Gag anchoring\n. Elife \n2017 ; 6 .\n32 \nDick RA Vogt VM \nMembrane interaction of retroviral Gag proteins\n. Front Microbiol \n2014 ; 5 : 187 .24808894 \n33 \nChukkapalli V Hogue IB Boyko V , et al\nInteraction between the human immunodeficiency virus type 1 Gag matrix domain and phosphatidylinositol-(4,5)-bisphosphate is essential for efficient gag membrane binding\n. J Virol \n2008 ; 82 : 2405 –2417\n.18094158 \n34 \nMonde K Chukkapalli V Ono A \nAssembly and replication of HIV-1 in T cells with low levels of phosphatidylinositol-(4,5)-bisphosphate\n. J Virol \n2011 ; 85 : 3584 –3595\n.21270152 \n35 \nBurniston MT Cimarelli A Colgan J , et al\nHuman immunodeficiency virus type 1 gag polyprotein multimerization requires the nucleocapsid domain and RNA and is promoted by the capsid-dimer interface and the basic region of matrix protein\n. J Virol \n1999 ; 73 : 8527 –8540\n.10482606 \n36 \nBowzard JB Bennett RP Krishna NK , et al\nImportance of basic residues in the nucleocapsid sequence for retrovirus gag assembly and complementation rescue\n. J Virol \n1998 ; 72 : 9034 –9044\n.9765448 \n37 \nMark-Danieli M Laham N Kenan-Eichler M , et al\nSingle point mutations in the zinc finger motifs of the human immunodeficiency virus type 1 nucleocapsid alter RNA binding specificities of the gag protein and enhance packaging and infectivity\n. J Virol \n2005 ; 79 : 7756 –7767\n.15919928 \n38 \nThomas JA Gagliardi TD Alvord WG , et al\nHuman immunodeficiency virus type 1 nucleocapsid zinc-finger mutations cause defects in reverse transcription and integration\n. Virology \n2006 ; 353 : 41 –51\n.16784767\n\n",
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"keywords": "ART; CD4 T cell counts; HIV viral load; HIV-1; gag mutation; treatment failure",
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{
"abstract": "We report a patient with AIDS who had an anaphylactic-like reaction from trimethoprim-sulfamethoxazole. Clinical suspicion of anaphylaxis should be considered in patients presenting with fever, hypotension, eosinophilia, rash, flushing or pulmonary infiltrates after initial exposure and re-exposure to the medication. This case highlights the need for healthcare professionals to be reminded of the association between this unusual antibiotic reaction resembling sepsis and HIV disease.",
"affiliations": "Department of Internal Medicine, Riverside County Regional Medical Center, Moreno Valley, CA, USA jpersich@co.riverside.ca.us.;Infectious Disease Section, Riverside County Regional Medical Center, Moreno Valley, CA, USA.",
"authors": "Persichino|Jon|J|;Sutjita|Made|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "England",
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"doi": "10.1177/0956462415587442",
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"issn_linking": "0956-4624",
"issue": "27(7)",
"journal": "International journal of STD & AIDS",
"keywords": "AIDS; HIV; Trimethoprim-sulfamethoxazole; adverse drug reaction; anaphylaxis; sepsis",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D000707:Anaphylaxis; D000900:Anti-Bacterial Agents; D004342:Drug Hypersensitivity; D005260:Female; D005334:Fever; D006801:Humans; D011020:Pneumonia, Pneumocystis; D063106:Transgender Persons; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "595-7",
"pmc": null,
"pmid": "25999169",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anaphylactic-like reaction from trimethoprim-sulfamethoxazole in a patient with AIDS.",
"title_normalized": "anaphylactic like reaction from trimethoprim sulfamethoxazole in a patient with aids"
} | [
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{
"abstract": "Coronavirus disease 2019 (COVID-19) was first identified at the end of 2019 as a cluster of pneumonia cases in Wuhan, China. By February 2020, this virus quickly spread, becoming a global pandemic. The spectrum of symptomatic infection severity can range from mild, severe, and critical disease. Many correlated comorbidities were established, including smoking, socioeconomic background, gender (male prevalence), hypertension, obesity, cardiovascular disease, chronic lung disease, diabetes mellitus, cancer, and chronic kidney disease. In an extensive literature search, post-COVID-19 necrotizing Staphylococcus aureus pneumonia with pneumothorax has not been recorded. We present a case about a 62-year-old male who presented with symptoms of COVID-19 with many underlying comorbidities, including hypertension and hyperlipidemia. He was on ventilatory support during his first week in the hospital and then received supplemental oxygenation as he recovered from his COVID-19 pneumonia. Nearly a month and a half after his initial presentation, he quickly decompensated and was started on supplemental oxygen and the necessary treatments. It was then, with the aid of lab work and imaging, that we determined that he had developed necrotizing Staphylococcus aureus pneumonia with pneumothorax. He was adequately treated, and once he was stable, he was discharged home and was told to continue his therapy.",
"affiliations": "Post-Acute Medical Rehabilitation Hospital of Dover, Dover, DE, USA.;Christiana Care Health System, Newark, DE, USA.;Christiana Care Health System, Newark, DE, USA.;Christiana Care Health System, Newark, DE, USA.;Post-Acute Medical Rehabilitation Hospital of Dover, Dover, DE, USA.",
"authors": "Chaudhry|Bilal|B|;Alekseyev|Kirill|K|;Didenko|Lidiya|L|https://orcid.org/0000-0003-3066-8135;Malek|Andrew|A|https://orcid.org/0000-0001-9583-198X;Ryklin|Gennadiy|G|",
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"doi": "10.1177/2050313X211005996",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211005996\n10.1177_2050313X211005996\nCase Report\nPost COVID-19 MSSA pneumonia\nChaudhry Bilal 1\nAlekseyev Kirill 2\nhttps://orcid.org/0000-0003-3066-8135\nDidenko Lidiya 2\nhttps://orcid.org/0000-0001-9583-198X\nMalek Andrew 2\nRyklin Gennadiy 1\n1 Christiana Care Health System, Newark, DE, USA\n2 Post-Acute Medical Rehabilitation Hospital of Dover, Dover, DE, USA\nLidiya Didenko, Post-Acute Medical Rehabilitation Hospital of Dover, 1240 McKee Road, Dover, DE 19904, USA. Email: lidiyadid@yahoo.com\n8 4 2021\n2021\n9 2050313X21100599621 2 2021\n4 3 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nCoronavirus disease 2019 (COVID-19) was first identified at the end of 2019 as a cluster of pneumonia cases in Wuhan, China. By February 2020, this virus quickly spread, becoming a global pandemic. The spectrum of symptomatic infection severity can range from mild, severe, and critical disease. Many correlated comorbidities were established, including smoking, socioeconomic background, gender (male prevalence), hypertension, obesity, cardiovascular disease, chronic lung disease, diabetes mellitus, cancer, and chronic kidney disease. In an extensive literature search, post-COVID-19 necrotizing Staphylococcus aureus pneumonia with pneumothorax has not been recorded. We present a case about a 62-year-old male who presented with symptoms of COVID-19 with many underlying comorbidities, including hypertension and hyperlipidemia. He was on ventilatory support during his first week in the hospital and then received supplemental oxygenation as he recovered from his COVID-19 pneumonia. Nearly a month and a half after his initial presentation, he quickly decompensated and was started on supplemental oxygen and the necessary treatments. It was then, with the aid of lab work and imaging, that we determined that he had developed necrotizing Staphylococcus aureus pneumonia with pneumothorax. He was adequately treated, and once he was stable, he was discharged home and was told to continue his therapy.\n\nCOVID-19\nnecrotizing pneumonia\nStaphylococcus aureus\npneumothorax\ncommunity-acquired pneumonia\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nWith the increase in the number of COVID-19 cases, many different complications of COVID-19 pneumonia are now coming to light. In COVID-19 pneumonia, it is proposed that alveolar damage can lead to alveolar rupture. The pathophysiology of the air-leak has not yet been well recognized. In comparison, it is well-documented that a pneumothorax can arise as a mechanical ventilation complication. In a retrospective case series, data showed that 1% of the patients admitted to the hospital and 2% of those in the intensive care unit (ICU) with COVID-19 pneumonia develop pneumothorax as a complication. They further explain that it has been seen in patients without mechanical ventilation or pre-existing lung disease, and occurred at a higher rate in males than females at a ratio of 3.3:1.1\n\nConcurrently, post-COVID-19 necrotizing Staphylococcus aureus pneumonia with pneumothorax has not yet been documented in the literature. In 2003, there was a reported increase of S. aureus superinfections with the severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) outbreak. Some of these cases led to necrotizing pneumonia, induced by Panton–Valentine leukocidin (PVL) secreting methicillin-susceptible S. aureus (MSSA). This strain of S. aureus has only been established in a few patients infected with COVID-19.2 A case-cohort study found that COVID-19 pneumonia patients had a higher risk of developing ICU bloodstream infections (ICU-BSIs) compared to patients who were critically ill without COVID-19 infection. The top eight microorganisms linked in these ICU-BSI were coagulase-negative Staphylococci (35.9%), Enterobacterales (12.8%), Pseudomonas aeruginosa (12.8%), Candida albicans (10.3%), Enterococcus spp (10.3%), S. aureus (7.7%), other Gram-positive (7.7%) and anaerobic bacteria (2.6%). In addition, their analyzed data concluded that COVID-19 patients receiving immune-modulatory therapies such as tocilizumab or anakinra had a significantly higher risk of ICU-BSI.3\n\nTherefore, secondary ICU-BSIs occur at a higher rate in COVID-19 pneumonia patients, especially on immune-modulating therapies compared to those without COVID-19 pneumonia. The timeline of symptoms, lab work, and imaging all play a crucial role in determining whether complications such as a pneumothorax is secondary to COVID-19 pneumonia or to a BSI that has occurred concurrently or shortly after the COVID-19 pneumonia.\n\nCase report\n\nWe present a case about a 62-year-old Hispanic male brought to the hospital’s emergency room due to increasing shortness of breath and dizziness. He had multiple comorbidities, including hypertension and hyperlipidemia. Before arrival at the emergency department (ED), emergency medical services (EMS) noted that his saturations were in the ’40s. They quickly placed him on 100% O2 via a non-rebreather, and they noticed improvement in his saturations to 91%. He was febrile with a 38.5°C temperature and had tachypnea recorded in the ’30s on 100% O2 high-flow nasal cannula (NC) in the ED. Due to his high oxygen needs and significant work of breathing, the patient was subsequently intubated.\n\nWhen obtaining a history, he related that he had been getting progressively short of breath over 6 days. He also described high cyclical temperatures over the past 3 days, with the maximum recorded temperature of 38.9°C. When questioned further, he denied cough but did endorse anosmia starting 4 days earlier. A COVID-19 test was requested and returned positive for viral RNA with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RT-PCR. Labs revealed that his WBC and sodium were low at 4.2 × 109/L and 130 mmol/L, respectively. They also revealed high aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic acid, C-reactive protein (CRP), D-dimer, and fibrinogen at 160 U/L, 143 U/L, 3.4 mmol/L, 299 mg/L, 489 ng/mL, and 850 mg/dL, respectively. A chest X-ray was ordered and had positive findings for airspace disease with diffuse airspace opacities consistent with the findings of COVID-19 pneumonia.\n\nThe following was his disease progression during his stay in the hospital. On hospital day 1, he received tocilizumab and remdesivir. On the second day, he was given convalescent plasma. While reassessing the patient on day 5, there had been little improvement; his fever, shortness of breath, and anosmia persisted. He was started on a dose of methylprednisolone. By the seventh day, he was extubated, and he remained on 40%–50% O2 high-flow NC.\n\nHe started therapeutic enoxaparin on hospital day 14 due to persistently high oxygen requirements and elevated D-dimer. The following week, he remained symptomatic with a low-grade fever and increased oxygen requirements due to shortness of breath. On day 27, he was finally weaned down to 6 L of NC and was transferred to the step-down unit. He remained stable for about a week, only requiring oxygen, and his fever was no longer there. Hospital protocol indicated that a follow-up X-ray was necessary and revealed that his COVID-19 pneumonia was improving. On day 38 of his stay in the hospital, the Rapid Response Team was called. The patient decompensated significantly and required 100% O2 via high-flow NC.\n\nAn EKG and enzymes were ordered and were unremarkable. A computed tomography (CT) of the chest was subsequently ordered due to his progressive shortness of breath with increased oxygenation requirements. The CT revealed an air-leak into the chest cavity, as seen in Figure 1. The red arrows depict a right-sided pneumothorax. The CT also demonstrated ground-glass opacities. It was believed that he developed this pneumothorax secondary to the COVID-19 pneumonia.\n\nFigure 1. Chest CT: the red arrows depict a right-sided pneumothorax. The CT also demonstrated ground-glass opacities.\n\nThoracic surgery was consulted because of the CT findings and the patient’s symptomatology. It was decided that a pigtail catheter should be inserted. A few hours after tube placement, the patient spiked a fever. Blood, urine, and sputum cultures were ordered. Two out of two sets of the blood cultures resulted in S. aureus. He was started on vancomycin and piperacillin/tazobactam until the sensitivities were conclusive. A total of three sets of blood cultures were ordered, and all came back positive for MSSA. The patient’s medications were adjusted to oxacillin accordingly.\n\nAfter 48 h of receiving the new treatment, he was still having shortness of breath but no longer had a fever. A transesophageal echo was ordered and displayed no abnormalities. It was then that a repeat chest CT scan was ordered. The CT revealed that the patient continued to have persistent air-leaks for 1 week in addition to decreased parenchymal enhancement. In Figure 2, the yellow arrow points to the pneumothorax that has persisted due to the air-leak, and the blue arrow depicts the irregular cavities destroying the right upper lobe. The medical team concluded that the cause of these irregular cavities causing the pneumothorax was necrotizing S. aureus pneumonia that had developed secondary to his COVID-19 pneumonia.\n\nFigure 2. Follow-up chest CT: the yellow arrow points to the pneumothorax that has persisted due to the air-leak, and the blue arrow depicts the irregular cavities destroying the right upper lobe.\n\nDue to the persistent leak visualized in the CT, he underwent right upper lobe endoscopic endobronchial valve. Shortly after valve placement, the air-leak stopped, and his shortness of breath resolved. Soon after, the chest tubes were clamped and subsequently removed. He had a peripherally inserted central catheter (PICC) line placed, and oxacillin treatment continued for 6 weeks. Once he was stabilized, he was discharged and was instructed to complete his antibiotics course.\n\nDiscussion\n\nIn December 2019, according to the World Health Organization (WHO), SARS-CoV-2, which causes COVID-19 pneumonia, was first reported in Wuhan, China. Subsequently, following the virus’s discovery and identification, more than 60,000,000 cases have been confirmed worldwide, along with more than 1,400,000 deaths.4 The increasing severity of the disease is correlated to many risk factors. These risk factors include age > 60 years, diabetes, hypertension, cardiac disease, chronic lung disease, cerebrovascular disease, chronic kidney disease, immunosuppression, and cancer.5 The Wuhan Data suggested that 8% of patients hospitalized with COVID-19 had a bacterial/fungal co-infection. The WHO had recommended not prescribing antimicrobials for COVID-19 pneumonia patients, especially if there is a low suspicion for bacterial infection. However, recent studies have shown that 1% of hospitalized COVID-19 patients and 2% of those in the ICU are at a greater risk of developing secondary BSIs. It is then that one must identify the secondary infection and treat it accordingly.1\n\nBuetti et al.3 describe an increase in secondary and superinfections with SARS-CoV-2 similar to those seen in the early 2000s with the SARS-CoV-1 outbreak and the reported increase of S. aureus superinfections. In 1919, during the 1918–1919 influenza pandemic, S. aureus was recognized to cause secondary bacterial infection by Chickering. At that time, it was reported in healthy adults who did not have an underlying risk factor.5–7 According to Rothberg, if a viral influenza-like infection is followed by a period of complete resolution of symptoms, and then 4–14 days later was followed by a recurrence of fever, dyspnea, productive cough, and or pulmonary consolidation, most often this was due to S. pneumonia, S. aureus, or Haemophilus influenzae.7\n\nS. aureus is considered an infrequent cause of community-acquired pneumonia (CAP). It accounts for about 3% of cases in which a bacterium is the identified cause. In comparison, S. aureus has been identified as one of the organisms that develop in the bloodstream at a rate of 7.7% in COVID-19 patients that develop these BSIs. However, it is a recognized cause of influenza-associated CAP.8–10 It is also noted that even though S. aureus pneumonia happens throughout the entire year, co-infections of influenza and S. aureus pneumonia commonly peak together.11,12\n\nWhen S. aureus is detected as the cause of pneumonia, especially with an underlying influenza-like infection, such as SARS-CoV-2, it is usually associated with severe disease. Disease progression may lead to pulmonary necrosis, neutropenia, and shock.12 The proposed pathophysiology behind the development of this pulmonary necrosis is linked to PVL. PVL is a cytotoxin produced by S. aureus that can lead to necrotizing pneumonia due to a rapid increase of immune cells to lung tissues. Together, influenza-like diseases and the destruction of the cells by PVL ultimately damage the lungs’ epithelium.2 Furthermore, necrotizing pneumonia is described as a separate disease entity characterized by sudden onset and rapid worsening of the symptoms, leukopenia, airway hemorrhages, severe respiratory failure, necrotic destruction of vast areas of the lung, and a high mortality rate.13,14 This can ultimately lead to the development of a pneumothorax due to all of the damages occurring, as seen in our patient. When this happens, it is vital that the patients have lab work and appropriate imaging to assess both complications and treatment.\n\nIn comparison, in the setting of COVID-19 pneumonia, sudden respiratory decompensation with severe onset hypoxemia should also be investigated. Imaging revealing a pneumothorax is a well-established complication of mechanical ventilation, which may become evident.15 There have been documented cases of delayed pneumothorax and pneumomediastinum with mechanical ventilation and non-invasive ventilation such as high-flow NC. Less common is the pneumothorax’s delayed occurrence long after the discontinuation of mechanical ventilation.16,17 Martinelli et al. describe 60 cases of pneumothorax in which 58 had confirmed COVID-19 as the cause. They noted that not all of the patients had undergone mechanical ventilation and that inflammation and ischemic parenchymal damage were the causes of cyst formation leading to air-leaks. In addition, there was no need to operatively intervene in any of these cases, as the chest tube was sufficed enough.\n\nFurthermore, blood, sputum, and urinary cultures can help narrow the cause of the lung trauma, whether from COVID-19 pneumonia or a secondary BSIs. Blood cultures help narrow the antibiotic therapy choices, while sputum cultures are also interpreted based on the clinical correlation and quantitation of the growth. Urinary antigen testing has been more sensitive and specific than Gram stains and sputum cultures, making them the most commonly done test.12 Specific lab values, including CRP, blood cultures, sputum cultures, and urinary antigens, play a vital role in diagnosing CAP. Findings that show a CRP > 40 mg/L, as seen in our patient, have a sensitivity of 70% and specificity of 90% for bacterial pneumonia. Ultimately, it must be interpreted in the context of the clinical presentation.\n\nA secondary delayed necrotizing MSSA pneumonia presenting with pneumothorax from pulmonary necrosis has not been reported following COVID-19 pneumonia. In addition to imaging, further investigation may be required, especially if necrotizing S. aureus pneumonia is suspected to be the cause of the pneumothorax. During our patient’s hospital stay, he had a resolution of his COVID-19 pneumonia. He had been receiving tocilizumab, an immune-modulatory therapy, which significantly increased ICU-BSI risk. He then developed severe respiratory failure once more. All of the cultures, lab work, and imagining obtained from our patient demonstrated that he had developed MSSA necrotizing pneumonia. In addition, his MSSA pneumonia was further complicated with the development of a pneumothorax, for which he was treated correctly.\n\nConclusion\n\nIn brief, as the COVID-19 pandemic continues to evolve, we are continuously learning about possible complications from this new virus. S. aureus infection secondary to influenza-like illness, such as COVID-19, can lead to severe pulmonary compromise, including necrotizing pneumonia and pneumothorax. Therefore, in patients with COVID-19 pneumonia, especially those hospitalized, it is imperative to monitor the lungs and their overall function.\n\nAuthor contribution: All authors contributed to investigating, writing, reviewing, and editing.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iDs: Lidiya Didenko https://orcid.org/0000-0003-3066-8135\n\nAndrew Malek https://orcid.org/0000-0001-9583-198X\n==== Refs\nReferences\n\n1. Martinelli AW Ingle T Newman J , et al . COVID-19 and pneumothorax: a multicentre retrospective case series. Eur Respir J 2020; 56 (5 ): 2002697.32907891\n2. Duployez C Le Guern R Tinez C , et al . Panton-valentine leukocidin-secreting Staphylococcus aureus pneumonia complicating COVID-19. Emerg Infect Dis 2020; 26 (8 ): 1939–1941\n3. Buetti N Ruckly S de Montmollin E , et al . COVID-19 increased the risk of ICU-acquired bloodstream infections: a case-cohort study from the multicentric OUTCOMEREA network. Intensive Care Medicine 2021; 47 (2 ): 180–187.33506379\n4. Coronavirus COVID-19. 2019-nCoV, 2020, https://www.arcgis.com/apps/opsdashboard/index.html?fbclid=IwAR15YZf9ZFqXmITAxmZxQVz1orlYaIJpKEX60TIGOsBdgvAFAn3v-ERUkFg (accessed 25 November 2020).\n5. Guan WJ Ni ZY Hu Y , et al . China medical treatment expert group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382 (18 ): 1708–1720.\n6. Holshue ML DeBolt C Lindquist S , et al . Washington State 2019-nCoV case investigation team. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382 (10 ): 929–936.32004427\n7. Rothberg MB Haessler SD Brown RB. Complications of viral influenza. Am J Med 2008; 121 (4 ): 258–264.18374680\n8. Martin CM Kunin CM Gottlieb LS , et al . Asian influenza A in Boston, 1957-1958. II. Severe staphylococcal pneumonia complicating influenza. AMA Arch Intern Med 1959; 103 (4 ): 532–542\n9. Chickering HT Park JH. Staphylococcus aureus pneumonia. N Engl J Med 1919; 72 : 617–626\n10. Fine MJ Smith MA Carson CA , et al . Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA 1996; 275 (2 ): 134–141.8531309\n11. Self WH Wunderink RG Williams DJ , et al . Staphylococcus aureus community-acquired pneumonia: prevalence, clinical characteristics, and outcomes. Clin Infect Dis 2016; 63 (3 ): 300–309.27161775\n12. Bartlett JG Breiman RF Mandell LA , et al . Community-acquired pneumonia in adults: guidelines for management. The infectious diseases society of America. Clin Infect Dis 1998; 26 (4 ): 811–838.9564457\n13. Li HT Zhang TT Huang J , et al . Factors associated with the outcome of life-threatening necrotizing pneumonia due to community-acquired Staphylococcus aureus in adult and adolescent patients. Respiration 2011; 81 (6 ): 448–460.21051855\n14. Löffler B Niemann S Ehrhardt C , et al . Pathogenesis of Staphylococcus aureus necrotizing pneumonia: the role of PVL and an influenza coinfection. Expert Rev Anti Infect Ther 2013; 11 (10 ): 1041–1051.24073746\n15. Macia I Moya J Ramos R , et al . Spontaneous pneumomediastinum: 41 cases. Eur J Cardiothorac Surg 2007; 31 (6 ): 1110–1114\n16. Zhou C Gao C Xie Y , et al . COVID-19 with spontaneous pneumomediastinum. Lancet Infect Dis 2020; 20 (4 ): 510.32164830\n17. Manna S Maron SZ Cedillo MA , et al . Spontaneous subcutaneous emphysema and pneumomediastinum in non-intubated patients with COVID-19. Clin Imaging 2020; 67 : 207–213.32871424\n\n",
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"keywords": "COVID-19; Staphylococcus aureus; community-acquired pneumonia; necrotizing pneumonia; pneumothorax",
"medline_ta": "SAGE Open Med Case Rep",
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"references": "32298228;32164830;32109013;33506379;32871424;13636471;9564457;32004427;17420139;8531309;32907891;24073746;18374680;27161775;21051855",
"title": "Post COVID-19 MSSA pneumonia.",
"title_normalized": "post covid 19 mssa pneumonia"
} | [
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{
"abstract": "BACKGROUND\nPheochromocytomas and paragangliomas (Pheo/PGL) are rare, vascular, sometimes malignant endocrine tumors. Case reports indicate the activity of vascular endothelium growth factor receptor-targeted kinase inhibitors in these cancers.\n\n\nOBJECTIVE\nTo assess the antitumor activity and tolerability of pazopanib in progressive malignant Pheo/PGL.\n\n\nMETHODS\nThis multicenter Phase II trial (MC107C) enrolled individuals ≥18 years old with disease progression ≤ 6 months prior to registration, Eastern Cooperative Oncology Group PS 0-2, and measurable disease (response evaluation criteria in solid tumors 1.0). Pazopanib was administered in 28-day cycles, with the regimen ultimately being as follows: cycle 1: 400 mg daily on days 1-14, cycle 2: 800 mg daily on days 1-14, and then cycle 2 + : 800 mg daily on all days.\n\n\nRESULTS\nThe study was halted due to poor accrual. Seven patients were enrolled (05/2011-11/2014). One patient withdrew consent prior to treatment, leaving six evaluable patients. Treatment was discontinued, due to the following reasons: disease progression (4); withdrawal (1); and grade 4 (Takotsubo) cardiomyopathy (1). The median number of cycles administered was 4 (range: 2-29, total: 49). Four patients had >1 dose reduction due to the following reasons: fatigue (1), abnormal liver tests (2), hypertension and (Takotsubo) cardiomyopathy (1), and headaches (1). Common severe (Common Terminology Criteria for Adverse Events v3.0 grades 3-5) toxicities were as follows: hypertension (3/6), (Takotsubo) cardiomyopathy (2/6), diarrhea (1/6), fatigue (1/6), headache (1/6), and hematuria (1/6). One confirmed partial response was observed in PGL (17%, duration 2.4 years); median progression-free survival and overall survival were 6.5 and 14.8 months, respectively.\n\n\nCONCLUSIONS\nPazopanib has activity in Pheo/PGL requiring more study; optimal alpha- and beta-blockade are imperative pre-therapy in patients with secretory tumors, as risk of hypertension and cardiomyopathy are potentially life threatening.",
"affiliations": "Department of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;University of Texas, MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX, 77030, USA.;National Institute of Health (NIH/NCI), 9000 Rockville Pike, Bethesda, MD, 20892, USA.;Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Division of Medical Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA.;Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine and Department of Pharmacology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA.;Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. bible.keith@mayo.edu.",
"authors": "Jasim|Sina|S|;Suman|Vera J|VJ|;Jimenez|Camilo|C|;Harris|Pamela|P|;Sideras|Kostandinos|K|;Burton|Jill K|JK|;Worden|Francis Paul|FP|;Auchus|Richard J|RJ|;Bible|Keith C|KC|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D040262:Receptors, Vascular Endothelial Growth Factor",
"country": "United States",
"delete": false,
"doi": "10.1007/s12020-017-1359-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-008X",
"issue": "57(2)",
"journal": "Endocrine",
"keywords": "Metastatic; Paraganglioma; Pazopanib; Takotsubo cardiomyopathy",
"medline_ta": "Endocrine",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D018572:Disease-Free Survival; D004562:Electrocardiography; D004701:Endocrine Gland Neoplasms; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D010235:Paraganglioma; D010673:Pheochromocytoma; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D040262:Receptors, Vascular Endothelial Growth Factor; D013449:Sulfonamides; D017211:Treatment Failure",
"nlm_unique_id": "9434444",
"other_id": null,
"pages": "220-225",
"pmc": null,
"pmid": "28685225",
"pubdate": "2017-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "20851682;19001511;12780519;22965939;15369446;19017755;12368197;8957477;12490855",
"title": "Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma.",
"title_normalized": "phase ii trial of pazopanib in advanced progressive malignant pheochromocytoma and paraganglioma"
} | [
{
"companynumb": "PHHY2017US106577",
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},
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"drugdosagetext": "400 MG, QD",
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"drugindication": "PARAGANGLION NEOPLASM",
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"reaction": [
{
"reactionmeddrapt": "Hypertensive crisis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiomyopathy",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
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}
],
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},
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"literaturereference": "JASIM S, SUMAN VJ, JIMENEZ C, HARRIS P, SIDERAS K, BURTON JK ET AL.. PHASE II TRIAL OF PAZOPANIB IN ADVANCED/PROGRESSIVE MALIGNANT PHEOCHROMOCYTOMA AND PARAGANGLIOMA. ENDOCRINE. 2017;57:220-5",
"literaturereference_normalized": "phase ii trial of pazopanib in advanced progressive malignant pheochromocytoma and paraganglioma",
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},
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},
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{
"abstract": "Pulmonary vein isolation (PVI) is becoming the therapy of choice for symptomatic paroxysmal drug-refractory atrial fibrillation (AF). The most frequently reported complications are vascular complications (1.4%). Bleeding complications of the central nervous system have rarely been described. We report a case of spontaneous spinal bleed after PVI.\nA 68-year-old woman with a 2-year history of highly symptomatic paroxysmal AF (EHRA 3) was referred for a PVI redo procedure. A high-density mapping showed pulmonary vein reconnection of all pulmonary veins successfully isolated by radiofrequency ablation. During the entire procedure, the patient had sinus rhythm with an ACT around 300 s. No intraprocedural and peri-procedural complications occurred. Four hours after haemostasis, the anticoagulation clotting time (ACT) was 110 s and rivaroxaban (20 mg) was reinitiated. In the following hours, the patient developed fluctuating neurological lower limb symptoms. A lumbar magnetic resonance imaging showed a subdural spinal haematic collection with an associated epidural component from L3 to S2 exerting compression over the dural sheath. A conservative treatment approach was adopted with progressive recovery of sensorial and motor deficits. After 5 months, the patient still presented residual lower limb motor deficits necessitating the support of a walking stick.\nWe describe the first case of a spontaneous spinal bleeding following PVI. Given the gradual diffusion of PVI to treat AF in more clinically complex patients with a larger range of comorbidities, particular consideration should be given to seek predisposing bleeding factors in order to assess the risk for neurological complications.",
"affiliations": "Department of Cardiology, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland.;Department of Cardiology, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland.;Department of Cardiology, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland.;Department of Cardiology, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland.",
"authors": "Cioffi|Giacomo Maria|GM|0000-0002-8539-1949;Regoli|François|F|;Conte|Giulio|G|;Auricchio|Angelo|A|",
"chemical_list": null,
"country": "England",
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"fulltext": "\n==== Front\nEur Heart J Case RepEur Heart J Case RepehjcrEuropean Heart Journal: Case Reports2514-2119Oxford University Press 10.1093/ehjcr/ytz109ytz109Case ReportsAcute fluctuating neurological deficits after pulmonary vein isolation: unmasking a rare complication due to spontaneous spinal subdural bleeding: a case report http://orcid.org/0000-0002-8539-1949Cioffi Giacomo Maria Regoli François Conte Giulio Auricchio Angelo \nDepartment of Cardiology, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, SwitzerlandBiering-Sørensen Tor Handling EditorAbumuaileq Rami Riziq Yousef EditorKhan Habib EditorMukherjee Rahul EditorMehta Vishal Shahil Editor Corresponding author. Tel: +41 (0) 91 805 33 47, Fax: +41 (0) 91 805 31 67, Email: giacomo.cioffi@swissonline.ch9 2019 05 7 2019 05 7 2019 3 3 ytz10910 1 2019 4 2 2019 17 6 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nPulmonary vein isolation (PVI) is becoming the therapy of choice for symptomatic paroxysmal drug-refractory atrial fibrillation (AF). The most frequently reported complications are vascular complications (1.4%). Bleeding complications of the central nervous system have rarely been described. We report a case of spontaneous spinal bleed after PVI.\n\nCase summary\nA 68-year-old woman with a 2-year history of highly symptomatic paroxysmal AF (EHRA 3) was referred for a PVI redo procedure. A high-density mapping showed pulmonary vein reconnection of all pulmonary veins successfully isolated by radiofrequency ablation. During the entire procedure, the patient had sinus rhythm with an ACT around 300 s. No intraprocedural and peri-procedural complications occurred. Four hours after haemostasis, the anticoagulation clotting time (ACT) was 110 s and rivaroxaban (20 mg) was reinitiated. In the following hours, the patient developed fluctuating neurological lower limb symptoms. A lumbar magnetic resonance imaging showed a subdural spinal haematic collection with an associated epidural component from L3 to S2 exerting compression over the dural sheath. A conservative treatment approach was adopted with progressive recovery of sensorial and motor deficits. After 5 months, the patient still presented residual lower limb motor deficits necessitating the support of a walking stick.\n\nDiscussion\nWe describe the first case of a spontaneous spinal bleeding following PVI. Given the gradual diffusion of PVI to treat AF in more clinically complex patients with a larger range of comorbidities, particular consideration should be given to seek predisposing bleeding factors in order to assess the risk for neurological complications.\n\nPulmonary vein isolationAtrial fibrillationCase reportSpinal bleedingHaematomyeliaAnticoagulation\n==== Body\nLearning points\n\nCatheter ablation has a growing role in the management of patients with atrial fibrillation and a growing number of patients with multiple comorbidities are being treated. These are fragile patients and may present high bleeding risk.\n\nPost-pulmonary vein isolation neurological complications are very rare events and potentially life-threatening.\n\nSpinal cord bleeding can have insidious and misleading presentation with fluctuating central or peripheral neurological symptoms.\n\n\n\n\n\n\n\nIntroduction\nPulmonary vein isolation (PVI) is becoming the therapy of choice for symptomatic paroxysmal drug-refractory atrial fibrillation (AF). The most frequently reported complications are vascular complications (1.4%) in a setting of overall low complication rate (<2.9%).3 Bleeding complications of the central nervous system (CNS) have rarely been described. We report a case of spontaneous spinal bleeding after PVI not reported in the literature so far.\n\nTimeline\nTimeline\tEvents\t\n7 months before presentation\tFirst pulmonary vein isolation (PVI) procedure.\t\n3 months before presentation\tNew severely symptomatic atrial fibrillation episodes.\t\nDay 1\tPVI redo procedure performed.\t\n4 h later\tRestarting oral anticoagulation (Rivaroxaban).\t\n6–9 h later\tBeginning of neurological fluctuating deficits. Thoracic, chest, and cerebral angio-computed tomography scan was performed.\t\n12 h later\tWorsening symptoms. A cervical, dorsal and lumbar native magnetic resonance imaging was performed with evidence of subdural spinal haematic collection with an associated epidural component from L3 to S2.\t\n24 h later\tElevated surgical risk. Conservative approach.\t\nDay 6\tClinical stability with minimal improvement.\t\nDay 9\tDischarge from cardiology department to neurological rehabilitation centre.\t\n5 months after discharge\tStill minor sensorial and motor deficits. Need of a walking stick.\t\nCase presentation\nA 68-year-old woman with a 2-year history of highly symptomatic drug-refractory paroxysmal AF (EHRA 3), previously treated with a previous PVI procedure, was referred to our division for a PVI redo procedure. The patient (height 160 cm, weight 69 kg) presented a history of two-vessel coronary artery disease treated with percutaneous revascularization, a CHA2DS2-VASc score of 4, and HAS-BLED score of 2. She had a history of hypertension, hypothyroidism, and a congenital ostium secundum atrial septal defect with a left-right spontaneous shunt. The patient presented also moderate kyphoscoliosis of the vertebral column, most prominent at the lumbar level. She was treated with rivaroxaban 20 mg/day, aspirin, sotalol, thyroxin, furosemide/spironolactone medication, and pantoprazole. The pre-procedural blood values, including routine coagulation indices were all normal.\n\nThe anticoagulation therapy was interrupted 36 h before the procedure and a transoesophageal echocardiogram performed on the same day of the procedure excluded left atrial appendage thrombi. The procedure was performed under general anaesthesia and vascular access was obtained through the right femoral vein. High-density mapping was performed during sinus rhythm and showed pulmonary vein reconnection of all pulmonary veins. A radiofrequency ablation catheter (Thermocool Smarttouch, Inc., Irvine, CA, USA) was performed; it showed a reconnection of three pulmonary veins. A mapping procedure obtained 20 min after the last ablation point showed a persistent deconnection of all pulmonary veins. Atrial programmed stimulation as well as repeated high-rate pacing bursts did not induce AF. During the entire procedure, the patient had a sinus rhythm, remained stable with vital signs within range of normality; ACT was stable around 300 s with a final procedural value of 259 s. No reversion of anticoagulation was performed and no intraprocedural and peri-procedural complications occurred. The patient was then carefully transferred to the ward bed with the aid of a sliding mat; a mandatory 4 h bed rest and immobilization was prescribed.\n\nAt the time of femoral vein haemostasis (4 h after PVI completion), the ACT was 110 s; rivaroxaban (20 mg) was then administered. In the following hours, the patient developed right gluteal and bilateral lumbar pain, right lower limb paraesthesia, and motor deficits below the knee [patellar and achillean hyporeflexia; iliopsoas, quadriceps, ankle dorsiflexors, plantar flexors, and long toe extensors motor deficits (MMT 2)]. A psoas sign was also present. The neurological symptoms fluctuated presenting an on–off pattern intermittently affecting either the right or left lower limb; there was the suspicion for either a transient central or peripheral involvement. A complete thoracic, chest, and cerebral angio-computed tomography scan was performed and acute retroperitoneal or cerebral bleeding were excluded.\n\nFurthermore, a cervical, dorsal, and lumbar native magnetic resonance imaging was then performed. This examination showed a subdural spinal haematic collection with an associated epidural component from L3 to S2 (8 × 11 mm in the axial plane, see Figure 1; 65 × 11 mm in the sagittal plane, see Figure 2). The subdural spinal haematoma exerted compression over the dural sheath, abolishing the liquoral representation around the cauda equina lateral right nerve roots within L3–L4 and L4–L5 and within L5–S1 mainly in the posterior bilateral location.\n\n\nFigure 1 Subdural spinal haematic collection 8 x 11 mm, axial plane.\n\nFigure 2 Subdural spinal haematic collection 65 x 11 mm, sagittal plane.\n\nAfter consultation with neurologists and neurosurgeons, a ‘wait-and-see’ treatment approach by withholding anticoagulation therapy and patient immobilization was taken. Indeed, the operative risk of subsequent lower limb paralysis associated to the surgical approach was estimated too high and exceeding possible benefit. In the following 9 days, a neurological rehabilitation and sub-therapeutic anticoagulation regimen was initiated. There was progressive recovery of sensorial and motor deficits. After 5 months though, the patient still presented residual lower limb motor deficits necessitating the support of a walking stick.\n\nDiscussion\nTo our knowledge, this is the first case of spontaneous spinal subdural bleeding observed after a PVI procedure.\n\nAlthough this complication has never been reported following PVI, it emphasizes the need of careful evaluation of multimorbidity patients and of possible muscle-skeletal changes beyond the pathologies included in the HAS-BLED score.\n\nOral anticoagulation was interrupted 36 h before the procedure; this was in agreement with the 2017 HRS/EHRA/APHRS/SOLAECE recommendations12, when the procedure was performed. Subsequently, recommendations by scientific societies13 changed into uninterrupted DOACs at the time of PVI. Although speculative, during uninterrupted DOACs (in cases when CHA2DS2-VASc ≥3, availability of cardiac imaging assessment at procedural time) or interrupted within 12–24 h, the bleeding risk in a patient could even be higher than that assessed by the HAS-BLED score. Indeed, anatomic conditions may increase the bleeding risk and are not part of the HAS-BLED score.\n\nVascular complications are the most frequent procedure-related adverse events following PVI procedure. These include generic haematoma of the groin, retroperitoneal haematoma, pseudoaneurysm, arteriovenous fistula, and hemothorax (subclavian or internal jugular venous access) with an incidence in the range of 1–2%3. Peri-procedure anticoagulation regimen seems to be an important factor in the occurrence of these complications.\n\nIntracranial severe spontaneous bleeding complications are rare after PVI (incidence of 0.31). However, as described in the present case, such complications may cause invalidating and irreversible body injury which may be particularly limitative in more compromised patients. As observed in the present case, even careful procedural planning with guidelines recommendations of peri-procedural anticoagulation management did not prevent a severe CNS bleeding adverse event.2–3\n\nSpinal cord bleeding is a unique condition with significant disabling consequences. It is classified based on the primary location of bleeding into intramedullary (haematomyelia), subarachnoid haemorrhage (SAH), subdural haemorrhage, and epidural haemorrhage. It requires emergency investigation and treatment.4–6 Based on the existing literature spinal vascular malformations such as intradural arteriovenous malformations are the most common cause of atraumatic intramedullary spinal cord haemorrhage. Additional causative factors include warfarin or heparin anticoagulation, hereditary or acquired bleeding disorders, primary spinal cord tumours, spinal cord metastases, or a delayed complication of spinal radiation7–11.\n\nOnset may vary with sudden, severe back or neck pain and sometimes radicular or with rapidly progressive flaccid quadri/biparesis, with subsequent ventilatory failure reported in cases where bleeding involves the cervical and superior dorsal spine. Magnetic resonance imaging with and without gadolinium is the gold standard neurological imaging modality. There are no clinical trials to guide the management of acute intramedullary spinal cord haemorrhage, and subsequent treatment is usually directed towards the underlying cause. Early surgical treatment is always indicated when the patient’s neurological status progressively deteriorates with severe central complications (such as ventilatory failure) but also conservative treatment is possible, whenever neurological impairment is minimal and self-limiting.\n\nConclusion\nIn conclusion, for the first time spinal subdural bleeding after PVI is reported. Careful peri-procedural management of anticoagulation therapy as well as assessment of patient bleeding risk are mandatory. Little is known on the predisposing factors that could identify which patients may be at risk of bleeding complications such as that reported in this case.\n\nLead author biography\nGiacomo Maria Cioffi, 34, raised in Lugano (CH), works for Cardiocentro Ticino as resident in Cardiology since 2018, with special interest in Electrophysiology.\n\nSupplementary Material\nytz109_Supplementary_Slide_Set Click here for additional data file.\n\n Supplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.\n\n\nConflict of interest: A. A. has been a consultant to Medtronic, Boston Scientific, Biosense Webster, and LivaNova and has received speakers’ fees from Medtronic, Boston Scientific, and LivaNova. F. R. consultation and speaker fees Medtronic, Boston Scientific, LivaNova/Microport, Bayer, Abbott and Daichi Sankyo. G.C. and G.M.C. have declared no conflict of interest.\n==== Refs\nReferences\n1 \nKirchhof P , Haeusler KG , Blank B , De Bono J , Callans D , Elvan A , Fetsch T , Van Gelder IC , Gentlesk P , Grimaldi M , Hansen J , Hindricks G , Al-Khalidi HR , Massaro T , Mont L , Nielsen JC , Nölker G , Piccini JP , De Potter T , Scherr D , Schotten U , Themistoclakis S , Todd D , Vijgen J , Di Biase L. \nApixaban in patients at risk of stroke undergoing atrial fibrillation ablation . Eur Heart J 2018 ;39 :2942 –2955 .29579168 \n2 \nMarrouche NF , Brachmann J , Andresen D , Siebels J , Boersma L , Jordaens L , Merkely B , Pokushalov E , Sanders P , Proff J , Schunkert H , Christ H , Vogt J , Bänsch D. \nCatheter ablation for atrial fibrillation with heart failure . N Engl J Med 2018 ;378 :417 –427 .29385358 \n3 \nHoyt H , Bhonsale A , Chilukuri K , Alhumaid F , Needleman M , Edwards D , Govil A , Nazarian S , Cheng A , Henrikson CA , Sinha S , Marine JE , Berger R , Calkins H , Spragg DD. \nComplications arising from catheter ablation of atrial fibrillation: temporal trends and predictors . Heart Rhythm 2011 ;8 :1869 –1874 .21798230 \n4 \nBrinkmeier-Theofanopoulou M , Tzamalis P , Wehrkamp-Richter S , Radzewitz A , Merkel M , Schymik G , van Mark G , Bramlage P , Schmitt C , Luik A. \nPeriprocedural anticoagulation during left atrial ablation: interrupted and uninterrupted vitamin K-antagonists or uninterrupted novel anticoagulants . 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BMC Neurol 2015 ;15 :123. 26224095 \n10 \nHelmy A , Mellor G. \nSpontaneous cervical cord haemorrhage: an unusual presentation . Emerg Med J 2007 ;24 :e16. 17351210 \n11 \nKim JS , Lee SH. \nSpontaneous spinal subarachnoid hemorrhage with spontaneous resolution . 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Heart Rhythm 2017 ;14 :e275 –e444 .28506916 \n13 \nSteffel J , Verhamme P , Potpara TS , Albaladejo P , Antz M , Desteghe L , Haeusler KG , Oldgren J , Reinecke H , Roldan-Schilling V , Rowell N , Sinnaeve P , Collins R , Camm AJ , Heidbüchel H. \nThe 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation . Eur Heart J 2018 ;39 :1330 –1393 .29562325\n\n",
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"medicinalproduct": "THYROXIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "UNKNOWN",
"drugdosagetext": "UNK",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ACETYLSALICYLIC ACID"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SOTALOL"
},
"drugadditional": null,
"drugadministrationroute": null,
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"drugcharacterization": "2",
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SOTALOL."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PANTOPRAZOLE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
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"drugdosagetext": "UNK",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PANTOPRAZOLE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": null,
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"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FUROSEMIDE."
}
],
"patientagegroup": null,
"patientonsetage": "68",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": "69",
"reaction": [
{
"reactionmeddrapt": "Spinal subdural haematoma",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Labelled drug-drug interaction medication error",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Spinal cord compression",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Motor dysfunction",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product administration error",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CIOFFI GM, REGOLI F, CONTE G, AURICCHIO A. ACUTE FLUCTUATING NEUROLOGICAL DEFICITS AFTER PULMONARY VEIN ISOLATION: UNMASKING A RARE COMPLICATION DUE TO SPONTANEOUS SPINAL SUBDURAL BLEEDING: A CASE REPORT. EUROPEAN HEART JOURNAL - CASE REPORTS. 2019?3:3:ARTICLE NUMBER: YTZ109",
"literaturereference_normalized": "acute fluctuating neurological deficits after pulmonary vein isolation unmasking a rare complication due to spontaneous spinal subdural bleeding a case report",
"qualification": "3",
"reportercountry": "CH"
},
"primarysourcecountry": "CH",
"receiptdate": "20191113",
"receivedate": "20191113",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17027546,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200122"
}
] |
{
"abstract": "The clinicopathologic characteristics, acquired resistance patterns, and outcomes among patients with atypical EGFR mutations and HER2 alterations remain underexplored.\n\n\n\nA single-center retrospective review was conducted. Oncogenes assessed include typical EGFR (t-EGFR; exon 19 del and L858R), atypical EGFR (a-EGFR; G719X, exon 20, L861Q), HER2 (exon 19, exon 20, amplifications), gene fusions (ALK, ROS1, RET), RAS (KRAS, NRAS), and RAF (BRAF V600E). Progression-free survival (PFS), overall survival (OS), disease control rate, and objective response rate (Response Evaluation Criteria in Solid Tumors 1.1) were collected.\n\n\n\nAmong 570 patients, we found 55 a-EGFR mutations (13 G719X, 38 exon 20, 4 L861Q) and 31 HER2 alterations (2 exon 19 mutations, 27 exon 20 insertions, 2 amplifications). Patients with EGFR and HER2 alterations had increased lung and bone metastases relative to patients with gene fusions, RAS/RAF mutations, and no identified driver oncogenes (P < .001). Patients with EGFR exon 20 insertions had a median PFS to EGFR tyrosine kinase inhibitors (TKIs) of 5 months and an OS of 16 months-significantly worse than exon 19 del and L858R (Bonferroni correction; P < .001), but not G719X or L861Q. Relative to t-EGFR mutations, T790M and MET amplification occurred less frequently as acquired resistance mechanisms among a-EGFR samples (P < .001). Ten patients with a-EGFR mutations and HER2 alterations received single-agent immune checkpoint inhibitors (ICIs) with no radiographic responses and a median PFS of 2 months.\n\n\n\nEGFR and HER2-mutated NSCLC have a high rate of synchronous lung and bone metastases. Patients with a-EGFR mutations have inferior responses to EGFR-directed therapies with lower rates of acquired T790M and MET amplification. Responses to ICIs are uniformly poor. Novel therapeutic approaches are needed.",
"affiliations": "Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO. Electronic address: tejas.patil@cuanschutz.edu.;Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO.;Department of Internal Medicine, University of Colorado School of Medicine, Aurora, CO.;Department of Internal Medicine, University of Colorado School of Medicine, Aurora, CO.;Department of Internal Medicine, University of Colorado School of Medicine, Aurora, CO.;Department of Pathology, University of Colorado School of Medicine, Aurora, CO.;Department of Pathology, University of Colorado School of Medicine, Aurora, CO.;Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO.;Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO.;Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO.;Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO.;Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO.;Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO.",
"authors": "Patil|Tejas|T|;Mushtaq|Rao|R|;Marsh|Sydney|S|;Azelby|Christine|C|;Pujara|Miheer|M|;Davies|Kurtis D|KD|;Aisner|Dara L|DL|;Purcell|William T|WT|;Schenk|Erin L|EL|;Pacheco|Jose M|JM|;Bunn|Paul A|PA|;Camidge|D Ross|DR|;Doebele|Robert C|RC|",
"chemical_list": "D014408:Biomarkers, Tumor; C512478:EGFR protein, human; C508053:ERBB2 protein, human; D066246:ErbB Receptors; D018719:Receptor, ErbB-2",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cllc.2019.11.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-7304",
"issue": "21(3)",
"journal": "Clinical lung cancer",
"keywords": "Bone metastases; ERBB2; Exon 20 insertion; Immune checkpoint inhibitor; Tyrosine kinase inhibitor",
"medline_ta": "Clin Lung Cancer",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "100893225",
"other_id": null,
"pages": "e191-e204",
"pmc": null,
"pmid": "31859066",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "24894944;30825613;26723242;19949011;15329413;25456362;15118125;29765525;24682604;26598547;15709185;19692680;29863955;27333219;28743157;28521651;16014882;31125062;24142049;23610105;30922878;28676220;30548240;28958502;27262212;23371856;23485129;20573926;28945865;29151359;27875527;23816960;26051236;25668120;30563752;21764376;29290256;30596880;17610986;30685684;28363995;24439929;31086949;22282022;28514610;29658856;16014883;22956644;15118073;15741570;23328547;17290067;22285168;19884552",
"title": "Clinicopathologic Characteristics, Treatment Outcomes, and Acquired Resistance Patterns of Atypical EGFR Mutations and HER2 Alterations in Stage IV Non-Small-Cell Lung Cancer.",
"title_normalized": "clinicopathologic characteristics treatment outcomes and acquired resistance patterns of atypical egfr mutations and her2 alterations in stage iv non small cell lung cancer"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-024710",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "201292",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER STAGE IV",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"medicinalproduct": "GILOTRIF"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "201292",
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"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "EGFR GENE MUTATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "GILOTRIF"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Malignant neoplasm progression",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PATIL T, MUSHTAQ R, MARSH S, AZELBY C, PUJARA M, DAVIES K, ETAL.. CLINICOPATHOLOGIC CHARACTERISTICS, TREATMENT OUTCOMES, AND ACQUIRED RESISTANCE PATTERNS OF ATYPICAL EGFR MUTATIONS AND HER2 ALTERATIONS IN STAGE IV NON- SMALL-CELL LUNG CANCER. CLINICAL LUNG CANCER. 2020?21(3):E191-E204.",
"literaturereference_normalized": "clinicopathologic characteristics treatment outcomes and acquired resistance patterns of atypical egfr mutations and her2 alterations in stage iv non small cell lung cancer",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200521",
"receivedate": "20200521",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 17810196,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200714"
}
] |
{
"abstract": "Drug overdose mortality is a major public health concern in the United States, with prescription opioids contributing substantially to recent increases in drug overdose deaths. Compared to unintentional drug overdose deaths, relatively little data describes intentional self-inflicted drug overdose deaths (i.e., suicide by drug overdose). The aim of this study was to examine the characteristics of self-inflicted drug overdose deaths, overall and in comparison to unintentional drug overdose deaths.\n\n\n\nWe linked vital statistics, prescription drug monitoring program, and toxicology data for self-inflicted and unintentional drug overdose deaths among North Carolina residents in 2012.\n\n\n\nMost self-inflicted (79.2%) and unintentional (75.6%) drug overdose decedents had a prescription for a controlled substance within one year of death. Toxicology results revealed that antidepressants contributed to a significantly higher percent of self-inflicted compared to unintentional drug overdose deaths (45.0% vs. 8.1%). Among deaths in which commonly prescribed opioids (oxycodone, hydrocodone) or benzodiazepines (alprazolam, clonazepam) contributed to death, a significantly higher percent of self-inflicted drug overdose decedents had a prescription for the substance within 30days of death compared to unintentional drug overdose decedents.\n\n\n\nThe results highlight the use of prescription opioids, benzodiazepines, and antidepressants among self-inflicted drug overdose decedents. Importantly, the results indicate that self-inflicted drug overdose decedents were more likely than unintentional drug overdose decedents to have potential contact with the health care system in the weeks preceding death, offering an opportunity for professionals to identify and intervene on risk factors or signs of distress and potential for self-harm.",
"affiliations": "Department of Maternal and Child Health and Injury Prevention Research Center, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, United States. Electronic address: anna.austin@unc.edu.;Injury and Violence Prevention Branch, Chronic Disease and Injury Section, Division of Public Health, North Carolina Department of Health and Human Services, United States.;Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, United States.;Drug Control Unit, Division of Mental Health, Developmental Disabilities, and Substance Abuse Services, North Carolina Department of Health and Human Services, United States.",
"authors": "Austin|Anna E|AE|;Proescholdbell|Scott K|SK|;Creppage|Kathleen E|KE|;Asbun|Alex|A|",
"chemical_list": "D055553:Prescription Drugs; D011619:Psychotropic Drugs",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.drugalcdep.2017.09.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0376-8716",
"issue": "181()",
"journal": "Drug and alcohol dependence",
"keywords": "Benzodiazepine; Opioid; Prescription drug; Self-inflicted drug overdose; Suicide",
"medline_ta": "Drug Alcohol Depend",
"mesh_terms": "D000328:Adult; D062787:Drug Overdose; D005260:Female; D006801:Humans; D033182:Intention; D008297:Male; D008875:Middle Aged; D009657:North Carolina; D055553:Prescription Drugs; D011619:Psychotropic Drugs; D012307:Risk Factors; D012651:Self Medication; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "7513587",
"other_id": null,
"pages": "44-49",
"pmc": null,
"pmid": "29032024",
"pubdate": "2017-12-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Characteristics of self-inflicted drug overdose deaths in North Carolina.",
"title_normalized": "characteristics of self inflicted drug overdose deaths in north carolina"
} | [
{
"companynumb": "US-NEOS THERAPEUTICS, LP-2018NEO00087",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROCODONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "091671",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HYDROCODONE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Completed suicide",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "AUSTIN AE, PROESCHOLDBELL SK, CREPPAGE KE, ASBUN A. CHARACTERISTICS OF SELF?INFLICTED DRUG OVERDOSE DEATHS IN NORTH CAROLINA. DRUG ALCOHOL DEPEND (DOI: 10.1016/J.DRUGALCDEP.2017.09.014). 2017?181:44?49",
"literaturereference_normalized": "characteristics of self inflicted drug overdose deaths in north carolina",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180725",
"receivedate": "20180725",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15198209,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20181010"
}
] |
{
"abstract": "Background Myelin oligodendrocyte glycoprotein (MOG) is located on the surface of oligodendrocytes and myelin in the central nervous system. MOG-IgG is associated with acute disseminated encephalomyelitis (ADEM), relapsing and bilateral optic neuritis (NNO), and transverse myelitis (TM) in both paediatric and adult patients. The combination of NNO and TM or other inflammatory brain lesions is a typical feature of neuromyelitis optica spectrum disorders (NMO-SD) which are associated with specific pathogenic autoantibodies against the water channel aquaporin-4 (AQP4-IgG). However, children with NMO-SD are often seronegative for AQP4-IgG but seropositive for MOG-IgG. Therefore, the course and therapy of MOG-IgG positive NNO in children were of special interest. Patients The course of disease of two male patients with acute NNO is presented (bilateral NNO, age of onset 8 years each, AQP4-IgG negative, MOG-IgG positive). Several relapses of NNO occurred in patient 1 with persisting MOG-IgG in spite of immunsuppressive therapy. He suffered from increasing optic atrophy, considerable visual loss and transient brainstem affection. Patient 2 showed a monophasic course of disease with a rapid decline in MOG-IgG titre and only minor asymmetric optic atrophy. Conclusions MOG-IgG in children is associated with recurrent NNO and cerebral lesions characteristic of ADEM or NMO-SD. High titres of MOG-IgG are observed during the acute phase of clinical symptoms. Relapses of NNO lead to increasing loss of retinal nerve fibre layer. Diagnostic investigation includes the determination of AQP4-IgG and MOG-IgG as well as magnetic resonance imaging (MRI) of brain and spinal cord. The therapeutic consequence of this is consistent immunsuppressive treatment, starting with intravenous steroids and followed by second-line therapy with steroid sparing immunosuppressants, including mycophenolate or azathioprine, followed in refractory cases by rituximab. The therapeutic effect should be controlled by laboratory tests of MOG-IgG titre.",
"affiliations": "Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Leipzig, Leipzig.;Neuropädiatrie, Universitätsklinik und Poliklinik für Kinder und Jugendliche Leipzig, Leipzig.",
"authors": "Tegetmeyer|Helmut|H|;Merkenschlager|Andreas|A|",
"chemical_list": "D051401:Aquaporin 4; D007074:Immunoglobulin G; D063308:Myelin-Oligodendrocyte Glycoprotein",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0043-120067",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-2165",
"issue": "234(10)",
"journal": "Klinische Monatsblatter fur Augenheilkunde",
"keywords": null,
"medline_ta": "Klin Monbl Augenheilkd",
"mesh_terms": "D000328:Adult; D051401:Aquaporin 4; D002648:Child; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D063308:Myelin-Oligodendrocyte Glycoprotein; D009471:Neuromyelitis Optica; D009902:Optic Neuritis",
"nlm_unique_id": "0014133",
"other_id": null,
"pages": "1243-1249",
"pmc": null,
"pmid": "29025172",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anti-Myelin Oligodendrocyte Glycoprotein Antibodies in Paediatric Patients with Optic Neuritis.",
"title_normalized": "anti myelin oligodendrocyte glycoprotein antibodies in paediatric patients with optic neuritis"
} | [
{
"companynumb": "DE-MYLANLABS-2017M1078173",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNK",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"summary": null
},
"primarysource": {
"literaturereference": "TEGETMEYER H, MERKENSCHLAGER A. ANTI-MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODIES IN PAEDIATRIC PATIENTS WITH OPTIC NEURITIS. KLIN MONATSBL AUGENHEILKD (CLINICAL MONTHLY JOURNAL ON OPHTHALMOLOGY). 2017;234(10):1243-1249.",
"literaturereference_normalized": "anti myelin oligodendrocyte glycoprotein antibodies in paediatric patients with optic neuritis",
"qualification": "1",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20171228",
"receivedate": "20171213",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
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"safetyreportversion": 2,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
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"seriousnesslifethreatening": null,
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}
] |
{
"abstract": "Patients who decline blood transfusions, including members of the Jehovah's Witness faith, often face challenges when they require or desire prolonged operations such as free tissue transfer (FTT). This study aims to outline our institution's experience with treating bloodless medicine patients and offers the first anatomically comprehensive evaluation of FTT in this population. All patients undergoing FTT from 2017 to 2020 at a single institution were retrospectively reviewed. Patients who declined blood products were selected. Outcomes of interest include flap success, operative complications, and changes to hemoglobin measurements. Ten patients undergoing 11 FTT procedures were identified. Average age was 62.4 years (SD 7.6). Most patients were female (n = 9) and Black (n = 8). Average body mass index was 31.3 (SD 5.6), American Society of Anesthesiologists Physical Status was 2.9 (SD 0.5), and Charlson Comorbidity Index was 3.8 (SD 1.1). Sites of FTT reconstruction were breast (6), lower extremity (3), and scalp (2). Average operative time was 390 min (SD 85.1), with an average estimated blood loss of 170 mL (SD 100.4). The difference between preoperative hemoglobin to first postoperative hemoglobin measurement averaged 2.2 g/dL (SD 1.4). Average patient follow-up was 12 months (SD 7.8). Flap success occurred in 10 cases. One patient with flap failure was successfully reconstructed with a second procedure. Despite a small, heterogeneous cohort, our success rate in this highly comorbid population indicates that FTT can be performed effectively for patients who cannot use blood products. Bloodless medicine protocols are beneficial to providers serving patients with transfusion restrictions and systems that strive to limit transfusion volume and risk.",
"affiliations": "Georgetown University School of Medicine, Washington, District of Columbia USA.;Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, Washington, District of Columbia USA.;Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, Washington, District of Columbia USA.;Bloodless Medicine and Surgery Program, MedStar Georgetown University Hospital, Washington, District of Columbia USA.;Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, Washington, District of Columbia USA.;Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, Washington, District of Columbia USA. Electronic address: Karen.K.Evans@gunet.georgetown.edu.",
"authors": "Bhardwaj|Priya|P|;Bekeny|Jenna C|JC|;Zolper|Elizabeth G|EG|;Verstraete|Richard|R|;Fan|Kenneth L|KL|;Evans|Karen K|KK|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.bjps.2021.08.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1748-6815",
"issue": null,
"journal": "Journal of plastic, reconstructive & aesthetic surgery : JPRAS",
"keywords": "Bloodless medicine; Free Flap; Free tissue transfer; Jehovah's witness; Transfusion Averse",
"medline_ta": "J Plast Reconstr Aesthet Surg",
"mesh_terms": null,
"nlm_unique_id": "101264239",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34776392",
"pubdate": "2021-09-17",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A single-center experience with head-to-toe microsurgical reconstruction in bloodless medicine patients.",
"title_normalized": "a single center experience with head to toe microsurgical reconstruction in bloodless medicine patients"
} | [
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{
"abstract": "Interleukin (IL)-12 is composed of p35 and p40 subunits; in this case, IL-12p40 deficiency is a rare genetic etiology of Mendelian susceptibility to mycobacterial disease. Salmonellosis has been reported in almost half of these patients and mostly present in recurrent extraintestinal form. In this report, we described an 18-month-old boy with absence of IL-12p40 production suffering from chronic disseminated nontyphoidal salmonellosis. To the best of our knowledge, this is the first-reported case.",
"affiliations": null,
"authors": "Alaki|Emadia Mohammad|EM|;Aljobair|Fahad|F|;Alaklobi|Faisal|F|;Al Shamrani|Mobarak|M|;Al-Zahim|Fahad|F|;Dongues|Aziza|A|;Casanova|Jean-Laurent|JL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D053762:Interleukin-12 Subunit p40",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000001701",
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"issn_linking": "0891-3668",
"issue": "37(1)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000900:Anti-Bacterial Agents; D003937:Diagnosis, Differential; D006801:Humans; D007223:Infant; D053762:Interleukin-12 Subunit p40; D008297:Male; D009154:Mutation; D009164:Mycobacterium Infections; D012480:Salmonella Infections",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "90-93",
"pmc": null,
"pmid": "28723869",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20736739;12590259;11992286;14894415;20158401;21234109;16418797;12830418;23429356;22587967;18083507;10971505;16181679;21057261;22752519;9603732;16765581;16531420;15661020",
"title": "Chronic Disseminated Salmonellosis in a Patient With Interleukin-12p40 Deficiency.",
"title_normalized": "chronic disseminated salmonellosis in a patient with interleukin 12p40 deficiency"
} | [
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{
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},
{
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},
{
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},
{
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},
{
"reactionmeddrapt": "Gastroenteritis",
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"reactionoutcome": "1"
}
],
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},
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"literaturereference": "ALAKI EM, ALJOBAIR F, ALAKLOBI F, AL SHAMRANI M, AL-ZAHIM F, DONGUES A, CASANOVA J-L. CHRONIC DISSEMINATED SALMONELLOSIS IN A PATIENT WITH INTERLEUKIN-12P40 DEFICIENCY. PEDIATRIC INFECTIOUS DISEASE JOURNAL. 2018?37:1:90-93",
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] |
{
"abstract": "Clozapine, a second-generation antipsychotic (SGA), is known for its superior efficacy in the treatment of refractory schizophrenia. Clozapine's hallmark side effects are well-known, including, but not limited to, drug-induced seizures associated with daily goal doses greater than 600mg and rapid dose escalation, which can also contribute to significant risk of orthostatic hypotension, bradycardia, and syncope. However, less well-known is the potential withdrawal that can occur from its rapid discontinuation. Here, we describe a case of seizure-like activity that occurred 72 hours after an abrupt high-dose clozapine discontinuation in a patient with schizoaffective disorder, bipolar type. Seizures, although known to be a high-serum-concentration-dependent side effect of clozapine, could not be excluded as a possible withdrawal syndrome in this patient.",
"affiliations": "Drs. Skelly, Demler, and Lee are with the State University at Buffalo (SUNY) School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacy Practice in Buffalo, New York.;Drs. Skelly, Demler, and Lee are with the State University at Buffalo (SUNY) School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacy Practice in Buffalo, New York.;Drs. Skelly, Demler, and Lee are with the State University at Buffalo (SUNY) School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacy Practice in Buffalo, New York.",
"authors": "Skelly|Megan K|MK|;Demler|Tammie Lee|TL|;Lee|Claudia|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2158-8333",
"issue": "16(7-08)",
"journal": "Innovations in clinical neuroscience",
"keywords": "Clozapine; psychopharmacology; seizure; withdrawal",
"medline_ta": "Innov Clin Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101549695",
"other_id": null,
"pages": "22-24",
"pmc": null,
"pmid": "31832260",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "3088645;8938913;12465085;21815323;30291;9608419;412427;26565383;28396815;10786215;9283512;15602101;9228890;11479394;11769826;7492259;8071251;6433395;23753931;10890315;25537107",
"title": "High-dose Clozapine Withdrawal: A Case Report and Timeline of a Single Potential Withdrawal Seizure.",
"title_normalized": "high dose clozapine withdrawal a case report and timeline of a single potential withdrawal seizure"
} | [
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{
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],
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Constipation",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Orthostatic hypotension",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
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},
{
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
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},
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},
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},
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},
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},
{
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Abdominal distension",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Cerebrovascular accident",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood potassium increased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dizziness",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Orthostatic hypotension",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "SKELLY M, DEMLER T, LEE C. HIGH-DOSE CLOZAPINE WITHDRAWAL: A CASE REPORT AND TIMELINE OF A SINGLE POTENTIAL WITHDRAWAL SEIZURE. INNOV CLIN NEUROSCI. 2019 JUL 1?16(7-08):22-24. ECOLLECTION 2019 JUL-AUG.",
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},
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},
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"abstract": "Active surveillance for transfusion reactions is critically important among pediatric patients undergoing chemotherapy. Among pediatric-adolescent-young-adult (AYA) hematology/oncology patients, who have been typically excluded from transfusion reaction studies, this profile remains poorly characterized.\nWe assessed the incidence and clinical characteristics of transfusion reactions (n = 3246 transfusions) in this population (n = 201 patients) at our center.\nThe incidence of adjudicated transfusion reactions was 2·04%. The incidence was higher for platelet (2·78%) compared to packed red blood cell transfusions (1·49%) (p = 0·0149). The majority (61·4%) of all reactions were classified as febrile non-haemolytic transfusion, while 35·7% were considered allergic, and 2·9% were classified as transfusion-associated circulatory overload. The incidence of transfusion reactions in patients who were pre-medicated was higher (2·51%) than in patients who were not (1·52%) (p = 0·0406). Sub-set analysis revealed a 3·95% incidence of adjudicated transfusion reactions among recipients of immune effector cells (IECs) (n = 3), all of which occurred during the potential window for cytokine release syndrome; two-thirds of these reactions were severe/potentially life-threatening.\nThe incidence of transfusion reactions among pediatric-AYA hematology/oncology patients may be lower than the general pediatric population. Patients with a prior history of transfusion reactions and those receiving platelet transfusions may be at higher risk for reaction. From our limited sample, IEC recipients may be at risk for severe transfusion reactions. Large multi-center prospective studies are needed to characterize transfusion reactions in this population. Appropriate characterization of reactions in this population may inform risk stratification and mitigate missed opportunities for prompt recognition and appropriate management.\nNone.",
"affiliations": "Stem Cell Transplant and Cellular Therapy, Division of Pediatrics, 1515 Holcombe Blvd., Unit 0087, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Stem Cell Transplant and Cellular Therapy, Division of Pediatrics, 1515 Holcombe Blvd., Unit 0087, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Stem Cell Transplant and Cellular Therapy, Division of Pediatrics, 1515 Holcombe Blvd., Unit 0087, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Stem Cell Transplant and Cellular Therapy, Division of Pediatrics, 1515 Holcombe Blvd., Unit 0087, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Division of Electronic Health Record Analytics and Reporting, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Division of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Stem Cell Transplant and Cellular Therapy, Division of Pediatrics, 1515 Holcombe Blvd., Unit 0087, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Kohorst|Mira A|MA|;Khazal|Sajad J|SJ|;Tewari|Priti|P|;Petropoulos|Demetrios|D|;Mescher|Benjamin|B|;Wang|Jian|J|;Mahadeo|Kris M|KM|;Kelley|James M|JM|",
"chemical_list": null,
"country": "England",
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"doi": "10.1016/j.eclinm.2020.100514",
"fulltext": "\n==== Front\nEClinicalMedicine\nEClinicalMedicine\nEClinicalMedicine\n2589-5370 Elsevier \n\nS2589-5370(20)30258-3\n10.1016/j.eclinm.2020.100514\n100514\nResearch paper\nTransfusion reactions in pediatric and adolescent young adult haematology oncology and immune effector cell patients\nKohorst Mira A. makohorst@mdanderson.orga⁎ Khazal Sajad J. a Tewari Priti a Petropoulos Demetrios a Mescher Benjamin b Wang Jian c Mahadeo Kris M. a1 Kelley James M. d1 a Stem Cell Transplant and Cellular Therapy, Division of Pediatrics, 1515 Holcombe Blvd., Unit 0087, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\nb Division of Electronic Health Record Analytics and Reporting, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\nc Division of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\nd Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\n⁎ Corresponding author. makohorst@mdanderson.org1 These author contributed equally.\n\n\n09 9 2020 \n9 2020 \n09 9 2020 \n26 10051410 6 2020 27 7 2020 4 8 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nActive surveillance for transfusion reactions is critically important among pediatric patients undergoing chemotherapy. Among pediatric-adolescent-young-adult (AYA) hematology/oncology patients, who have been typically excluded from transfusion reaction studies, this profile remains poorly characterized.\n\nMethods\nWe assessed the incidence and clinical characteristics of transfusion reactions (n = 3246 transfusions) in this population (n = 201 patients) at our center.\n\nFindings\nThe incidence of adjudicated transfusion reactions was 2·04%. The incidence was higher for platelet (2·78%) compared to packed red blood cell transfusions (1·49%) (p = 0·0149). The majority (61·4%) of all reactions were classified as febrile non-haemolytic transfusion, while 35·7% were considered allergic, and 2·9% were classified as transfusion-associated circulatory overload. The incidence of transfusion reactions in patients who were pre-medicated was higher (2·51%) than in patients who were not (1·52%) (p = 0·0406). Sub-set analysis revealed a 3·95% incidence of adjudicated transfusion reactions among recipients of immune effector cells (IECs) (n = 3), all of which occurred during the potential window for cytokine release syndrome; two-thirds of these reactions were severe/potentially life-threatening.\n\nInterpretation\nThe incidence of transfusion reactions among pediatric-AYA hematology/oncology patients may be lower than the general pediatric population. Patients with a prior history of transfusion reactions and those receiving platelet transfusions may be at higher risk for reaction. From our limited sample, IEC recipients may be at risk for severe transfusion reactions. Large multi-center prospective studies are needed to characterize transfusion reactions in this population. Appropriate characterization of reactions in this population may inform risk stratification and mitigate missed opportunities for prompt recognition and appropriate management.\n\nFunding\nNone.\n==== Body\nResearch in context\nEvidence before this study\nTransfusions are frequently required in pediatric and adolescent-young adult (AYA) hematology/oncology patients. Transfusion reactions can be a severe and/or life-threatening complication of blood product administration. There is a striking paucity of data and understanding of transfusion reaction incidence and clinical characteristics in this pediatric-AYA hematology/oncology population. We searched PubMed using the terms “transfusion reactions,” “pediatric,” “hematology,” “oncology,” “immune effector cell,” with no date restrictions, for reports in any written language. A paucity of transfusion reaction data exists in pediatric-AYA hematology/oncology populations. This prompted us to investigate transfusion reactions in this population.\n\nAdded value of this study\nThis is the first study to evaluate transfusion reaction incidence and characterization in pediatric-AYA hematology/oncology patients. The incidence of transfusion reactions among pediatric-AYA hematology/oncology patients was 2•04%, which may be lower than the general pediatric population. Two-thirds of the transfusion reactions were febrile nonhaemolytic transfusion reactions in this immunocompromised population, compared to approximately one-third in general pediatric populations. Patients with a prior history of transfusion reactions and those receiving platelet transfusions may be at higher risk for reaction. From our limited sample, immune effector cell recipients may be at high risk for severe transfusion reactions.\n\nImplications of all the available evidence\nAppropriate characterization of transfusion reactions in this population may inform risk stratification and improve prompt recognition and appropriate management. Large multi-center prospective studies are needed to further characterize transfusion reactions in this population.\n\nAlt-text: Unlabelled box\n\n\n\n1 Introduction\nPatients receiving cytotoxic and in particular, myeloablative chemotherapy as used for conditioning in haematopoietic cell transplant (HCT), require frequent transfusions to prevent complications of therapy-induced pancytopenia [1]. Novel immunotherapies including immune effector cells (IEC) have been associated with impressive disease-free outcomes but also prolonged cytopenias that may require transfusion support. IEC patients may develop overlapping symptoms as a result of unique associated toxicities such as cytokine release syndrome (CRS). Haemovigilance is important for detection of various types of transfusion reactions such as febrile nonhaemolytic transfusion reactions (FNHTRs), allergic transfusion reactions, transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), septic transfusion reactions, and haemolytic transfusion reactions among others [2]. The clinical characteristics and management of these transfusion reactions are listed in Table 1.Table 1 Transfusion reaction signs/symptoms and management [3].\n\nTable 1Transfusion Reaction Type\tSigns/Symptoms\tManagement\t\nFebrile nonhaemolytic transfusion reaction (FNHTR)\tIncrease in temperature by ≥1 °C and/or temperature ≥38 °C\n+/- transient hypertension, chills, rigors, and discomfort\tStop transfusion, initiate transfusion reaction work-up looking for signs of infection and haemolysis, provide antipyretic/supportive care\t\nAllergic transfusion reaction\tMild: rash, pruritus, urticaria, localized angioedema\nSevere: anaphylaxis (bronchospasm, respiratory distress, hypotension in addition to mild symptoms)\tMild: Stop transfusion. Administer antihistamine +/- corticosteroid, if symptoms resolve transfusion can be restarted.\nSevere/anaphylactic: Stop transfusion. Rapidly administer intramuscular epinephrine +/- antihistamine (H1 and H2), bronchodilator, corticosteroid. Do not resume transfusion.\t\nTransfusion associated circulatory overload (TACO)\tNew onset or worsening of ≥3 of the following within 6 h of transfusion cessation:• Respiratory distress\n\n• Elevated brain natriuretic peptide\n\n• Raised central venous pressure\n\n• Left heart failure\n\n• Positive fluid balance\n\n• Pulmonary edema\n\n\tStop transfusion. Administer supplemental oxygen and diuretics as needed. Consider prolonging the time of transfusion for future transfusions. Consider prophylactically administering diuretics before or after future transfusions.\t\nTransfusion-related acute lung injury (TRALI)\tDyspnea, tachypnea, hypoxemia, +/- fever, hypothermia, rigors, hypotension, hypertension, or tachycardia. (Symptoms typically within 6 h of end of transfusion, though delayed cases are possible)\nTransient leukopenia may be observed. Bilateral interstitial infiltrates on imaging.\tStop transfusion. Supportive management with supplemental oxygen, mechanical ventilation if needed (restrictive tidal volume), and restrictive fluid strategy.\t\nSeptic transfusion reaction\tFevers (increase in temperature by ≥1 °C and/or temperature ≥38 °C; increase by ≥2 °C heightens clinical suspicion), rigors, hypotension. Diagnosis requires isolation of organism from blood product and patient.\tStop transfusion. Blood cultures should be obtained from the patient and from the blood product. Broad-spectrum antibiotics should be started.\t\nAcute haemolytic transfusion reaction\tFever, chills, back/flank pain, hypotension, dyspnea. May have haemoglobinuria, haemoglobinemia, acute renal failure, disseminated intravascular coagulation, shock, death.\tStop transfusion. Supportive management.\t\n\n\nTransfusion reactions may be categorized as non-severe, severe, life-threatening, or resulting in death. For non-severe reactions, medical intervention may be required but the lack of intervention does not result in permanent damage. Severe reactions are defined as requiring inpatient hospitalization or prolongation of hospitalization as a result of the adverse transfusion reaction. If no medical intervention occurs, these reactions may lead to permanent damage. Life-threatening transfusion reactions are defined as those requiring major intervention such as vasopressors, intubation, or transfer to the intensive care unit to prevent death. These biovigilance definitions have been generated by the Center for Disease Control and Prevention to provide a consistent standard nationwide [3].\n\nWith active haemovigilance, the reported incidence of transfusion reactions across the general adult population is approximately 2% [4], while general pediatric patients may experience 1·9–2·6 times more reactions than adults [5,6]. We hypothesized that immunocompromised pediatric-adolescent-young adult (AYA) hematology/oncology and HCT/IEC patients may have a different transfusion reaction profile from the general population. The therapeutic armamentarium for young hematology/oncology and HCT/IEC patients is rapidly evolving and there is a dearth of information regarding the incidence or clinical characteristics of transfusion reactions in these patients. Improved characterization and recognition of transfusion reactions in this population is important as overlapping toxicity profiles may complicate adjudication and hinder preventative and/or appropriate interventions when indicated.\n\n2 Methods\nWe conducted a retrospective review of all transfusions and transfusion reactions in patients aged less than 25 years at our cancer center over a six-month period from July 1, 2019 to January 1, 2020. Approval for this study was obtained through the Institutional Review Board. Data was accessed using the electronic medical record and Haemovigilance Unit data.\n\nHaemovigilance and adjudication occurred as followed: bedside staff generated a report for any of the following signs or symptoms during or within 6 h following transfusion: fever, chills/rigors, nausea/vomiting, anxiety, diarrhea, feeling of impending doom, loss of consciousness, hypotension, hypertension, tachycardia, edema, rash, flushing, urticaria, pruritus, cyanosis, infusion site pain, abdominal pain/cramps, chest pain/chest tightness, flank pain, low back pain, new-onset headache, discoloration of urine, dyspnea/labored breathing, wheezing, stridor, shortness of breath, hypoxemia, cough, tachypnea, bleeding, swollen lips/tongue/mucous membranes, difficulty speaking, or any other concerning symptoms.\n\nAll transfusion reaction reports created by bedside staff were then assessed by expert adjudication (Table 2), whereby Transfusion Medicine physicians used the National Healthcare Safety Network Biovigilance Component Haemovigilance Module Surveillance Protocol guidelines [3] to determine if the patient's symptoms met criteria for a specific transfusion reaction. Imputability and severity were also determined using these guidelines. In addition to reporting by bedside staff, there was also active, remote Haemovigilance Unit monitoring and investigation for changes in vital signs and temperature for all patients receiving blood product transfusions. Discussion with primary treatment team to assist with adjudication occurred as appropriate.Table 2 Transfusion reaction adjudication.\n\nTable 2Report/Adjudication\tExamples\t\nTransfusion Reaction Diagnosis\tFebrile nonhaemolytic transfusion reaction, allergic transfusion reaction, transfusion-associated circulatory overload, transfusion-related acute lung injury, septic transfusion, acute haemolytic transfusion reaction, etc.\t\nTesting Results\tGram stain and culture of product, blood culture of patient, urinalysis, direct Coombs, lactate dehydrogenase, total bilirubin, chest radiograph, etc.\t\nTransfusion Reaction Severity\tNon-severe, severe, life-threatening, death, not determined\t\nTransfusion Reaction Imputability\tDefinite, possible, doubtful, ruled out, not determined\t\nOutcome\tMinor or no sequelae, major or long term sequelae, death, not determined\t\nRecommendations\tTreatment and monitoring recommendations advised\t\n\n\nStatistical analysis was performed using Wilcoxon Rank Sum Test for two-group comparisons and Kruskal-Wallis Rank Sum Test for multiple-group comparisons when assessing differences in average number of transfusions per patient in each category. When comparing the transfusion reaction rates between different groups, Fisher's exact test was used for assessing p-values. A p-value less than 0·05 was considered significant. Statistical analyses were conducted using R package [7].\n\n2.1 Role of the funding source\nNo funding involved in this study.\n\n3 Results\n3.1 Patient characteristics\nThe median age of our study population (n = 201) was 17 (range 0–24) years. This was a racially/ethnically diverse group with 36·8% Caucasian, 32·8% Hispanic/Latino, 13·4% Black, 12·5% Asian, and 4·5% other/unknown. Almost half (42·8%) were female. Underlying diagnosis and transplant status were also varied with 46·3% solid tumors, 29·4% leukemia/lymphoma patients, 18·8% HCT/IEC patients, and 5·5% benign hematology conditions (Table 3).Table 3 Demographics and transfusion information.\n\nTable 3\tNumber of Patients\tPercentage of Patients (%) (Total N = 201 Patients)\tNumber of Transfusion Events\tPercentage (%) (Total N = 3426 Transfusion Events)\tAverage Transfusions per Person\tP value\t\nSex\t\t\t\t\t\t0·5164\t\n Female\t86\t42·8\t1857\t54·2\t21·6\t\t\n Male\t115\t57·2\t1569\t45·8\t13·6\t\t\nAge\t\t\t\t\t\t0·0314\t\n 0–10 years\t60\t29·8\t465\t13·6\t7·8\t\t\n 11–18 years\t57\t28·4\t999\t29·1\t17·5\t\t\n 19–25 years\t84\t41·8\t1962\t57·3\t23·4\t\t\nRace/Ethnicity\t\t\t\t\t\t0·6084\t\n Caucasian (non-Hispanic/Latino)\t74\t36·8\t1086\t31·7\t14·7\t\t\n Hispanic/Latino\t66\t32·8\t1415\t41·3\t21·5\t\t\n Black\t27\t13·4\t492\t14·4\t18·2\t\t\n Asian\t25\t12·5\t204\t5·9\t8·2\t\t\n Other/Unknown\t9\t4·5\t229\t6·7\t25·4\t\t\nUnderlying diagnosis\t\t\t\t\t\t<0·0001\t\n Haematopoietic cell transplant\t37\t18·8\t1171\t34·2\t31·6\t\t\n Autologous\t8\t4·0\t255\t7·4\t31·9\t\t\n Immune effector cell therapy\t7\t3·5\t76\t2·2\t10·9\t\t\n Allogeneic\t22\t11·0\t840\t24·5\t38·2\t\t\n Matched related donor\t6\t3·0\t120\t3·5\t20·0\t\t\n Matched unrelated donor\t8\t4·0\t272\t7·9\t34·0\t\t\n Haploidentical\t4\t2·0\t117\t3·4\t29·3\t\t\n Mismatched unrelated donor\t1\t0·5\t23\t0·7\t23·0\t\t\n Umbilical cord blood\t3\t1·5\t308\t9·0\t102·7\t\t\n Bone marrow source\t11\t5·5\t325\t9·5\t29·5\t\t\n Peripheral blood stem cells\t8\t4·0\t207\t6·0\t25·9\t\t\n Myeloablative\t18\t8·9\t728\t21·2\t40·4\t\t\n Reduced toxicity conditioning\t4\t2·0\t112\t3·3\t28·0\t\t\n Non-haematopoietic cell transplant\t164\t81·6\t2255\t65·8\t13·8\t\t\n Leukemia/lymphoma\t60\t29·8\t1422\t41·5\t24·1\t\t\n Acute lymphoblastic leukemia\t35\t17·4\t573\t16·7\t16·4\t\t\n Acute myeloid leukemia\t16\t8·0\t795\t23·2\t49·7\t\t\n Lymphoma\t9\t4·5\t66\t1·9\t7·3\t\t\n Solid tumors\t93\t46·3\t651\t19·0\t7·0\t\t\n Ewing sarcoma\t14\t7·0\t153\t4·5\t10·9\t\t\n Osteosarcoma\t15\t7·5\t132\t3·9\t8·8\t\t\n Rhabdomyosarcoma\t14\t7·0\t58\t1·7\t4·1\t\t\n Brain tumors\t16\t8·0\t104\t3·0\t6·5\t\t\n Other\t34\t16·9\t204\t6·0\t6·0\t\t\n Benign haematologic conditions\t11\t5·5\t170\t5·0\t15·5\t\t\nProduct\t\t\t\t\t\t\t\n Platelets\t–\t–\t1726\t50·4\t–\t\t\n Red blood cells\t–\t–\t1476\t43·1\t–\t\t\n Fresh frozen plasma\t–\t–\t87\t2·5\t–\t\t\n Cryoprecipitate\t–\t–\t\t3·3\t–\t\t\n Granulocytes\t–\t–\t24\t0·7\t–\t\t\nPremedication status\t\t\t\t\t\t–\t\n Any premedication\t–\t–\t1789\t52·2\t–\t–\t\n Premedication for fever (acetaminophen and/or hydrocortisone)\t–\t–\t1608\t46·9\t–\t\t\n Premedication for allergic reaction (diphenhydramine and/or hydrocortisone)\t–\t–\t1715\t50·1\t–\t\t\nTransfusion reactions reported by bedside staff\t52\t25·9\t93\t2·71\t–\t–\t\nTransfusion reactions adjudicated by Transfusion Medicine\t45\t22·4\t70\t2·04\t–\t–\t\n\n\n3.2 Transfusion history\nDuring the study period, 3426 blood products were transfused. Of those, 50·4% were platelets, 43·1% were packed red blood cells (pRBC), 3·3% were cryoprecipitate, 2·5% were thawed plasma, and 0·7% were granulocyte infusions. The average number of transfusions per person in the entire cohort was 17·0 blood product administrations/patient. Females were transfused an average of 21·4 transfusions/patient and males received 13·6 transfusions/patient (p = 0·5164). There were significant differences in transfusion burden based on age, with older patients receiving more transfusions (23·4 transfusions/patient) compared to younger children (7·8 transfusions/patient) (p = 0·0314). As shown in Fig. 1A, transfusion burden did not vary significantly by race/ethnicity (p = 0·6084). There was a significant difference in transfusion rate based on underlying diagnosis/treatment (Fig. 1B). Patients undergoing allogeneic HCT and those with a diagnosis of acute myeloid leukemia (AML) had the average highest rates of transfusion at 38·2 transfusions/patient and 49·7 transfusions/patient respectively (p = 0·0007).Fig. 1 (A) Average number of transfusions per patient in each demographic category. (B) Average number of transfusions per patient with each underlying diagnosis or transplant status. (C) Transfusion reaction rate of each type of reaction within the diagnostic categories listed.\n\nFig 1\n\n3.3 Haemovigilance and incidence of transfusion reactions\nWith haemovigilance, 93 transfusion reaction reports were generated by bedside staff (2·71% of all transfusions). The incidence of true transfusion reactions (n = 70) as determined by expert adjudication was 2·04% (Table 4). Adjudicated transfusion reactions occurred in 22·3% (n = 45) of our patients. Median age at the time of reaction was 19 years (range 1–24 years). Males and females had similar rates of transfusion reactions respectively. Younger children aged less than 10 years had a slightly higher transfusion reaction rate at 3·23% compared to those aged 11–18 years or 19–25 years with rates of 1·40%, and 2·09% respectively, though this difference did not reach statistical significance in our cohort (p = 0·0757) (Fig. 2A).Table 4 Transfusion reaction characterization.\n\nTable 4\tNumber of adjudicated transfusion reactions\tPercentage (%) of total adjudicated transfusion reactions (N = 70)\tPercentage (%) of total transfusions in each group\tP value\t\nSex\t\t\t\t0·9036\t\n Female\t37\t52·9\t1·99\t\t\n Male\t33\t47·1\t2·10\t\t\nAge\t\t\t\t0·0757\t\n 0–10 years\t15\t21·4\t3·23\t\t\n 11–18 years\t14\t20·0\t1·40\t\t\n 19–25 years\t41\t58·6\t2·09\t\t\nRace/Ethnicity\t\t\t\t0·9359\t\n Caucasian (non-Hispanic/Latino)\t25\t35·7\t2·30\t\t\n Hispanic/Latino\t27\t38·6\t1·91\t\t\n Black\t11\t15·7\t2·24\t\t\n Asian\t3\t4·3\t1·47\t\t\n Other/Unknown\t4\t5·7\t1·75\t\t\nProduct\t\t\t\t0·0318\t\n Platelets\t48\t68·6\t2·78\t\t\n Red blood cells\t22\t31·4\t1·49\t\t\n Thawed plasma\t0\t0\t0\t\t\n Cryoprecipitate\t0\t0\t0\t\t\n Granulocytes\t0\t0\t0\t\t\nUnderlying diagnosis\t\t\t\t\t\nHaematopoietic cell transplant\t23\t32·9\t1·96\t0·7940 (major diagnosis categories)\t\n Autologous\t9\t12·9\t3·53\t0·1047 (diagnosis subtypes)\t\n Immune effector cell therapy\t3\t4·3\t3·95\t\t\n Allogeneic\t11\t15·7\t1·31\t\t\n Matched related donor\t3\t4·2\t2·50\t\t\n Matched unrelated donor\t3\t4·2\t1·10\t\t\n Haploidentical\t0\t0\t0\t\t\n Mismatched unrelated donor\t0\t0\t0\t\t\n Umbilical cord blood\t5\t14·2\t1·62\t\t\n Bone marrow source\t4\t5·7\t1·23\t\t\n Peripheral blood stem cells\t2\t2·9\t0·97\t\t\n Myeloablative\t11\t15·7\t1·51\t\t\n Reduced toxicity conditioning\t0\t0\t0\t\t\nNon-haematopoietic cell transplant\t47\t67·1\t2·08\t\t\n Leukemia/lymphoma\t29\t41·4\t2·04\t\t\n Acute lymphoblastic leukemia\t14\t20·0\t2·44\t\t\n Acute myeloid leukemia\t15\t21·4\t1·89\t\t\n Lymphoma\t0\t0\t0\t\t\n Solid tumors\t16\t22·9\t2·46\t\t\n Ewing sarcoma\t2\t2·9\t1·31\t\t\n Osteosarcoma\t5\t7·1\t3·79\t\t\n Rhabdomyosarcoma\t0\t0\t0\t\t\n Brain tumors\t5\t7·1\t4·81\t\t\n Other\t4\t5·7\t1·96\t\t\n Benign haematologic conditions\t2\t2·9\t1·18\t\t\nTransfusion reaction type\t\t\t\t\t\n Febrile non-haemolytic transfusion reaction\t43\t61·4\t–\t–\t\n Premedication with acetaminophen and/or hydrocortisone\t(24/43)\t(55·8)\t\t\t\n Allergic\t25\t35·7\t–\t\t\n Premedication with diphenhydramine and/or hydrocortisone\t(19/25)\t(76·0)\t\t\t\n Transfusion-associated circulatory overload\t2\t2·9\t–\t\t\n Transfusion-associated acute lung injury\t0\t0\t–\t\t\n Haemolytic transfusion reaction\t0\t0\t–\t\t\nSeverity\t\t\t\t\t\n Non-severe\t62\t88·6\t\t\t\n Severe/Life-threatening\t5\t7·1\t\t\t\n Death\t0\t0\t\t\t\n Not determined\t3\t4·3\t\t\t\nFig. 2 (A) Transfusion reaction rate by demographic characteristics. (B) Transfusion reaction rate by underlying diagnosis. (C) Transfusion reaction rate by blood product.\n\nFig 2\n\n3.4 Transfusion reaction classification\nThe majority (61·4%) of transfusion reactions were classified as febrile non-haemolytic transfusion reactions (FNHTR), while 35·7% were considered allergic and 2·9% were diagnosed as transfusion-associated circulatory overload (TACO). Both of the TACO transfusion reactions occurred in HCT/IEC patients, one after double cord blood allogeneic transplantation, and one after IEC administration. In both of these patients, there was evidence of fluid volume overload with increasing respiratory distress, positive fluid balance, pulmonary edema and new oxygen requirement. Neither of these patients had a prior history of TACO or were pre-medicated with diuretics. Of the transfusions administered to patients with benign haematologic diseases, none resulted in FNHTR and two resulted in an allergic reaction. The HCT/IEC, leukemia/lymphoma, and solid tumor groups had similar rates of NHFTRs and allergic transfusion reactions (Fig. 1C). Of the 70 total reactions, five were potentially life-threatening (7·1% of reactions). One severe allergic reaction occurred in an IEC patient, two severe FNHTRs occurred in pediatric oncology patients (ALL and brain tumor) and two TACOs occurred in HCT/IEC patients (one cord blood recipient and one IEC recipient). None of the transfusion reactions were associated with death.\n\n3.5 Transfusion reactions characterized by underlying diagnosis/treatment\nAn underlying diagnosis of leukemia was associated with 41·4% and HCT/IEC was associated with 32·9% of all transfusion reactions respectively. Of the 23 reactions in HCT/IEC patients, 11 occurred in allogeneic HCT recipients, nine were in autologous HCT recipients, and three were in patients receiving IEC. The reactions that occurred in IEC patients (three reactions out of 76 transfusions, incidence 3·95%) were distinguished from cytokine release syndrome (CRS: fever, hypotension, hypoxia, fluid retention, and rashes among other symptoms) [8]; all three reactions occurred during the potential window for CRS (2–6 days post IEC infusion) and adjudication was done in consultation with the primary treatment team. True reactions occurred in two patients who had received tumor infiltrating lymphocytes (TIL) with interleukin-2 (IL-2). Adjudicated true reactions in this sub-group included TACO (n = 1), FNHTR (n = 1) and severe allergic reaction (n = 1). The patient who developed TACO had signs of fluid volume overload with weight gain, pulmonary edema, pleural effusions, and increasing oxygen requirement during a transfusion on day +3 following IEC infusion. This same patient experienced a severe allergic reaction during a transfusion three days later as characterized by rash, angioedema, and dyspnea. Adjudication of transfusion reaction was complicated by concurrent CRS from day +3 to day +8 following IEC infusion. CRS was managed conservatively without medication management. The IEC patient with the FNHTR had a temperature increase of 1·6 °C to 38·6 °C approximately 4 h after completion of a platelet transfusion, on day +5 following IEC infusion. This patient too had signs/symptoms possibly consistent with CRS, including fevers from day +5 to day +7 following IEC infusion. There was one “false positive” (negatively-adjudicated) transfusion reaction in this subgroup in a CD19 chimeric antigen receptor (CAR) T-cell patient with dyspnea that was attributed to CRS. Transfusion reaction rates across all underlying diagnoses/treatments are summarized in Fig. 2B.\n\n3.6 Transfusion reactions characterized by product type\nPlatelets accounted for the majority (68·6%) of positively adjudicated reactions, while pRBCs were associated with 31·4%. Thus, of all platelet transfusions (n = 1726), reactions were documented in 2·78%, and of all RBC transfusions (n = 1476), reactions were documented in 1·49%, suggesting a higher reaction rate with platelets than with RBC transfusions (p = 0·0149) (Fig. 2C). There were no reactions identified with cryoprecipitate, thawed plasma, or granulocyte infusions, though these products comprised only 6·5% of all transfusions (n = 224).\n\n3.7 Transfusion reactions characterized by pre-medication status\nThe majority of transfusion reactions occurred in the setting of pre-medication. More than half (55·8%) of FNHTRs occurred in patients who were pretreated with acetaminophen and/or hydrocortisone; and 76% of allergic transfusion reactions occurred in patients who were pre-treated with diphenhydramine and/or hydrocortisone. The incidence of transfusion reactions in patients who were pre-medicated with anti-pyretics and/or anti-histamines was significantly higher (2·51%) compared to patients who were not pre-medicated (1·52%) (p-value 0·0406).\n\n3.8 Characteristics of negatively-adjudicated reactions\nAlmost one quarter (24·7%) of bedside reports of transfusion reactions were subsequently adjudicated as negative; an alternative attribution was determined and appropriate medical intervention occurred. Of the 23 reports that were not adjudicated as true transfusion reactions, 19 (83%) were generated for fever, two for tachycardia, one for dyspnea, and one for hypotension; all were deemed unrelated to the transfusion and subsequently attributed to other causes, most commonly underlying infection and/or neutropenic fever.\n\n4 Discussion\nTo our knowledge, this study is the first to report the incidence and characterize the spectrum of transfusion reactions seen in immune-compromised pediatric-AYA, hematology/oncology and HCT/IEC patients. These findings are important as, historically, there has been concern for underreporting of transfusion reactions in oncology patients [9,10]. In our population, the incidence of transfusion reactions among pediatric-AYA hematology/oncology patients (2·04%) was similar to the reported general adult and lower than the general pediatric population incidence. Understanding the incidence and characteristics associated with transfusion reactions in this population may improve our ability to detect and promptly manage these potentially life-threatening complications.\n\nThe incidence of transfusion reactions varies widely depending on the study design and type of haemovigilance system used—active versus passive [4,[11], [12], [13], [14], [15], [16], [17], [18]]. Active haemovigilance reporting systems have observed higher rates of transfusion reactions compared to passive systems. Hendrickson et al. using systematic active surveillance and expert adjudication, identified a transfusion reaction rate of approximately 2% [4]. However, in a study which reviewed the transfusion reactions reported to the National Healthcare Safety Network Haemovigilance Module, only 5136 reactions were reported among 2144,723 components transfused (0·24%) [19].\n\nIn our study, platelet transfusions and pre-medication were associated with higher incidence of transfusion reactions. Younger children appeared to have a higher incidence of reactions, but in our relatively older cohort, we may not have been powered to detect significance. Febrile non-haemolytic transfusion reactions were the most common reaction observed. Potentially life-threatening reactions were rare but occurred most commonly in IEC recipients. These findings may inform future haemovigilance prediction systems for this population.\n\nCellular and immunotherapies (i.e., immune effector cells and checkpoint inhibitors) have revolutionized the field of oncology but are associated with unique toxicities and potentially overlapping symptoms associated with transfusion reactions [8,20]. Haemovigilance adjudication protocols in this population should include input from primary treatment teams; patients receiving these therapies are at risk for haemodynamic compromise and transfusion reactions may easily be incorrectly attributed to CRS and/or other expected toxicities. Prompt recognition of transfusion reactions and initiation of appropriate management among these patients may be life-saving. One patient in our IEC cohort developed a severe transfusion reaction and another patient developed TACO concurrent with CRS. The observed symptoms during both transfusions were associated with clinical deterioration compared to pre-transfusion baseline and after consultation with the primary treatment team were subsequently adjudicated as true transfusion reactions. Active haemovigilance was associated with conservative management in this clinically labile patient.\n\nInterestingly, prior reports have found a higher incidence of transfusion reactions and in particular allergic transfusion reactions among pediatric patients as compared to adults [5,6]. We observed a lower incidence of reactions in our immune-compromised population compared to historical reports among all pediatric patients. Yet, we observed a higher incidence of FNHTR than reported among adult and general pediatric patients [5,6]. The differences in observations in our population may be related to different physiology, pre-medication rates, and/or intensity of monitoring [6]. It is possible that comorbidities including frequent infections (resulting in fevers) and immune dysfunction/dysregulation may influence transfusion reaction presentation in this pediatric-AYA hematology/oncology population. Of note, the majority of reactions that were negatively-adjudicated were also related to fever, which was deemed unrelated to the transfusion. Prospective studies are needed to investigate this further. Our study was limited by its retrospective nature and the intrinsic biases that are involved in this study design.\n\nIn summary, the incidence of transfusion reactions among pediatric-AYA hematology/oncology patients may be similar to the reported general adult and lower than the general pediatric population incidence. Patients with a prior history of transfusion reactions and those receiving platelet transfusions may be at higher risk for reaction. IEC recipients may be at high risk for severe transfusion reactions and large multi-center prospective studies are needed to further characterize this sub-population. Emerging data may allow development of optimized risk stratification, early and more accurate detection of transfusion reactions and facilitate appropriate management.\n\nFunding\nNo sources of funding to declare.\n\nAuthor contributions\nM.A.K. completed data collection, analysis, and wrote the manuscript; S.J.K., P.T., D.P, J.M.K. and K.M.M treated the patients and assisted in editing the manuscript; B.M. assisted in data collection and editing the manuscript; J.W. assisted with biostatistical analyses and editing the manuscript; K.M.M and J.M.K conceptualized the study, analyzed the data and wrote the manuscript; All co-authors reviewed the manuscript and made significant contributions.\n\nData sharing statement\nDatasets available upon request to corresponding author.\n\nDeclaration of Competing Interest\nThe authors declare no conflicts of interest.\n\nAcknowledgements\nWe wish to acknowledge our patients and their caregivers; we also thank our nursing unit and Haemovigilance Unit staff.\n==== Refs\nReferences\n1 Lieberman L. 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"literaturereference": "KELLEY J, KHAZAL S, TEWARI P, PETROPOULOS D, MAHADEO K, MESCHER B, WANG J, KOHORST M. TRANSFUSION REACTIONS IN PEDIATRIC AND ADOLESCENT YOUNG ADULT HAEMATOLOGY ONCOLOGY AND IMMUNE EFFECTOR CELL PATIENTS. ECLINICAL MEDICINE. 2020?26:1-8.",
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"abstract": "Infection with nontyphoidal Salmonella is traditionally characterized by intestinal manifestations. However, extra-intestinal infections are known to occur, with purulent pericarditis associated with cardiac tamponade being rare. This case report is of a 57-year-old male with Crohn's disease initiated on infliximab therapy two months prior to presentation. He presented with recurrent chest pain and a single occurrence of fever. A Computed Tomography (CT) scan of the chest revealed a pericardial effusion. An echocardiogram confirmed the presence of the fluid with tamponade physiology, requiring immediate surgical decompression. The pericardial fluid culture grew Salmonella enterica, despite the patient having only a single episode of fever, disproportionate to the severity of the infection. Conceivably, the lack of systemic symptoms may be attributed to recent infliximab therapy. Upon conducting a literature review, immunosuppressive factors seem to play a significant role in nontyphoid Salmonella enterica pericardial effusion presenting with cardiac tamponade.",
"affiliations": "DeTar Healthcare System, 506 E San Antonio St, Victoria, TX, 77901, United States.;Universidad Nacional Autónoma de Honduras, Facultad de Ciencias Médicas, Hospital Escuela Universitario, Boulevard Suyapa, Tegucigalpa, Honduras.;Department of Biology & Chemistry, Texas A&M International University, 5201 University Blvd, Laredo, TX, 78045, United States.;Loyola Medicine MacNeal Hospital, 3249 S Oak Park Ave Berwyn, IL, 60402, United States.;Loyola Medicine MacNeal Hospital, 3249 S Oak Park Ave Berwyn, IL, 60402, United States.;Department of Infectious Disease, Citizens Medical Center, 2701 Hospital Dr, Victoria, TX 77901, United States.;Department of Cardiology, DeTar Healthcare System, 506 E. San Antonio, Victoria, TX, 77901, United States.;Baylor Scott & White Health- Temple, 2401 South 31 Street, Temple, TX, 76508, United States.;Baylor Scott & White Health- Temple, 2401 South 31 Street, Temple, TX, 76508, United States.;Department of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, United States.",
"authors": "Saddler|Kimberly|K|;Castro-Lainez|Miriams T|MT|;Deliz-Aguirre|Rafael|R|;Muñoz|Julieta|J|;Aguilar Espinal|Jorge Augusto|JA|;Sierra-Hoffman|Miguel|M|;Chandna|Harish|H|;Howel|Alan|A|;Midturi|John|J|;Winn|Richard|R|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.idcr.2019.e00500",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30220-810.1016/j.idcr.2019.e00500e00500ArticleNontyphoidal Salmonella purulent pericarditis presenting with pericardial tamponade in a patient on infliximab therapy Saddler Kimberly aCastro-Lainez Miriams T mtcastrolainez@gmail.comb⁎Deliz-Aguirre Rafael cMuñoz Julieta dAguilar Espinal Jorge Augusto dSierra-Hoffman Miguel eChandna Harish fHowel Alan gMidturi John gWinn Richard ha DeTar Healthcare System, 506 E San Antonio St, Victoria, TX, 77901, United Statesb Universidad Nacional Autónoma de Honduras, Facultad de Ciencias Médicas, Hospital Escuela Universitario, Boulevard Suyapa, Tegucigalpa, Hondurasc Department of Biology & Chemistry, Texas A&M International University, 5201 University Blvd, Laredo, TX, 78045, United Statesd Loyola Medicine MacNeal Hospital, 3249 S Oak Park Ave Berwyn, IL, 60402, United Statese Department of Infectious Disease, Citizens Medical Center, 2701 Hospital Dr, Victoria, TX 77901, United Statesf Department of Cardiology, DeTar Healthcare System, 506 E. San Antonio, Victoria, TX, 77901, United Statesg Baylor Scott & White Health- Temple, 2401 South 31st Street, Temple, TX, 76508, United Statesh Department of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, United States⁎ Corresponding author. mtcastrolainez@gmail.com01 2 2019 2019 01 2 2019 15 e005003 12 2018 28 1 2019 28 1 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/).Infection with nontyphoidal Salmonella is traditionally characterized by intestinal manifestations. However, extra-intestinal infections are known to occur, with purulent pericarditis associated with cardiac tamponade being rare. This case report is of a 57-year-old male with Crohn’s disease initiated on infliximab therapy two months prior to presentation. He presented with recurrent chest pain and a single occurrence of fever. A Computed Tomography (CT) scan of the chest revealed a pericardial effusion. An echocardiogram confirmed the presence of the fluid with tamponade physiology, requiring immediate surgical decompression. The pericardial fluid culture grew Salmonella enterica, despite the patient having only a single episode of fever, disproportionate to the severity of the infection. Conceivably, the lack of systemic symptoms may be attributed to recent infliximab therapy. Upon conducting a literature review, immunosuppressive factors seem to play a significant role in nontyphoid Salmonella enterica pericardial effusion presenting with cardiac tamponade.\n==== Body\nIntroduction\nNontyphoidal Salmonellosis is a common food-borne illness worldwide, usually presenting with acute diarrhea which typically resolves without treatment. We present a case of purulent pericarditis manifesting with pericardial tamponade due to nontyphoidal Salmonella. The pericardial fluid and stool cultures revealed nontyphoid Salmonella, despite no growth on blood cultures. Risk factor for development of Salmonella infection was Crohn’s disease with a recent initiation of infliximab therapy.\n\nCase Report\nA 57-year-old Caucasian male with a past medical history of hypertension, hepatitis C, Crohn’s disease, and Prinzmetal angina, presented with recurrent chest pain, single episode of fever, general malaise, and diarrhea. The patient attributed his symptoms to his Crohn’s disease. His immune status was compromised by his Crohn’s disease treatments, infliximab that was recently started and azathioprine. The patient lives in a rural community, actively involved in poultry farming with significant exposure to several animals known to harbor Salmonella species, as well as ongoing alcohol and tobacco abuse. The patient also reported a remote history of cocaine abuse. Three weeks prior to admission, he presented with substernal chest pain meriting a coronary angiography revealing Prinzmetal angina without need for coronary angioplasty. His substernal chest pain recurred, prompting presentation to a rural hospital where a CT scan of the chest identified a large pericardial effusion, and he was transferred to our facility.\n\nUpon initial physical exam, vitals revealed blood pressure of 90/60 mmHg, temperature of 36.8 °C (98.2 °F), tachycardia, respiratory rate of 26 breaths per minute and noted finding of dehydration upon oral mucosal examination. Laboratory data upon admission revealed leukocytosis with left shift and negative troponin level. A transthoracic echocardiogram (Fig. 1) revealed cardiac tamponade physiology; therefore, a cardiothoracic consultation was obtained. A pericardial window was performed with drainage of 500 mL purulent fluid. The pericardial fluid and stool specimen grew nontyphoid Salmonella enterica, without further serotype. Blood cultures were collected on admission, and no growth was detected after five days of incubation. Vancomycin and piperacillin/tazobactam were initiated as empiric therapy and then de-escalated to ceftriaxone 2 g intravenously every 12 hours. His hospital course required ten days of care in an intensive care unit with subsequent transfer to the general medical ward on telemetry. He then developed recurrence of fevers up to 40 °C (104 °F) without hemodynamic instability. A comprehensive investigation for other causes of fever or nosocomial infection returned negative, and his fever eventually resolved with no change in therapy. The late fevers were believed to be a result of clearance of infliximab and a reconstitution of the immune system. Upon further interview, his last dose of infliximab was two weeks prior to admission. The patient completed four weeks of ceftriaxone 2 g IV every 12 hours, and at eight-week follow-up, the patient was completely asymptomatic.Fig. 1 Transthoracic echocardiogram with parasternal long axis (A)and subcostal (B) views with moderate to large pericardial effusion and impending cardiac tamponade.\n\nFig. 1\n\nDiscussion\nSalmonella is a leading water/food-borne fecal-oral zoonosis worldwide [1,2]. This Gram-negative genus is of the family Enterobacteriaceae related to Escherichia and Shigella [3]. Salmonellosis is classified as typhoid or nontyphoid. Typhoid fever is a non-zoonotic febrile systemic infection [4]. Vaccines and improved sanitation have reduced cases of typhoid fever [5]. Our focus, however, is the nontyphoidal Salmonella, a zoonotic pathogen present worldwide, and the leading cause of gastroenteritis although extra-intestinal manifestations have been reported, including septicemia, acute endocarditis, osteomyelitis, meningitis, vascular infection, and rarely pericarditis [6]. Gastrointestinal forms typically resolve without treatment. However, nontyphoid salmonellosis still represents the most common, most expensive, and deadliest foodborne illness in the United States [7]. The global burden of invasive nontyphoidal Salmonella is estimated to be 49 cases per 100,000 population [8]. Compared to other foodborne illnesses, ingestion of high concentrations of the organism are generally required to cause overt infection [9]. Weaponization of Salmonella makes it a bio-threat and increasingly the organism has become more antimicrobial resistant [6,[10], [11], [12]].\n\nWhile 44 species of Salmonella (Lignières, 1900) existed in 1934, molecular biologists identified one species and seven serovars within Salmonella by 1987 [[13], [14]]. In 2005, Salmonella enterica became the official name with six subspecies, the remainder became Salmonella bongori [[15], [16]]. Of 2600 sub-groups, the most clinically relevant nontyphoidal serovars are Enteritidis (43.5% cases), Typhimurium (17.1%) and Newport (3.5%) [17]. Serovar Typhi causes typhoid fever occurring four times more frequently than Paratyphi, causing paratyphoid fever [18,19]. In addition to many serotypes, the relationship between host genetics and clinical manifestation remains poorly understood [20,21].\n\nInfliximab is a monoclonal antibody approved in 1998 and indicated for Crohn’s disease and ulcerative colitis, as well as other autoimmune diseases. Infectious complications due to immune suppression are well documented in the literature [22]. In one large study, infliximab was found to have a slightly higher risk of infection as compared to other Tumor necrosis factor alpha (TNF-α) inhibitors in rheumatoid arthritis patients [23]. TNF-α inhibitors have been associated with numerous opportunistic infections [24,25]. Although the risk of opportunistic infections was low (152 cases per 100 000 patient years), the severity of illness tend to be significant [25]. The risk of infection was higher when TNF-α inhibitors were combined with steroids; doses of greater than prednisone 10 mg per day [25].\n\nPericarditis, or inflammation of the pericardial lining, has multiple etiologies; among infectious causes, viral infections are by far the leading causative agents. While viral etiology is usually benign, purulent or bacterial pericarditis can be a potentially catastrophic infection. Patients commonly present with chest pain, pericardial rub, and fever. The presence of pericardial effusion on the echocardiogram is also considered a criterion for diagnosis. In developing countries, Mycobacterium tuberculosis must be high in the differential. Prior to the antimicrobial era, extension from bacterial pneumonia was the most common cause. Hence, it is not surprising that the leading causes cited in the literature include Streptococcus pneumoniae, Staphylococcus aureus, and Group A streptococcus. Purulent pericarditis could occur from bacteremia, therefore additional bacterial pathogens to consider in the differential include enteric Gram-negative bacilli, Pseudomonas aeruginosa, Salmonella, Neisseria meningitidis, anaerobes and fungi. Prompt diagnosis is imperative since purulent pericarditis could present with life threatening manifestations. Echocardiography should be performed as soon as possible for diagnosis; this tool assesses for signs of cardiac tamponade and can assist in guided pericardiocentesis, if needed. Laboratory diagnosis is made based on purulent material with characteristics of exudate, predominance of polymorphonuclear leucocytes and lactate dehydrogenase, as well as low glucose from the pericardial effusion. Gram stain and culture, hematocrit, biochemistry, and cytology should also be performed.\n\nWe are reporting a patient presenting with nontyphoid Salmonella purulent pericarditis with cardiac tamponade while on infliximab treatment. We believe the suppressive effect of infliximab masked the expected systemic symptoms of a significant bacterial infection. Paradoxically, the patient did develop a robust inflammatory response ten days after the procedure that slowly resolved over three weeks upon completion of treatment. We conducted a literature review using the Medline and PubMed databases of articles published between 1992 and March 2018. We found twelve relevant articles in English and Spanish of nontyphoid Salmonella purulent pericarditis complicated with cardiac tamponade (Table 1). The disease was found exclusively in adults, (age range 23- 67 years), with a mean age of 55 years. Using the human development index (HDI), most cases (11/12, 92%) were reported from countries with very high human development (HDI ≥ 0.80), which represent 16% of the world population. The remaining case (1/12, 8%) came from a high human development country (0.80.>HDI ≥ 0.70), which represents 14% of the world population, if we distinguish the Republic of China from the People’s Republic of China. At first glance, the data leads us to believe that nontyphoid Salmonella purulent pericarditis complicated with cardiac tamponade is limited to developed countries. However, nontyphoid Salmonella is present worldwide, and presumably cases of nontyphoid Salmonella purulent pericarditis complicated with cardiac tamponade are underreported. Using the data from the countries with very high human development, at least 73 cases should have been reported worldwide. The majority of patients in this series had documented immunosuppressive factors, either iatrogenic or a preexisting medical condition. The most commonly reported symptoms among the study population were fever (75%), dyspnea (58%), and chest pain (33%). A third-generation cephalosporin was the most commonly prescribed antimicrobial therapy, with 92% surviving with antimicrobials alone or in addition to surgical intervention.Table 1 Cases of Nontyphoidal Salmonella pericardial effusion with cardiac tamponade.\n\nTable 1Case No.\tFirst Author (Reference)\tYear\tAge/Sex (yr)\tLocation\tMedical Conditions & Risk Factors\tPresenting Symptom\tTreatments\tOutcome\t\n1\tCanut Blasco\t1992\t53/M\tZamora, Castile, Spain\tMyocardial infarction, thrombophlebitis (lower extremities)\tFever\tCiprofloxacin, chloramphenicol (Failed)\tSurvived\t\n2\tClesham\t1993\t45/M\tLondon, England, United Kingdom\t–\tCough, dyspnea, chest pain, fever\t–\tSurvived\t\n3\tKiuchi\t1998\t39/M\tTokyo, Japan\tAlcoholic hepatitis, idiopathic thrombocytopenic purpura, malignant lymphoma, pneumonectomy, prior steroid use\tDyspnea, fever, night sweats\tAmpicillin, surgical drainage\tSurvived\t\n4\tSalavert\t2002\t61/M\tAlicante, Valencia, Spain\tIrritable bowel syndrome\tDyspnea, fever\tCefuroxime, amikacin\tSurvived\t\n5\tFernández Guerrero\t2004\t23/F\tMadrid, Castile, Spain\tSystemic lupus erythematosus, prior steroid use, immunosuppressant exposure\tDyspnea, chest pain, fever, night sweats\tCefotaxime, then ciprofloxacin\tSurvived\t\n6\tArruvito\t2004\t75/M\tBuenos Aires, Argentina\tGastric cancer sp gastrectomy, candida, herpetic esophagitis, arthritis, prior steroid use\tWeight loss\tAmpicillin, gentamicin, fluconazole, acyclovir\tDied\t\n7\tHoag\t2005\t47/F\tBaltimore, Maryland, United States\tMorbid obesity (Body-mass index of 49.7 kg/m2), human immunodeficiency virus\tDyspnea, fever, night sweats, weight loss\tCeftazidime, levofloxacin\tSurvived\t\n8\tTseng\t2010\t66/M\tTaoyuan, Taiwan, Republic of China\tEnd-stage renal disease, chronic glomerulonephritis, congestive heart failure, invasive medical device\tDyspnea\t–\tSurvived\t\n9\tOrtiz\t2014\t62/M\tMilwaukee, Wisconsin, United States\tHypertension, intermittent atrial fibrillation, drug-induced systemic lupus erythematosus, prior steroid use, immunosuppressant exposure, invasive medical device\tFever\tCeftriaxone, then levofloxacin. Right atrial and RV pericardiectomy\tSurvived\t\n10\tPulido-Arenas\t2016\t67/M\tBogotá, Colombia\tRheumatoid arthritis, prior steroid use, former smoker\tChest pain, weight loss\tCeftriaxone\tSurvived\t\n11\tChand\t2016\t67/M\tSt Leonards-on-Sea, England, United Kingdom\tHypertension, diabetes mellitus, hyperlipidemia, hepatitis B, previous stroke\tCough, dyspnea, fever\tCeftriaxone, ciprofloxacin\tSurvived\t\n12\tSaddler\n(This study)\t2018\t57/M\tVictoria, Texas, United States\tHypertension, hepatitis C, Crohn’s disease, coronary spasm, ongoing alcohol and tobacco abuse, distant history of cocaine abuse, immunosuppressant exposure\tCough, dyspnea, chest pain, fever\tCeftriaxone, surgical drainage\tSurvived\t\nSummary\t1992–2018\tMean, 55; (range, 23-75) M: 10/12 (83%)\tAmericas = 4 Asia = 3 Europe = 5\tImmunosupressed = 5/11 (45%)\nPrior steroid use = 2/11 (18%)\tCough = 25% Dyspnea = 58% Chest pain = 33% Fever = 75% Night sweats = 25% Weight loss = 25%\tAntimicrobials = 7/10 (70%) Antimicrobial & surgery = 3/10 (30%)\t11/12 (92%) survived\t\n\n\nNontyphoidal Salmonella pericarditis presenting with pericardial tamponade is rare; only twelve cases have been reported since 1992. Most patients are immunosuppressed, and an index of high suspicion is recommended in order to diagnose early, and implement appropriate surgical and medical treatments. With appropriate antimicrobials and surgical intervention there is a high probability of achieving a positive outcome.\n==== Refs\nReferences\n1 Kirk M.D. World Health Organization Estimates of the Global and Regional Disease Burden of 22 Foodborne Bacterial, Protozoal, and Viral Diseases. 2010; A Data Synthesis. PLoS Med. 12 2015 e1001921 \n2 Majowicz S.E. The global burden of nontyphoidal Salmonella gastroenteritis Clin. Infect. Dis. 50 2010 882 889 20158401 \n3 Hata H. Phylogenetics of family Enterobacteriaceae and proposal to reclassify Escherichia hermannii and Salmonella subterranea as Atlantibacter hermannii and Atlantibacter subterranea gen. nov., comb. nov Microbiol. Immunol. 60 2016 303 311 26970508 \n4 Maskalyk J. Typhoid fever CMAJ 169 2003 132 12874163 \n5 Crump J.A. Luby S.P. Mintz E.D. 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A large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars JAMA. 278 1997 389 395 9244330 \n12 Tacconelli E. Magrini N. Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics 2017 World Health Organization \n13 Salmonella Subcommittee of the Nomenclature Committee of the International Society for Microbiology. The Genus Salmonella Lignières J. Hyg. 1934 34 1900 333 350 \n14 Le Minor L. Popoff M.Y. Designation of Salmonella enterica sp. nov., nom. rev., as the Type and Only Species of the Genus Salmonella: Request for an Opinion Int. J. Syst. Bacteriol. 37 1987 465 468 \n15 Tindall B.J. Nomenclature and taxonomy of the genus Salmonella Int. J. Syst. Evol. Microbiol. 55 2005 521 524 15653930 \n16 Reeves M.W. Evins G.M. Heiba A.A. Plikaytis B.D. Farmer J.J. 3rd Clonal nature of Salmonella typhi and its genetic relatedness to other Salmonellae as shown by multilocus enzyme electrophoresis, and proposal of Salmonella bongori comb. nov J. Clin. Microbiol. 27 1989 313 320 2915026 \n17 Hendriksen R.S. Global monitoring of Salmonella serovar distribution from the World Health Organization Global Foodborne Infections Network Country Data Bank: results of quality assured laboratories from 2001 to 2007 Foodborne Pathog. Dis. 8 2011 887 900 21492021 \n18 Agbaje M. Begum R.H. Oyekunle M.A. Ojo O.E. Adenubi O.T. Evolution of Salmonella nomenclature: a critical note Folia Microbiol. 56 2011 497 503 22052214 \n19 Bhan M.K. Bahl R. Bhatnagar S. Typhoid and paratyphoid fever Lancet. 366 2005 749 762 16125594 \n20 Andino A. Hanning I. Salmonella enterica: survival, colonization, and virulence differences among serovars ScientificWorldJournal. 2015 2015 520179 \n21 Shi C. Singh P. Ranieri M.L. Wiedmann M. Switt A.I.M. Molecular methods for serovar determination of Salmonella Crit. Rev. Microbiol. 41 2013 309 325 24228625 \n22 Grijalva C.G. Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases JAMA. 306 2011 2331 2339 22056398 \n23 Slifman N.R. Gershon S.K. Lee J.-H. Edwards E.T. Braun M.M. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents Arthritis Rheum. 48 2003 319 324 12571839 \n24 Winthrop K.L. Mycobacterial diseases and antitumour necrosis factor therapy in USA Ann. Rheum. Dis. 72 2013 37 42 22523429 \n25 Salmon-Ceron D. Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry Ann. Rheum. Dis. 70 2011 616 623 21177290\n\n",
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"title": "Nontyphoidal Salmonella purulent pericarditis presenting with pericardial tamponade in a patient on infliximab therapy.",
"title_normalized": "nontyphoidal salmonella purulent pericarditis presenting with pericardial tamponade in a patient on infliximab therapy"
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"abstract": "We present 2 patients who developed spontaneous pneumothorax (SP) following rapid regression of lymphoma and rhabdomyosarcoma with lung metastases. Case 1, a 43-year old man was admitted to our hospital with dyspnea 10 days before admission. He denied any recent trauma or previous treatment for lung tuberculosis. Three weeks prior to admission, he received first cycle of CHOP for non-Hodgkin's lymphoma stage II BE. Chest X-ray consistent with right pneumothorax. After treatment with chest tube drainage for about 1 month, the patient recovered and chemotherapy could be continued without further complications. Case 2, a 35- year old man was admitted to other hospital with dyspnea and chest pain on day 4 after second cycle of systemic combined chemotherapy for rhabdomyosarcoma stage IV (lung metastases) with doxorubicin, ifosfamide, mesna, and dacarbazine. Chest X-ray showed hydropneumothorax on right and left lung. After treatment with chest tube drainage about 2 weeks, the patient recovered and chemotherapy could be continued without further complications. The mechanism of pneumothorax following chemotherapy is not clearly understood yet, however, several hypotheses have been considered: 1) the rupture of a subpleural bulla after chemotherapy; 2) the rupture of an emphysematous bulla in an over expanded portion of the lung which is partially obstructed by a neoplasm; 3) tumor lyses or necrosis due to cytotoxic chemotherapy directly induces the formation of fistula. Dyspnea and chest pain suddenly appear during successful chemotherapy for metastatic chemosensitive tumors should alert the physician to the possibility of SP. The treatment is directed toward lung re-expansion. Chemotherapy induced pneumothorax should be considered as oncologic emergency.",
"affiliations": "Department of Internal Medicine, Hasan Sadikin Hospital, Bandung, Indonesia.",
"authors": "Hendarsih|Een|E|;Fadjari|Trinugroho H|TH|;Oehadian|Amaylia|A|",
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"issue": "48(2)",
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"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002637:Chest Pain; D004322:Drainage; D006801:Humans; D008175:Lung Neoplasms; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D011030:Pneumothorax; D013902:Radiography, Thoracic; D014057:Tomography, X-Ray Computed",
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"pages": "134-8",
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"pubdate": "2016-04",
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"title": "Chemotherapy-induced Spontaneous Pneumothorax: Case Series.",
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{
"abstract": "OBJECTIVE\nThe PED is a new endoluminal construct designed to exclude aneurysms from the parent cerebrovasculature. We report the very late (>1 year) thrombosis of PED constructs in 2 patients.\n\n\nRESULTS\nTwo patients with very large fusiform basilar trunk aneurysms underwent parent artery reconstruction with the PED. Both patients were maintained on dual antiplatelet therapy throughout the first year following treatment. Follow-up conventional angiography, performed 12 months after treatment, demonstrated, in both patients, thrombosis of most of the aneurysm with minimal residual flow through the construct and into the aneurysm fundus. In response to the residual filling, clopidogrel was discontinued (aspirin therapy was maintained). Both patients presented with symptomatic acute occlusions of the PED constructs within 14 days of clopidogrel discontinuation.\n\n\nCONCLUSIONS\nPatient 1 presented with constitutional symptoms that progressed to severe headache without other neurologic signs or symptoms. Occlusion of the PED construct was confirmed with conventional angiography. MR imaging demonstrated no evidence of infarction or parenchymal injury. The headaches were managed successfully with steroid therapy. Patient 2 presented with a syndrome of acute basilar occlusion with brain stem stroke. Complete occlusion was confirmed on angiography. Emergent thrombolysis with mechanical revascularization was performed successfully; however, the patient ultimately succumbed to the infarction.\n\n\nCONCLUSIONS\nIt appears that flow-diverting constructs built across large circumferential aneurysms may remain thrombogenic for much longer than conventional intracranial or peripheral bare metal stents. Constructs in these patients may remain susceptible to very late thrombosis, >1 year after implantation. These patients likely require long-term dual antiplatelet therapy (>1 year) to provide adequate prophylaxis against thrombosis. If these types of aneurysms demonstrate persistent residual filling months after PED reconstruction, operators should consider the placement of additional devices as an alternative to the discontinuation of 1 of the antiplatelet medications.",
"affiliations": "Department of Neuroradiology, HELIOS Klinikum, Erfurt, Germany.",
"authors": "Klisch|J|J|;Turk|A|A|;Turner|R|R|;Woo|H H|HH|;Fiorella|D|D|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "United States",
"delete": false,
"doi": "10.3174/ajnr.A2571",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-6108",
"issue": "32(4)",
"journal": "AJNR. American journal of neuroradiology",
"keywords": null,
"medline_ta": "AJNR Am J Neuroradiol",
"mesh_terms": "D000328:Adult; D002533:Cerebral Angiography; D002548:Cerebral Revascularization; D002560:Cerebrovascular Circulation; D000077144:Clopidogrel; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D019635:Neurosurgical Procedures; D010975:Platelet Aggregation Inhibitors; D011183:Postoperative Complications; D017131:Thrombectomy; D013927:Thrombosis; D013988:Ticlopidine; D013997:Time Factors",
"nlm_unique_id": "8003708",
"other_id": null,
"pages": "627-32",
"pmc": null,
"pmid": "21436336",
"pubdate": "2011-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "20679914;20642887;21071538;20150304;18580809;20339842;19349825;19182301;10636274;19057425;9884378",
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{
"abstract": "Left ventricular assist device (LVAD) is an established therapy for patients with severe heart failure. Because the incidence of cardiotoxicity owing to anticancer agents is low, it is difficult to predict the recovery prospects when the cause of heart failure is due to anticancer agents. In this context, cancer patients who present with severe symptoms of heart failure and who fail medical therapy for heart failure may pose a dilemma, especially in countries such as Japan where implantable LVADs are not approved for purposes other than bridging to transplant. Recently, we encountered a 32-year-old woman with chemotherapy-related cardiomyopathy that developed after anticancer treatment using trastuzumab and anthracycline. LVAD therapy was the only option to save the young woman. The patient received an extracorporeal LVAD, her cardiac function gradually recovered while on support, and the device was successfully removed.",
"affiliations": "Department of Cardiovascular Surgery, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8677, Japan. nuinui5762@yahoo.co.jp.;Department of Cardiovascular Surgery, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8677, Japan.;Department of Cardiovascular Surgery, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8677, Japan.;Department of Cardiovascular Surgery, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8677, Japan.;Department of Cardiovascular Surgery, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8677, Japan.;Department of Cardiovascular Surgery, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8677, Japan.;Department of Cardiovascular Surgery, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8677, Japan.;Department of Cardiovascular Surgery, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8677, Japan.;Department of Cardiovascular Surgery, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8677, Japan. matsumg@faculty.chiba-u.jp.",
"authors": "Inui|Tomohiko|T|http://orcid.org/0000-0001-6465-4837;Kohno|Hiroki|H|;Matsuura|Kaoru|K|;Ueda|Hideki|H|;Tamura|Yusaku|Y|;Watanabe|Michiko|M|;Inage|Yuichi|Y|;Yakita|Yasunori|Y|;Matsumiya|Goro|G|",
"chemical_list": "D018943:Anthracyclines; D000970:Antineoplastic Agents; D000068878:Trastuzumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10047-019-01151-1",
"fulltext": null,
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"issn_linking": "1434-7229",
"issue": "23(3)",
"journal": "Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs",
"keywords": "Anthracycline; Artificial heart; Chemotherapy-related cardiomyopathy (CCM); Extracorporeal membrane oxygenation; Left ventricular assist device (LVAD); Trastuzumab",
"medline_ta": "J Artif Organs",
"mesh_terms": "D000328:Adult; D018943:Anthracyclines; D000970:Antineoplastic Agents; D005260:Female; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D000068878:Trastuzumab",
"nlm_unique_id": "9815648",
"other_id": null,
"pages": "270-274",
"pmc": null,
"pmid": "31897739",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of left ventricular assist device application for chemotherapy-related cardiomyopathy caused by trastuzumab and anthracycline.",
"title_normalized": "a case of left ventricular assist device application for chemotherapy related cardiomyopathy caused by trastuzumab and anthracycline"
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiac failure",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "INUI T, KOHNO H, MATSUURA K, UEDA H, TAMURA Y, WATANABE M, ET AL. A CASE OF LEFT VENTRICULAR ASSIST DEVICE APPLICATION FOR CHEMOTHERAPY-RELATED CARDIOMYOPATHY CAUSED BY TRASTUZUMAB AND ANTHRACYCLINE. J-ARTIF-ORGANS 2020?23(3):270-274.. 2020?23(3):270-274",
"literaturereference_normalized": "a case of left ventricular assist device application for chemotherapy related cardiomyopathy caused by trastuzumab and anthracycline",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20201106",
"receivedate": "20201106",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18472601,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20210114"
}
] |
{
"abstract": "BACKGROUND\nHemodynamically significant patent ductus arteriosus (PDA) is a common problem in preterm infants which often causes significant morbidities. Although PDA induces alterations in various tissue perfusion, there is scarce information about the effect of oral ibuprofen on hemodynamics of regional tissues.\n\n\nOBJECTIVE\nTo investigate, using near-infrared spectroscopy, the effect of oral ibuprofen on renal and mesenteric tissue oxygenation and oxygen extraction in preterm infants with a diagnosis of hemodynamically significant PDA.\n\n\nMETHODS\nFifteen infants (gestational age <32 weeks) with the diagnosis of hemodynamically significant PDA treated with oral ibuprofen were monitored for near-infrared spectroscopy - determined renal and mesenteric oxygenation. The infants with PDA were matched for gestational age, postnatal age with infants without PDA, who served as control subjects.\n\n\nRESULTS\nIn infants with PDA, mean arterial blood pressure was significantly lower compared with the control infants [39.3 (range:36-54) versus 51 (range:43-66) mmHg, respectively; p < 0.001)]. There were no significant differences in regional oxygen saturation and fractional oxygen extraction of renal and mesenteric tissues in PDA and control infants (p > 0.05). And ibuprofen treatment did not negatively influence renal and mesenteric oxygenation and extraction in infants with PDA (p > 0.05).\n\n\nCONCLUSIONS\nRenal and mesenteric tissue oxygenation and oxygen extraction were preserved in preterm infants with a diagnosis of hemodynamically significant PDA treated with oral ibuprofen.",
"affiliations": "Department of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital , Ankara , Turkey .",
"authors": "Guzoglu|Nilufer|N|;Sari|Fatma Nur|FN|;Ozdemir|Ramazan|R|;Oguz|Serife Suna|SS|;Uras|Nurdan|N|;Altug|Nahide|N|;Dilmen|Ugur|U|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D010100:Oxygen; D007052:Ibuprofen",
"country": "England",
"delete": false,
"doi": "10.3109/14767058.2013.811485",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4954",
"issue": "27(2)",
"journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians",
"keywords": null,
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004374:Ductus Arteriosus, Patent; D005865:Gestational Age; D006439:Hemodynamics; D006801:Humans; D007052:Ibuprofen; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D007668:Kidney; D008643:Mesentery; D010100:Oxygen; D010101:Oxygen Consumption",
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "197-203",
"pmc": null,
"pmid": "23735121",
"pubdate": "2014-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Renal and mesenteric tissue oxygenation in preterm infants treated with oral ibuprofen.",
"title_normalized": "renal and mesenteric tissue oxygenation in preterm infants treated with oral ibuprofen"
} | [
{
"companynumb": "US-JNJFOC-20150219049",
"fulfillexpeditecriteria": "2",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
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"drugbatchnumb": null,
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"drugindication": "PATENT DUCTUS ARTERIOSUS",
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"medicinalproduct": "IBUPROFEN."
}
],
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"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GUZOGLU N, SARI FN, OZDEMIR R, OGUZ SS, URAS, N, ALTUG N, ET AL. RENAL AND MESENTERIC TISSUE OXYGENATION IN PRETERM INFANTS TREATED WITH ORAL IBUPROFEN. JOURNOL OF MATERNAL-FETAL AND NEONATAL MEDICINE 2014?27(2):197-203.",
"literaturereference_normalized": "renal and mesenteric tissue oxygenation in preterm infants treated with oral ibuprofen",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20160218",
"receivedate": "20150827",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportversion": 2,
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},
"serious": 2,
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"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160525"
}
] |
{
"abstract": "OBJECTIVE\nTo present cases exhibiting possible effects of angiotensin II receptor blockers (ARBs) received in pregnancy on the fetus.\n\n\nMETHODS\nRetrospective analysis included women who delivered between 2002 and 2006 at Department of Obstetrics and Gynaecology Ljubljana.\n\n\nRESULTS\nAntihypertensive medications were prescribed to 346 of the 26,735 women. ARBs were given in only five pregnancies: two women received losartan, and three irbesartan. The therapy was stopped between 5 and 23 weeks of gestation. Two women delivered healthy babies at term; another term baby had one additional finger and toe. Other two pregnancies were complicated with oligohydramnios and ended in preterm delivery. One preterm infant had transient abnormal renal function tests.\n\n\nCONCLUSIONS\nWomen should be informed that ARB-antihypertensive therapy must be replaced/stopped before planning their pregnancy or at least as soon as the pregnancy is confirmed. Fetal morphology scan and monitoring of amniotic fluid volume should be obligatory, if ARBs are prescribed accidentally.",
"affiliations": "Department of Obstetrics and Gynaecology, University Medical Centre Ljubljana, Slajmerjeva 3, SI-1000 Ljubljana, Slovenia. ksenija.gersak@mf.uni-lj.si",
"authors": "Gersak|Ksenija|K|;Cvijic|Marta|M|;Cerar|Lilijana Kornhauser|LK|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077405:Irbesartan; D019808:Losartan",
"country": "United States",
"delete": false,
"doi": "10.1016/j.reprotox.2009.02.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-6238",
"issue": "28(1)",
"journal": "Reproductive toxicology (Elmsford, N.Y.)",
"keywords": null,
"medline_ta": "Reprod Toxicol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D005260:Female; D005865:Gestational Age; D006801:Humans; D006973:Hypertension; D007231:Infant, Newborn; D000077405:Irbesartan; D007674:Kidney Diseases; D019808:Losartan; D016104:Oligohydramnios; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D047928:Premature Birth; D012189:Retrospective Studies; D018570:Risk Assessment; D017524:Slovenia; D013777:Tetrazoles",
"nlm_unique_id": "8803591",
"other_id": null,
"pages": "109-12",
"pmc": null,
"pmid": "19491003",
"pubdate": "2009-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Angiotensin II receptor blockers in pregnancy: a report of five cases.",
"title_normalized": "angiotensin ii receptor blockers in pregnancy a report of five cases"
} | [
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"occurcountry": "SI",
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{
"actiondrug": "6",
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"medicinalproduct": "LYSINE ACETYLSALICYLATE"
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"medicinalproduct": "IRBESARTAN."
}
],
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"reaction": [
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},
{
"reactionmeddrapt": "Pre-eclampsia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GERSAK K, CVIJIC M, KORNHAUSERL. ANGIOTENSIN II RECEPTOR BLOCKERS IN PREGNANCY: A REPORT OF FIVE CASES. REPRODUCTIVE TOXICOLOGY. 2009?28:109?112",
"literaturereference_normalized": "angiotensin ii receptor blockers in pregnancy a report of five cases",
"qualification": "3",
"reportercountry": "SI"
},
"primarysourcecountry": "SI",
"receiptdate": "20210107",
"receivedate": "20210107",
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"receivertype": "6"
},
"reporttype": "2",
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"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210419"
},
{
"companynumb": "SI-MYLANLABS-2021M1037651",
"fulfillexpeditecriteria": "1",
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"actiondrug": "3",
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},
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"medicinalproduct": "IRBESARTAN."
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"medicinalproduct": "METHYLDOPA."
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"activesubstancename": "ASPIRIN DL-LYSINE"
},
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "LYSINE ACETYLSALICYLATE"
},
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "METHYLDOPA."
}
],
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"patientonsetage": "26",
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"reaction": [
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"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pre-eclampsia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Oligohydramnios",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GERSAK K, CVIJIC M, KORNHAUSERL.. ANGIOTENSIN II RECEPTOR BLOCKERS IN PREGNANCY: A REPORT OF FIVE CASES.. REPROD. TOXICOL.. 2009?28:109?112",
"literaturereference_normalized": "angiotensin ii receptor blockers in pregnancy a report of five cases",
"qualification": "3",
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},
"primarysourcecountry": "SI",
"receiptdate": "20210629",
"receivedate": "20210629",
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnessother": 1,
"transmissiondate": "20210717"
}
] |
{
"abstract": "BACKGROUND\nWe report on the serotonin syndrome after an alcohol intake in a patient with major depressive disorder treated with escitalopram and clomipramine.\n\n\nMETHODS\nA 26-year-old male patient with major depressive disorder had been stable on the treatment with escitalopram (20 mg/d) and clomipramine (50 mg/d) for 4 months. He had rarely taken alcohol, especially never with medication. One night after taking these drugs with a can of beer, he developed agitation, disorientation, myoclonus, hyperreflexia, tremor, tachycardia, diaphoresis, and hypertension, fulfilling the criteria for the serotonin syndrome. It was considered that the serotonin syndrome in the present case might be induced by alcohol's pharmacodynamic interaction with escitalopram and clomipramine leading to decreased clearance of extracellular serotonin in the brain and/or pharmacokinetic interaction with clomipramine leading to increased clomipramine levels.\n\n\nCONCLUSIONS\nThe present case report suggests that there may be an interaction between alcohol and antidepressants resulting in the serotonin syndrome, and clinicians should be aware of this possibility.",
"affiliations": "Department of Psychiatry, School of Medicine, Yamagata University, Yamagata, Japan.",
"authors": "Suzuki|Akihito|A|;Otani|Koichi|K|",
"chemical_list": "D000928:Antidepressive Agents; D017367:Serotonin Uptake Inhibitors; D015283:Citalopram; D002997:Clomipramine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000331",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "42(3)",
"journal": "Clinical neuropharmacology",
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},
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},
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},
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"medicinalproduct": "ALCOHOL."
},
{
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"activesubstancename": "CLOMIPRAMINE"
},
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"medicinalproduct": "CLOMIPRAMINE"
}
],
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"reaction": [
{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug interaction",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Serotonin syndrome",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SUZUKI A, OTANI K.. SEROTONIN SYNDROME AFTER AN ALCOHOL INTAKE IN A PATIENT TREATED WITH ESCITALOPRAM AND CLOMIPRAMINE.. CLIN NEUROPHARMACOL.. 2019?42(3):103-104",
"literaturereference_normalized": "serotonin syndrome after an alcohol intake in a patient treated with escitalopram and clomipramine",
"qualification": "1",
"reportercountry": "JP"
},
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"receiptdate": "20190613",
"receivedate": "20190613",
"receiver": {
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"receivertype": "6"
},
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"safetyreportid": 16423601,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190711"
}
] |
{
"abstract": "A 40-year-old primigravida woman with a monochorionic-triamniotic (MT) triplet pregnancy was hospitalized due to threatened abortion at 16 gestational weeks. Polyhydramnios in two fetuses and oligohydramnios in the third supported a diagnosis of feto-fetal transfusion syndrome (FFTS) at 23 weeks and 3 days of gestation. Severe dyspnea and liver dysfunction required intensive care unit admission and mechanical ventilation support, and abdominal compartment syndrome (ACS) caused by polyhydramnios was clinically diagnosed. When her general condition was not improved regardless of intensive care, the patient delivered the three fetuses by cesarean section at 23 weeks and 5 days gestation. Abdominal decompression was achieved with delivery, and the patient was discharged 13 days after operation without morbidity. This is the first case report of ACS caused by FFTS in a MT triplet pregnancy resulting in extremely preterm birth.",
"affiliations": "Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Anesthesiology and Intensive Care Medicine, Kobe University Hospital, Kobe, Japan.;Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan.",
"authors": "Obata|Kenta|K|;Tanimura|Kenji|K|;Masuko|Naohisa|N|;Imafuku|Hitomi|H|;Egi|Moritoki|M|;Terai|Yoshito|Y|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14905",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "47(9)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "abdominal compartment syndrome; amnioreduction; feto-fetal transfusion syndrome; polyhydramnios; triplet pregnancy",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D002585:Cesarean Section; D005260:Female; D005330:Fetofetal Transfusion; D006801:Humans; D007231:Infant, Newborn; D059325:Intra-Abdominal Hypertension; D011247:Pregnancy; D011256:Pregnancy Outcome; D059286:Pregnancy, Triplet; D047928:Premature Birth",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "3370-3373",
"pmc": null,
"pmid": "34235810",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Abdominal compartment syndrome in a monochorionic-triamniotic triplet pregnancy complicated by feto-fetal transfusion syndrome.",
"title_normalized": "abdominal compartment syndrome in a monochorionic triamniotic triplet pregnancy complicated by feto fetal transfusion syndrome"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2022-07036",
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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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}
],
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},
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"literaturereference": "Obata K, Tanimura K, Masuko N, Imafuku H, Egi M, Terai Y. Abdominal compartment syndrome in a monochorionic-triamniotic triplet pregnancy complicated by feto-fetal transfusion syndrome. The Journal Of Obstetrics and Gynaecology Research. 2021;47(9):3370-3373",
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"qualification": "3",
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},
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},
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}
] |
{
"abstract": "Glioblastoma is an aggressive brain tumor that requires multidisciplinary treatment including adjuvant radiotherapy, chemotherapy, and adjunct corticosteroids. Temozolomide is a commonly used chemotherapy drug and frequently causes lymphocytopenia. We describe the case of a 67-year-old woman with cutaneous invasive aspergillosis who had received long-term temozolomide and corticosteroid therapy for glioblastoma. She presented with multiple indurations, erythema, and purpura, some of which produced purulent discharge, in the anterior abdomen. Extensive intra- or inter-muscular abscesses of the right anterior abdominal wall were also observed. Her absolute lymphocyte counts were 156/μL on admission. Cultures obtained from the wound yielded Aspergillus fumigatus. She was diagnosed with secondary cutaneous invasive aspergillosis, which likely resulted from hematogenous dissemination. Although rare, this case illustrates that temozolomide-induced lymphocytopenia, especially in cases of concomitant corticosteroid use, can be associated with severe invasive aspergillosis.",
"affiliations": "Division of Hematology, Jichi Medical University Hospital, Tochigi, Japan.;Division of Infectious Diseases, Jichi Medical University Hospital, Tochigi, Japan.;Division of Infectious Diseases, Jichi Medical University Hospital, Tochigi, Japan.;Division of Infectious Diseases, Jichi Medical University Hospital, Tochigi, Japan.;Division of Infectious Diseases, Jichi Medical University Hospital, Tochigi, Japan.;Division of Infectious Diseases, Jichi Medical University Hospital, Tochigi, Japan.;Division of Hematology, Jichi Medical University Hospital, Tochigi, Japan; Division of Infectious Diseases, Jichi Medical University Hospital, Tochigi, Japan.;Division of Neurosurgery, Jichi Medical University Hospital, Tochigi, Japan.;Division of Infectious Diseases, Jichi Medical University Hospital, Tochigi, Japan; Division of General Internal Medicine, Jichi Medical University Hospital, Tochigi, Japan. Electronic address: shatake-tky@umin.ac.jp.;Division of Infectious Diseases, Jichi Medical University Hospital, Tochigi, Japan; Division of General Internal Medicine, Jichi Medical University Hospital, Tochigi, Japan.",
"authors": "Ikeda|Takashi|T|;Suzuki|Jun|J|;Norizuki|Masataro|M|;Okabe|Taro|T|;Onishi|Tsubasa|T|;Sasahara|Teppei|T|;Toshima|Masaki|M|;Yokota|Hidenori|H|;Hatakeyama|Shuji|S|;Morisawa|Yuji|Y|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D003606:Dacarbazine; D000077204:Temozolomide",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2016.10.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "23(4)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Corticosteroids; Cutaneous invasive aspergillosis; Glioblastoma; Temozolomide",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D001228:Aspergillosis; D001932:Brain Neoplasms; D003131:Combined Modality Therapy; D003606:Dacarbazine; D005260:Female; D005909:Glioblastoma; D006801:Humans; D012867:Skin; D000077204:Temozolomide",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "253-255",
"pmc": null,
"pmid": "27889247",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous invasive aspergillosis in a patient with glioblastoma receiving long-term temozolomide and corticosteroid therapy.",
"title_normalized": "cutaneous invasive aspergillosis in a patient with glioblastoma receiving long term temozolomide and corticosteroid therapy"
} | [
{
"companynumb": "JP-PFIZER INC-2017138798",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
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"drugdosagetext": "6 MG/KG, 2X/DAY",
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"drugindication": "ASPERGILLUS INFECTION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"medicinalproduct": "VORICONAZOLE."
},
{
"actiondrug": "6",
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},
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"medicinalproduct": "VORICONAZOLE."
}
],
"patientagegroup": null,
"patientonsetage": "67",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "IKEDA, T.. CUTANEOUS INVASIVE ASPERGILLOSIS IN A PATIENT WITH GLIOBLASTOMA RECEIVING LONG-TERM TEMOZOLOMIDE AND CORTICOSTEROID THERAPY. JOURNAL OF INFECTION AND CHEMOTHERAPY. 2017;23 (4):253-255",
"literaturereference_normalized": "cutaneous invasive aspergillosis in a patient with glioblastoma receiving long term temozolomide and corticosteroid therapy",
"qualification": "3",
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},
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"receiptdate": "20170403",
"receivedate": "20170403",
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},
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"safetyreportid": 13398174,
"safetyreportversion": 1,
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170830"
},
{
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"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
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"drugauthorizationnumb": "201742",
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"drugdosagetext": "LONG-TERM",
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"drugindication": "GLIOBLASTOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TEMOZOLOMIDE."
}
],
"patientagegroup": null,
"patientonsetage": "67",
"patientonsetageunit": "801",
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"reaction": [
{
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"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lymphopenia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
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"qualification": "3",
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},
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"receiptdate": "20170420",
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},
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},
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"transmissiondate": "20170830"
},
{
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"occurcountry": "JP",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
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"drugauthorizationnumb": null,
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"drugcumulativedosagenumb": "20100",
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"drugdosagetext": "90MG/M2 DAILY FOR FIVE DAYS FOLLOWED BY A 23 DAY DRUG FREE PERIOD",
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"drugindication": "GLIOBLASTOMA",
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},
{
"actiondrug": "5",
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},
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"drugdosagetext": "20 MILLIGRAM DAILY;",
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"medicinalproduct": "PREDNISOLONE."
},
{
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"activesubstancename": "PREDNISOLONE"
},
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"drugdosagetext": "15 MG/DAY; LATER INCREASED TO 20 MG/DAY",
"drugenddate": null,
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"drugindication": "PROPHYLAXIS",
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{
"abstract": "To describe a case of Sweet syndrome, a dermatologic inflammatory disease, with progressive, unrelenting ocular findings.\nCase report.\nA 73-year-old male was evaluated with a six-month history of Sweet syndrome, manifesting as cutaneous erythematous edematous papules on the dorsal arms and shins and confirmed with biopsy demonstrating neutrophil infiltration with nuclei fragmentation and lack of vasculitis. He initially noted a unilateral red eye with ocular pain and was found to have scleritis and choroidal infiltration. The patient's ocular disease progressed despite treatment with systemic corticosteroids, intraocular Ozurdex ®, systemic dapsone, and subtenons triamcinolone. Systemic evaluation was negative for malignancy or other inflammatory syndromes. Following 7 months of non-manageable ocular pain enucleation was offered to the patient, but he declined.\nSweet syndrome, a dermatologic condition, can be associated with unilateral scleritis and choroidal infiltration that are relentlessly progressive despite maximal systemic and ocular corticosteroid therapy.",
"affiliations": "Department of Ophthalmology and Visual Sciences, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.;Westmead and Central (Save Sight Institute) Clinical Schools, Discipline of Clinical Ophthalmology and Eye Health, University of Sydney, Sydney, Australia.;Department of Ophthalmology and Visual Sciences, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.;Department of Pathology, Queen Elizabeth Hospital, Charlottetown, Prince Edward Island, Canada.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.;Department of Ophthalmology and Visual Sciences, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.",
"authors": "Mishra|Amit V|AV|;Fung|Adrian T|AT|;Pollmann|Andre S|AS|;Henderson|Rosemary|R|;Shields|Carol|C|;Gupta|R Rishi|RR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2020.1788611",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": null,
"journal": "Ocular immunology and inflammation",
"keywords": "Sweet syndrome; choroidal infiltration; eye; scleritis; skin",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": null,
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "32813581",
"pubdate": "2020-08-19",
"publication_types": "D016422:Letter",
"references": null,
"title": "Relentlessly Progressive Sweet Syndrome of the Eye with Scleritis and Choroidal Infiltration.",
"title_normalized": "relentlessly progressive sweet syndrome of the eye with scleritis and choroidal infiltration"
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{
"abstract": "OBJECTIVE\nPatients with ovarian cancer have not benefited substantially from immunotherapy. We report a case of ovarian cancer, however, that responded well to the programmed cell death-ligand 1 inhibitor atezolizumab.\n\n\nMETHODS\nA 64-year-old woman with recurrent ovarian carcinoma, not responsive to platinum/taxane and bevacizumab therapy, was BRCA normal but showed loss of MLH1 and PMS2 proteins. She was treated with atezolizumab. After the third cycle, her CA 125 levels decreased to normal. Radiologic evaluation showed a near-complete response.\n\n\nCONCLUSIONS\nIdentifying response markers is important when choosing therapy for ovarian cancer patients.",
"affiliations": "Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey.;Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey.",
"authors": "Ak|Naziye|N|https://orcid.org/0000-0001-5790-7066;Vatansever|Sezai|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.13364",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "46(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "PD-L1; atezolizumab; immunotherapy; microsatellite instability; ovarian cancer",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": null,
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "1787-1791",
"pmc": null,
"pmid": "33458824",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Dramatic response to single-agent atezolizumab in a patient with MSI-H serous ovarian cancer.",
"title_normalized": "dramatic response to single agent atezolizumab in a patient with msi h serous ovarian cancer"
} | [
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{
"abstract": "BACKGROUND\nAtypical facial pain (ATFP) is challenging to manage and there are few proven therapies available. We present a case report describing application of peripheral subcutaneous field stimulation (PSFS) to a patient with chronic intractable ATFP which conventional treatment failed to ameliorate.\n\n\nMETHODS\nThe patient underwent an uneventful PSFS trial with percutaneous placement of two temporary eight-electrode leads (Medtronic Inc, Minneapolis, MN, USA) placed subdermally over the left mandible.\n\n\nRESULTS\nAfter experiencing excellent pain relief over the next two days, the patient was implanted with permanent leads and rechargeable generator two and a half weeks later and reported sustained pain relief at 12-month follow-up visit.\n\n\nCONCLUSIONS\nPeripheral subcutaneous field stimulation provides an effective treatment option for patients suffering from chronic ATFP who have failed conservative treatment. PSFS may provide pain relief with advantages over conservative treatments and more invasive techniques.\n\n\nCONCLUSIONS\nPeripheral subcutaneous field stimulation offers an alternative treatment option to select patients with intractable ATFP.",
"affiliations": "Comprehensive Pain Management of the Fox Valley, Appleton, WI, USA.",
"authors": "Yakovlev|Alexander E|AE|;Resch|Beth E|BE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/j.1525-1403.2009.00249.x",
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"issue": "13(2)",
"journal": "Neuromodulation : journal of the International Neuromodulation Society",
"keywords": null,
"medline_ta": "Neuromodulation",
"mesh_terms": null,
"nlm_unique_id": "9804159",
"other_id": null,
"pages": "137-40",
"pmc": null,
"pmid": "21992789",
"pubdate": "2010-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of chronic intractable atypical facial pain using peripheral subcutaneous field stimulation.",
"title_normalized": "treatment of chronic intractable atypical facial pain using peripheral subcutaneous field stimulation"
} | [
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{
"abstract": "Repetitive monomorphic ventricular tachycardia (RMVT) arising from the left His-Purkinje system can occasionally be encountered during clinical practice. We describe eight cases as a unique entity in this study to characterize the clinical and electrophysiological features of the patients.\n\n\n\nEight patients with frequent palpitation (five men with median age of 28 years) were included in the study from January 2003 to July 2018. Twelve-lead ECG (Electrocardiogram), Holter, and echocardiographic tests were performed after medical history interrogations and physical examinations. Antiarrhythmic drug therapy was essential to all patients, and catheter ablation was attempted if the patients could not tolerate or were not responsive to drug therapy.\n\n\n\nNo patients had a history of syncope and a family history of sudden cardiac death. ECGrecording was characterized by frequent ventricular extrasystoles, ventricular couplets, and salvos of nonsustained VT competitive with sinus rhythm. The QRS morphology of ectopic beats was in the right bundle branch block pattern with severe left axis deviation. The width of the QRS complex from ECG was 135 ms (120-140) during ventricular tachycardia. Verapamil had no effect on all VT individuals. Enlargement of the left ventricle was found in two patients. Four out of six cases were successful with catheter ablation treatment.\n\n\n\nRMVT arising from the left His-Purkinje system is a special arrhythmic and nonverapamil-sensitive entity. The electrophysiological mechanism of this treatment appears to be focal firing, which is amendable to catheter ablation in symptomatic and high-burden patients.",
"affiliations": "Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.;Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.;Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.;Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.;Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.;Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.;Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.",
"authors": "Wang|Cheng|C|;Ju|Weizhu|W|;Chen|Hongwu|H|;Yang|Gang|G|;Zhang|Fengxiang|F|0000-0003-0125-3926;Zhou|Lei|L|;Chen|Minglong|M|0000-0002-9844-486X",
"chemical_list": "D000889:Anti-Arrhythmia Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/pace.14055",
"fulltext": null,
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"issn_linking": "0147-8389",
"issue": "43(10)",
"journal": "Pacing and clinical electrophysiology : PACE",
"keywords": "His-Purkinje system; electrophysiology; repetitive monomorphic ventricular tachycardia",
"medline_ta": "Pacing Clin Electrophysiol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents; D017115:Catheter Ablation; D002648:Child; D004452:Echocardiography; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011690:Purkinje Fibers; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "7803944",
"other_id": null,
"pages": "1149-1155",
"pmc": null,
"pmid": "32886352",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The clinical and electrophysiological characteristics of nonsustained repetitive monomorphic ventricular tachycardia from the left His-Purkinje system.",
"title_normalized": "the clinical and electrophysiological characteristics of nonsustained repetitive monomorphic ventricular tachycardia from the left his purkinje system"
} | [
{
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}
],
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},
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"literaturereference": "Wang C, Ju W, Chen H, Yang G, Zhang F, Zhou L, et al.. The clinical and electrophysiological characteristics of nonsustained repetitive monomorphic ventricular tachycardia from the left His-Purkinje system. Pacing Clin Electrophysiol. 2020;43(10):1149-1155",
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}
],
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"patientonsetage": "15",
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"reaction": [
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "23.1",
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},
{
"reactionmeddrapt": "Drug ineffective",
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"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "CHEN M, WANG C, JU W, CHEN H, YANG G, ZHANG F, ET AL. THE CLINICAL AND ELECTROPHYSIOLOGICAL CHARACTERISTICS OF NONSUSTAINED REPETITIVE MONOMORPHIC VENTRICULAR TACHYCARDIA FROM THE LEFT HIS?PURKINJE SYSTEM. PACING AND CLINICAL ELECTROPHYSIOLOGY 43: 1149?1155, NO. 10, OCT 2020. AVAILABLE FROM: URL: HTTP://DOI.ORG/10.1111/PACE.14055",
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"transmissiondate": "20210420"
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] |
{
"abstract": "Little evidence is available for head-to-head comparisons of psychosocial interventions and pharmacological interventions in psychosis. We aimed to establish whether a randomised controlled trial of cognitive behavioural therapy (CBT) versus antipsychotic drugs versus a combination of both would be feasible in people with psychosis.\n\n\n\nWe did a single-site, single-blind pilot randomised controlled trial in people with psychosis who used services in National Health Service trusts across Greater Manchester, UK. Eligible participants were aged 16 years or older; met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service; were in contact with mental health services, under the care of a consultant psychiatrist; scored at least 4 on delusions or hallucinations items, or at least 5 on suspiciousness, persecution, or grandiosity items on the Positive and Negative Syndrome Scale (PANSS); had capacity to consent; and were help-seeking. Participants were assigned (1:1:1) to antipsychotics, CBT, or antipsychotics plus CBT. Randomisation was done via a secure web-based randomisation system (Sealed Envelope), with randomised permuted blocks of 4 and 6, stratified by gender and first episode status. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions. Choice and dose of antipsychotic were at the discretion of the treating consultant. Participants were followed up for 1 year. The primary outcome was feasibility (ie, data about recruitment, retention, and acceptability), and the primary efficacy outcome was the PANSS total score (assessed at baseline, 6, 12, 24, and 52 weeks). Non-neurological side-effects were assessed systemically with the Antipsychotic Non-neurological Side Effects Rating Scale. Primary analyses were done by intention to treat; safety analyses were done on an as-treated basis. The study was prospectively registered with ISRCTN, number ISRCTN06022197.\n\n\n\nOf 138 patients referred to the study, 75 were recruited and randomly assigned-26 to CBT, 24 to antipsychotics, and 25 to antipsychotics plus CBT. Attrition was low, and retention high, with only four withdrawals across all groups. 40 (78%) of 51 participants allocated to CBT attended six or more sessions. Of the 49 participants randomised to antipsychotics, 11 (22%) were not prescribed a regular antipsychotic. Median duration of total antipsychotic treatment was 44·5 weeks (IQR 26-51). PANSS total score was significantly reduced in the combined intervention group compared with the CBT group (-5·65 [95% CI -10·37 to -0·93]; p=0·019). PANSS total scores did not differ significantly between the combined group and the antipsychotics group (-4·52 [95% CI -9·30 to 0·26]; p=0·064) or between the antipsychotics and CBT groups (-1·13 [95% CI -5·81 to 3·55]; p=0·637). Significantly fewer side-effects, as measured with the Antipsychotic Non-neurological Side Effects Rating Scale, were noted in the CBT group than in the antipsychotics (3·22 [95% CI 0·58 to 5·87]; p=0·017) or antipsychotics plus CBT (3·99 [95% CI 1·36 to 6·64]; p=0·003) groups. Only one serious adverse event was thought to be related to the trial (an overdose of three paracetamol tablets in the CBT group).\n\n\n\nA head-to-head clinical trial of CBT versus antipsychotics versus the combination of the two is feasible and safe in people with first-episode psychosis.\n\n\n\nNational Institute for Health Research.",
"affiliations": "Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK. Electronic address: tony.morrison@gmmh.nhs.uk.;Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Manchester Academic Health Science Centre Clinical Trials Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.;Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.;Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.;Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK.",
"authors": "Morrison|Anthony P|AP|;Law|Heather|H|;Carter|Lucy|L|;Sellers|Rachel|R|;Emsley|Richard|R|;Pyle|Melissa|M|;French|Paul|P|;Shiers|David|D|;Yung|Alison R|AR|;Murphy|Elizabeth K|EK|;Holden|Natasha|N|;Steele|Ann|A|;Bowe|Samantha E|SE|;Palmier-Claus|Jasper|J|;Brooks|Victoria|V|;Byrne|Rory|R|;Davies|Linda|L|;Haddad|Peter M|PM|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1016/S2215-0366(18)30096-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2215-0366",
"issue": "5(5)",
"journal": "The lancet. Psychiatry",
"keywords": null,
"medline_ta": "Lancet Psychiatry",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D015928:Cognitive Behavioral Therapy; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders; D012559:Schizophrenia; D012563:Schizophrenia, Paranoid; D016037:Single-Blind Method; D006113:United Kingdom; D055815:Young Adult",
"nlm_unique_id": "101638123",
"other_id": null,
"pages": "411-423",
"pmc": null,
"pmid": "29605187",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "18180760;17927296;17606657;22579152;27733935;23846995;24816049;25934299;18541627;20357133;6880820;23473656;24385461;28498599;16823384;8532986;24508320;28541090;26500570;10782554;17962231;28669774;18374841;23810019;9672396;20360319;21292923;3616518;25805118",
"title": "Antipsychotic drugs versus cognitive behavioural therapy versus a combination of both in people with psychosis: a randomised controlled pilot and feasibility study.",
"title_normalized": "antipsychotic drugs versus cognitive behavioural therapy versus a combination of both in people with psychosis a randomised controlled pilot and feasibility study"
} | [
{
"companynumb": "GB-JNJFOC-20180434728",
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"literaturereference": "MORRISON AP, LAW H, CARTER L, SELLERS R, EMSLEY R, PYLE M, ET AL. ANTIPSYCHOTIC DRUGS VERSUS COGNITIVE BEHAVIOURAL THERAPY VERSUS A COMBINATION OF BOTH IN PEOPLE WITH PSYCHOSIS: A RANDOMISED CONTROLLED PILOT AND FEASIBILITY STUDY.. THE LANCET PSYCHIATRY MAY-2018?5 (5):411-423.",
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] |
{
"abstract": "Amlodipine, a dihydropyridine calcium channel blocker, is commonly prescribed for the treatment of hypertension. Ingestion of an overdose leads to severe hypotension; if the hypotension is not treated, death may be imminent. Conventional and unconventional interventions were used to treat an adolescent who ingested a life-threatening dose of amlodipine. Severe hypotension resistant to conventional treatment with intralipids and hyperinsulinemia-euglycemia therapy led to the use of plasmapheresis and a pneumatic antishock garment as lifesaving measures. Plasmapheresis has been described in only one other case of severe amlodipine overdose, and the use of a pneumatic antishock garment has never been described in the management of a calcium channel blocker overdose. Because short-term use of a pneumatic antishock garment has associated risks, the critical care nurse's anticipation of side effects and promotion of safe use of the garment were instrumental in the patient's care and outcome. (Critical Care Nurse 2016; 36[4]:64-69).",
"affiliations": "Karin E. Reuter-Rice is an associate professor and a Robert Wood Johnson Foundation scholar, School of Nursing and School of Medicine, Department of Pediatrics, Duke University, Durham, North Carolina. She is also a pediatric nurse practitioner in critical care at Duke University Health System and formerly at Rady Children's Hospital, San Diego, California.Bradley M. Peterson is a senior consultant to the pediatric intensive care unit, Rady Children's Hospital. karin.reuter-rice@duke.edu.;Karin E. Reuter-Rice is an associate professor and a Robert Wood Johnson Foundation scholar, School of Nursing and School of Medicine, Department of Pediatrics, Duke University, Durham, North Carolina. She is also a pediatric nurse practitioner in critical care at Duke University Health System and formerly at Rady Children's Hospital, San Diego, California.Bradley M. Peterson is a senior consultant to the pediatric intensive care unit, Rady Children's Hospital.",
"authors": "Reuter-Rice|Karin E|KE|;Peterson|Bradley M|BM|",
"chemical_list": "D000931:Antidotes; D017311:Amlodipine",
"country": "United States",
"delete": false,
"doi": "10.4037/ccn2016524",
"fulltext": null,
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"issn_linking": "0279-5442",
"issue": "36(4)",
"journal": "Critical care nurse",
"keywords": null,
"medline_ta": "Crit Care Nurse",
"mesh_terms": "D000293:Adolescent; D017311:Amlodipine; D000931:Antidotes; D003131:Combined Modality Therapy; D003422:Critical Care; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D005260:Female; D005500:Follow-Up Studies; D015600:Glasgow Coma Scale; D006801:Humans; D008297:Male; D010956:Plasmapheresis; D018570:Risk Assessment; D013406:Suicide, Attempted",
"nlm_unique_id": "8207799",
"other_id": null,
"pages": "64-9",
"pmc": null,
"pmid": "27481803",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Conventional and Unconventional Lifesaving Therapies in an Adolescent With Amlodipine Ingestion.",
"title_normalized": "conventional and unconventional lifesaving therapies in an adolescent with amlodipine ingestion"
} | [
{
"companynumb": "US-ORCHID HEALTHCARE-1057559",
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
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}
],
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"reaction": [
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},
{
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood lactic acid increased",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood creatine phosphokinase increased",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Intentional overdose",
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},
{
"reactionmeddrapt": "Anuria",
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},
{
"reactionmeddrapt": "Troponin increased",
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},
{
"reactionmeddrapt": "Blood creatine phosphokinase MB increased",
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},
{
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"literaturereference": "REUTER-RICE KE, PETERSON BM. CONVENTIONAL AND UNCONVENTIONAL LIFESAVING THERAPIES IN AN ADOLESCENT WITH AMLODIPINE INGESTION. CRIT CARE NURSE 2016; 36(4):64-9.",
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"medicinalproduct": "AMLODIPINE BESYLATE."
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},
{
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},
{
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},
{
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},
{
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},
{
"reactionmeddrapt": "Overdose",
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},
{
"reactionmeddrapt": "Blood lactic acid increased",
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}
],
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"literaturereference": "REUTER-RICE K, PETERSON B. CONVENTIONAL AND UNCONVENTIONAL LIFESAVING THERAPIES IN AN ADOLESCENT WITH AMLODIPINE INGESTION. CRIT CARE NURSE. 2016;36(4):64-9.",
"literaturereference_normalized": "conventional and unconventional lifesaving therapies in an adolescent with amlodipine ingestion",
"qualification": "1",
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},
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},
{
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},
{
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},
{
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"reactionoutcome": "2"
},
{
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"reactionoutcome": "2"
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"literaturereference": "REUTER-RICE K, PETERSON B. CONVENTIONAL AND UNCONVENTIONAL LIFESAVING THERAPIES IN AN ADOLESCENT WITH AMLODIPINE INGESTION. CRITICAL CARE NURSE. 2016 AUG;36(4):64-69.",
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{
"abstract": "Vaccination can prevent infection and disease due to SARS-CoV-2. Early reports indicate that immune suppressed or immune compromised populations have reduced immune responses to US emergency use authorized (EUA) vaccines. Patients with autoimmune disorders are at risk for severe COVID-19, and are frequently immune suppressed related to therapy, the underlying disease, or both. Myasthenia gravis (MG) is an autoimmune disorder characterized by antibodies that interrupt neuromuscular transmission. Chronic immune suppressive therapy is typically required. We report the case of a 74 year old woman with MG receiving mycophenolate, prednisone, and eculizumab in whom mRNA vaccination failed to elicit detectable circulating vaccine-specific IgG or IFN-γ T cell responses. Eculizumab was discontinued, and repeat vaccination with two doses of an alternative EUA mRNA vaccine led to circulating IgG specific for the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein, and to detectable S-specific T cell responses. While it is not known if these responses will protect against SARS-CoV-2 infection or disease, a repeat course of mRNA vaccination appears to be safe and was broadly immunogenic in this individual.",
"affiliations": "Retired Internal Medicine/Geriatrics, Seattle, WA, USA.;Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.;Department of Medicine, University of Washington, Seattle, WA, USA.;Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.",
"authors": "Plymate|Lisa C|LC|;Pepper|Gregory|G|;Krist|Maxwell P|MP|;Koelle|David M|DM|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jtauto.2021.100114",
"fulltext": "\n==== Front\nJ Transl Autoimmun\nJ Transl Autoimmun\nJournal of Translational Autoimmunity\n2589-9090\nElsevier\n\nS2589-9090(21)00034-4\n10.1016/j.jtauto.2021.100114\n100114\nCase report\nImmunogenicity of repeat COVID-19 mRNA vaccinations in a patient with myasthenia gravis receiving mycophenolate, prednisone, and eculizumab\nPlymate Lisa C. MD a\nPepper Gregory b\nKrist Maxwell P. c\nKoelle David M. MD dkoelle@medicine.washington.edu\nbcdef∗\na Retired Internal Medicine/Geriatrics, Seattle, WA, USA\nb Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA\nc Department of Medicine, University of Washington, Seattle, WA, USA\nd Department of Global Health, University of Washington, Seattle, WA, USA\ne Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA\nf Benaroya Research Institute, Seattle, WA, USA\n∗ Corresponding author. University of Washington, 750 Republican Street, Seattle, WA, 98109, USA. dkoelle@medicine.washington.edu\n19 8 2021\n2021\n19 8 2021\n4 10011412 8 2021\n18 8 2021\n© 2021 Published by Elsevier B.V.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nVaccination can prevent infection and disease due to SARS-CoV-2. Early reports indicate that immune suppressed or immune compromised populations have reduced immune responses to US emergency use authorized (EUA) vaccines. Patients with autoimmune disorders are at risk for severe COVID-19, and are frequently immune suppressed related to therapy, the underlying disease, or both. Myasthenia gravis (MG) is an autoimmune disorder characterized by antibodies that interrupt neuromuscular transmission. Chronic immune suppressive therapy is typically required. We report the case of a 74 year old woman with MG receiving mycophenolate, prednisone, and eculizumab in whom mRNA vaccination failed to elicit detectable circulating vaccine-specific IgG or IFN-γ T cell responses. Eculizumab was discontinued, and repeat vaccination with two doses of an alternative EUA mRNA vaccine led to circulating IgG specific for the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein, and to detectable S-specific T cell responses. While it is not known if these responses will protect against SARS-CoV-2 infection or disease, a repeat course of mRNA vaccination appears to be safe and was broadly immunogenic in this individual.\n\nHighlights\n\n• T and B cell immune responses to SARS-CoV-2 mRNA vaccine reduced in an immune suppressed patient.\n\n• Repeat vaccination course with an alternative mRNA vaccine led to detectable, specific T and B cell responses.\n\n• Persons with autoimmune disease receiving immune suppression may benefit from additional doses of vaccine.\n\nKeywords\n\nMycophenolate sodium\nCorticosteroid\nSARS-CoV-2\nVaccine\nEculizumab\nMyasthenia gravis\n==== Body\npmc1 Introduction\n\nVaccines are highly effective in preventing infection and disease due to SARS-CoV-2 [1]. The mRNA and recombinant adenovirus formats used in US EUA products are novel for vaccines in general use. Little is known concerning mRNA vaccine immunogenicity or efficacy in immune suppressed/immune compromised (IS/IC) populations. Data suggest that neutralizing antibodies (nAb), other functional antibodies, and virus-specific T cells contribute to protection [1]. Myasthenia gravis (MG) is an autoimmune disorder characterized by antibodies that interrupt neuromuscular transmission. Individuals with MG are at risk for severe respiratory infections, including COVID-19, due to diaphragmatic weakness and long-term immune suppressive treatment [2]. We report the case of a patient with MG for whom mRNA vaccination failed to elicit detectable circulating IgG or IFN-γ T cell responses specific for the vaccine antigen. Repeat vaccination with two doses of an alternative EUA mRNA vaccine led to IgG specific for the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein and to detectable S-specific T cell responses.\n\n1.1 Case report\n\nA 74 year old woman was diagnosed with generalized MG 44 months prior to initial SARS-CoV-2 vaccination. Serologic testing showed elevated antibodies to acetylcholine receptors. For 18 months prior to and including the vaccine time course, treatment with 1440 mg mycophenolate sodium and prednisone 11 mg daily resulted in clinically stability. There was a remote history of ductal carcinoma in situ and Hashimoto's thyroiditis, and no history of opportunistic infection. Peripheral blood monitoring showed 8700 leukocytes and 800 lymphocytes per microliter (9%), consistent with mild lymphopenia. Three months prior to initial vaccination, the patient began treatment with eculizumab, an anti-C5 monoclonal antibody with activity in MG [3]. Eculizumab was given weekly and then biweekly per US labelling. The indication was adjunctive therapy to bridge elective surgery, which was uneventful. Eight weeks after surgery, BNT162b2 vaccination was started and two doses were administered 21 days apart. Eculizumab administration time points included 10 days prior to dose 1 of BNT162b2 and 3 days prior to dose 2, with the last dose given 11 days later.\n\nBlood was initially tested 71 days after the second dose of BNT162b2. The SARS-CoV-2 RBD binding antibody level (Abbott Architect IgG II) was 19 arbitrary units (AU)/ml, with values below 50 considered negative (https://www.fda.gov/media/146371/download). QuantiFERON SARS-CoV-2 RUO (Qiagen), an S-peptide-based interferon-γ release assay (IGRA) similar to the QFT-Plus assay for Mycobacterium tuberculosis-specific T cells, was performed per the manufacturer. SARS-CoV-2 S peptide pool S1 and S2 net values of 0.02 international units (IU)/ml and 0.03 IU/ml were summed to 0.05 IU/ml to provide a single metric. Negative (nil) and positive (mitogen) control values were 0.02 IU/ml and >10 IU/ml, indicating negligible background lymphocyte activation and intact activation potential. Amongst 14 healthy controls (HC) studied a median of 58 days (range, 10–107) after completing BNT162b2 (10 persons) or M1273 (4 persons), median net summary response to S was 1.27 IU/ml (range, 0.34 IU/ml-2.60 IU/ml). HC median nil was 0.03 IU/ml (range, 0.02 IU/ml-0.06 IU/ml) and each mitogen control was >10 IU/ml.\n\nAfter tests for vaccine immunogenicity returned negative, the patient sought repeat vaccination. At 85 days after completing BNT162b2, they received M1273, with a second dose 29 days later. Side effects were minimal. Immune response were tested 16 days after the second dose of M1273. The serum anti-SARS-CoV-2 RBD IgG level was 2999 AU/ml, considered positive. IGRA re-test 32 days after completing M1273 showed a net summary response to S peptides of 0.38 IU/ml IFN-γ, with nil and mitogen responses of 0.03 IU/ml and >10 IU/ml.\n\n2 Discussion\n\nThe SARS-CoV-2 pandemic has been particularly impactful for IS/IC populations. Passive immunization, selected immune suppressive drugs, and antivirals have a positive effect on disease course after infection, with less efficacy data available for IS/IC persons [4]. Prevention is preferred, and several vaccines have been authorized worldwide. There is currently controversy concerning homologous or heterologous booster doses for IS/IC patients, with case reports showing immunogenicity and apparent safety [5].\n\nDiverse IS/IC cohorts show lower ELISA responses than HC after EUA vaccination [6,7]. Circulating nAb is a candidate correlate of protection (CoP) and the ELISA-like binding assay used here correlates with nAb [8]. The elicitation of anti-RBD in this case indicates that B cell priming has occurred, and hopefully that long-lived antibody secreting and B-memory cells have also developed. S-specific T cell responses are readily detected after mRNA vaccination [9], with little data are available for IS/IC individuals. It is biologically expected that CD4 T cells and antibodies arise in concert. The IGRA test used here does not distinguish T cell subsets and alternative tests would be required to determine if both CD4 and CD8 T cell responses occurred. Overall, a repeat series of a heterologous but biologically similar mRNA vaccine can be well tolerated and elicit B and T cell responses, without required interruption of chronic immune suppression.\n\nMycophenolic acid is an antagonist of inosine-5′-monophosphate dehydrogenase that inhibits lymphocyte proliferation. Use can lead to peripheral blood lymphopenia, a variety of opportunistic infections, and poor responsiveness to vaccines including SARS-CoV-2 mRNA vaccination [10]. Corticosteroids such as prednisone have myriad effects including susceptibility to infection and diminished vaccine immunogenicity. In this patient, chronic receipt of mycophenolate and low-dose prednisone was combined with temporary use of eculizumab during the first vaccine series with BNT162b2. Complement activity is required for host defense to some Neisseria species in the infection context, but complement antagonism or deficiencies have not been associated with poor responses to vaccines. The BNT162b2 and M1273 products used sequentially also differ in mRNA content per dose, administration interval between doses, and details of the lipid nanoparticle formulations. The immune mechanism leading to apparent success with a repeat vaccination likely involves repeated antigen exposure, possibly modulated by cessation of anti-complement therapy, but overall remains unknown.\n\nThis report is limited by inclusion of a single patient and several other factors. The safety of booster vaccination may vary per patient. It is not known if the immune responses achieved by this patient are functionally protective against infection, viral shedding, or disease. There are no published interpretive criteria for the IGRA T cell assay used, and IGRA tests for SARS-CoV-2 have not achieved US Food and Drug Administration approval or EUA status. The heterogeneity of IS/IC individuals including influences from their underlying diseases precludes generalizations concerning booster vaccination. The durability of vaccine-elicited immune responses in this setting is unknown. Additionally, the safety and immunogenicity of the mRNA and adenovirus products, if used as boosters, may vary depending on vaccine identity, sequence, intervals, and number of doses.\n\nIn summary, two doses of M1273, three months after a standard course of BNT162b2, resulted in peripheral T- and B-cell conversion in a person dependent on mycophenolate and prednisone therapy to maintain MG clinical remission. A contribution of the transient eculizumab therapy to the lack of response to BNT162b2 cannot be ruled out, but vaccine hyporesponsiveness was more likely related to mycophenolate and prednisone. Maneuvers to increase host immunity may not be feasible in many IS/IC patients, and vaccine dose increases, extra doses, strong adjuvants, or heterologous prime/boost vaccine strategies are already used for other vaccine indications. These may be reasonable for SARS-CoV-2. Overall, pre-arming patients with circulating antibody and antigen-specific T cells is likely to be clinically beneficial. Additional studies of the safety, immunogenicity and clinical efficacy of homologous and heterologous SARS-CoV-2 vaccines are urgently required to better protect susceptible persons from the pandemic.\n\nFunding\n\n10.13039/100000002 NIH contract AI201800007 (to DMK). IRB: All subjects provided in-formed written consent. The protocol was approved by the University of Washington institutional Review Board.\n\nDeclaration of competing interest\n\nThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David M. Koelle reports financial support was provided by National Institutes of Health. David M. Koelle reports a relationship, not related to the current work, with Sanofi Pasteur Inc that includes: funding grants. David M. Koelle reports a relationship, not related to the current work, with Sensei Biotherapeutics that includes: funding grants. David M. Koelle reports a relationship, not related to the current work, with Merck & Co Inc that includes: funding grants. David M. Koelle reports a relationship, not related to the current work, with Curevo Vaccine that includes: consulting or advisory. David M. Koelle reports a relationship, not related to the current work, with MaxHealth LLC that includes: consulting or advisory. David M. Koelle reports receiving in-kind support from Adaptive Biotechnologies for separate research, not related to the current work, on immune responses to SARS-CoV-2 and vacccines.\n\nAcknowledgements\n\nThe authors thank the University of Washington Clinical Virology Laboratory and the healthy control blood donors.\n==== Refs\nReferences\n\n1 Sadarangani M. Marchant A. Kollmann T.R. Immunological mechanisms of vaccine-induced protection against COVID-19 in humans Nat. Rev. Immunol. 21 8 2021 475 484 34211186\n2 Jakubíková M. Týblová M. Tesař A. Horáková M. Vlažná D. Ryšánková I. Predictive factors for a severe course of COVID-19 infection in myasthenia gravis patients with an overall impact on myasthenic outcome status and survival Eur. J. Neurol. 2021\n3 Mantegazza R. Cavalcante P. Eculizumab for the treatment of myasthenia gravis Expet Opin. Biol. Ther. 20 9 2020 991 998\n4 Goldman J.D. Robinson P.C. Uldrick T.S. Ljungman P. COVID-19 in immunocompromised populations: implications for prognosis and repurposing of immunotherapies J. Immun. Canc. 9 6 2021\n5 Hill J.A. Ujjani C.S. Greninger A.L. Shadman M. Gopal A.K. Immunogenicity of a heterologous COVID-19 vaccine after failed vaccination in a lymphoma patient Canc. Cell 39 8 2021 1037 1038\n6 Boyarsky B.J. Werbel W.A. Avery R.K. Tobian A.A.R. Massie A.B. Segev D.L. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients JAMA 325 21 2021 2204 2206 33950155\n7 Couzin-Frankel J. Relief and worry for immune-suppressed people Science (New York, NY) 372 6541 2021 443 444\n8 Bradley B.T. Bryan A. Fink S.L. Goecker E.A. Roychoudhury P. Huang M.L. Anti-SARS-CoV-2 antibody levels measured by the Advise Dx SARS-CoV-2 assay are concordant with previously available serologic assays but are not fully predictive of sterilizing immunity J. Clin. Microbiol. 2021\n9 Sadoff J. Le Gars M. Shukarev G. Heerwegh D. Truyers C. de Groot A.M. Interim results of a phase 1-2a trial of Ad26.COV2.S covid-19 vaccine N. Engl. J. Med. 2021\n10 Furer V. Eviatar T. Zisman D. Peleg H. Paran D. Levartovsky D. Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study Ann. Rheum. Dis. 2021\n\n",
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"keywords": "Corticosteroid; Eculizumab; Myasthenia gravis; Mycophenolate sodium; SARS-CoV-2; Vaccine",
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"title": "Immunogenicity of repeat COVID-19 mRNA vaccinations in a patient with myasthenia gravis receiving mycophenolate, prednisone, and eculizumab.",
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"abstract": "We conducted a national retrospective survey on hospital practitioners to evaluate the magnitude of erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF) prescriptions in patients treated for chronic hepatitis C. Four hundred seventy-one questionnaires were sent, and 274 practitioners (58.2%) responded. Forty-six percent of practitioners used EPO, and 31% used G-CSF. The total number of HCV-infected patients receiving antiviral therapy per year was estimated at 6,630 patients, of whom 8.8% and 4% received EPO and G-CSF, respectively. EPO-beta was the main EPO molecule prescribed at a median dose of 30,000 IU/wk (range: 2,000-80,000). The indications for prescribing EPO varied greatly, including \"fragile patients\" (34%), \"low\" Hb level (8-11 g/dL) (19%), \"rapid decline\" in Hb level (2-5 g/dL during the first month of therapy) (12%), and symptomatic anemic patients (7%). G-CSF was mainly prescribed for a \"low\" level of neutrophils ranging from 400 to 750 neutrophils/mm3. In multivariate analysis, independent predictors of EPO and G-CSF prescription were age of practitioner less than 45 years (EPO: OR = 1.96, P = 0.03; G-CSF: OR = 2.27, P = 0.004), practice in university hospital (EPO: OR = 5.89, P < 0.0001; G-CSF: OR = 2.39, P = 0.003), and the high number of CHC treated/year (EPO: OR = 6.18, P < 0.0001; G-CSF: OR = 2.58, P = 0.002).\n\n\nCONCLUSIONS\nOur survey reveals an important rate of EPO and G-CSF prescriptions but with considerable disparity in the schedule of injections, the molecules used, and above all the indications. The suitable role of EPO and G-CSF as complements to HCV therapy urgently needs to be clarified.",
"affiliations": "Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Jean Minjoz, 25000 Besançon, France. tthevenot@chu-besancon.fr",
"authors": "Thévenot|Thierry|T|;Cadranel|Jean-François|JF|;Di Martino|Vincent|V|;Pariente|Alexandre|A|;Causse|Xavier|X|;Renou|Christophe|C|;Hagege|Hervé|H|;Denis|Jacques|J|;Lunel-Fabiani|Françoise|F|",
"chemical_list": "D016298:Hematopoietic Cell Growth Factors; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": "10.1002/hep.21517",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0270-9139",
"issue": "45(2)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D017024:Chemotherapy, Adjuvant; D004334:Drug Administration Schedule; D004921:Erythropoietin; D005260:Female; D005602:France; D016179:Granulocyte Colony-Stimulating Factor; D006306:Health Surveys; D016298:Hematopoietic Cell Growth Factors; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010818:Practice Patterns, Physicians'; D012189:Retrospective Studies",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "377-83",
"pmc": null,
"pmid": "17256721",
"pubdate": "2007-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C.",
"title_normalized": "a national french survey on the use of growth factors as adjuvant treatment of chronic hepatitis c"
} | [
{
"companynumb": "FR-AMGEN-FRASP2014062976",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
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"medicinalproduct": "NEULASTA"
},
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},
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"medicinalproduct": "NEORECORMON"
},
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},
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"medicinalproduct": "EPREX"
},
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"activesubstancename": "DARBEPOETIN ALFA"
},
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"medicinalproduct": "ARANESP"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
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"drugdosageform": "Unknown formulation",
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"medicinalproduct": "NEUPOGEN"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LENOGRASTIM"
},
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"medicinalproduct": "LENOGRASTIM"
}
],
"patientagegroup": null,
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"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Hypertension",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Arthralgia",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Bone pain",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pruritus allergic",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aplasia pure red cell",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Myalgia",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "A PARIENTE. A NATIONAL FRENCH SURVEY ON THE USE OF GROWTH FACTORS AS ADJUVANT TREATMENT OF CHRONIC HEPATITIS C.. HEPATOLOGY (BALTIMORE, MD). 2007;45 (2):377-383",
"literaturereference_normalized": "a national french survey on the use of growth factors as adjuvant treatment of chronic hepatitis c",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20140826",
"receivedate": "20140826",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10408859,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150326"
}
] |
{
"abstract": "BACKGROUND\nSeveral drug classes (antiarrhythmics, antimicrobials, antidepressants, phenothiazines, opiates, prokinetics of digestive tract, etc.) have been related to ventricular hyperkinetic arrhythmias such as torsade de pointes (TdP). TdPs are usually heralded by an abnormal prolongation of heart rate-corrected QT interval on the electrocardiogram, so-called drug-induced long heart rate-corrected QT (diLQTc). We do not know to what extent the drug-induced QTc prolongation is able to predict malignant arrhythmias. Thus, we have retrospectively examined the clinical history of patients with diLQTc.\n\n\nMETHODS\nThe case record, concerning the period January 2008-December 2017, was collected from two hospitals. diLQTc was defined as drug-induced heart rate-corrected QT of ≥ 450 ms or ≥ 470 ms, respectively in male or female patients. The primary purpose was to verify whether in diLQTc patients the length of this electrocardiographic segment was associated with the risk of symptoms or events (TdP, ventricular fibrillation).\n\n\nRESULTS\nSeventy-three validated cases of diLQTc were gathered. Among them, the QTc duration was not able to predict the occurrence of symptoms or events (odds ratio, 0.998; 95% CI, 0.984 to 1.013; p = 0.8821). Likewise, a diQTc lasting longer than 500 ms compared to diQTc comprised between 450 and 500 ms was not associated with an increased risk of arrhythmic events.\n\n\nCONCLUSIONS\nIn our diLQTc patients, QTc duration did not predict occurrence of symptoms, or arrhythmic events. Thus, other determinants should be postulated to clarify why sometimes diQTc prolongation propitiates ventricular malignant arrhythmias whereas in other cases this arrhythmogenic effect is lacking.",
"affiliations": "Preventive Cardiology and Rehabilitation Unit, DSB 29 \"S. Gennaro dei Poveri Hospital\", via S.Gennaro dei Poveri 25, 80136, Napoli, Italy. devecchis.erre@virgilio.it.;Division of Geriatrics, \"Casa Sollievo della Sofferenza\" Hospital, viale Cappuccini 2, 71013, San Giovanni Rotondo, Italy.;Division of Geriatrics, Clinic \"S. Maria del Pozzo\", via Pomigliano 40, 80049, Somma Vesuviana, Italy.;Mid-German Heart Center, Department of Internal Medicine III, Division of Cardiology, Angiology and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, ErnstGrube-Straße 40, 06120, Halle, Germany.",
"authors": "De Vecchis|Renato|R|http://orcid.org/0000-0002-3137-2814;Ariano|Carmelina|C|;Di Biase|Giuseppina|G|;Noutsias|Michel|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-018-2537-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "74(12)",
"journal": "European journal of clinical pharmacology",
"keywords": "Drug-induced long-QT syndrome; Prediction of cardiovascular events; QT corrected for heart rate; Torsade de pointes",
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018570:Risk Assessment; D016171:Torsades de Pointes; D014693:Ventricular Fibrillation",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "1645-1651",
"pmc": null,
"pmid": "30112668",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "11099628;28365182;22386296;14999113;17126428;18756841;27930499;13435203;3716982;15191637;24922496;28160473;29405316",
"title": "Acquired drug-induced long QTc: new insights coming from a retrospective study.",
"title_normalized": "acquired drug induced long qtc new insights coming from a retrospective study"
} | [
{
"companynumb": "IT-JNJFOC-20181201126",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "015923",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"drugrecurreadministration": "3",
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"medicinalproduct": "HALOPERIDOL."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "020634",
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"drugcharacterization": "1",
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"drugdosageform": "UNSPECIFIED",
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"drugrecurreadministration": "3",
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"medicinalproduct": "LEVOFLOXACIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "019813",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosageform": "UNSPECIFIED",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"drugrecurreadministration": "3",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "FENTANYL."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "999999",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PROMETHAZINE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Electrocardiogram QT prolonged",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DE VECCHIS R, ARIANO C, DI BIASE G, NOUTSIAS M. ACQUIRED DRUG-INDUCED LONG QTC: NEW INSIGHTS COMING FROM A RETROSPECTIVE STUDY. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY 2018?74/12:1645-1651.",
"literaturereference_normalized": "acquired drug induced long qtc new insights coming from a retrospective study",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20181207",
"receivedate": "20181207",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15700184,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190205"
}
] |
{
"abstract": "Blinatumomab and inotuzumab ozogamicin are now widely used to treat relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL).\n\n\n\nWe have reported the clinical course of 34 adult patients with r/r B-ALL receiving blinatumomab or inotuzumab ozogamicin at our institution from 2009 to 2019.\n\n\n\nBlinatumomab-based salvage therapy was applied for overt r/r B-ALL (n = 13) or minimal residual disease (MRD) positivity (n = 5). Of the 13 patients with r/r B-ALL, 9 (69%; 95% confidence interval [CI], 39%-91%) achieved complete remission (CR), with 78% of CR patients (95% CI, 40%-97%) reaching MRD negativity. MRD negativity was also achieved in all 5 patients treated for MRD positivity. The 1-year overall survival of patients receiving blinatumomab for r/r B-ALL and MRD positivity was 54% (n = 13; 95% CI, 26%-81%) and 80% (n = 5; 95% CI, 44-100), respectively. In the inotuzumab ozogamicin group, all 16 patients were treated for overt r/r B-ALL. The rate of CR was 94% (95% CI, 70%-100%), with 67% (95% CI, 38%-88%) of CR patients reaching MRD negativity. The 1-year OS after the first application of inotuzumab ozogamicin was 46% (95% CI, 18%-74%). Of those patients receiving blinatumomab and inotuzumab ozogamicin as a bridge-to-transplant strategy, 79% and 80%, respectively, proceeded to allogeneic stem cell transplantation. The most frequent drug-specific adverse events were similar to those previously reported, including cytokine release syndrome, capillary leak syndrome, and neurotoxicity for blinatumomab and transplant-associated veno-occlusive disease of the liver for inotuzumab ozogamicin.\n\n\n\nTogether with previous observations from phase III clinical trials, these data suggest that blinatumomab and inotuzumab ozogamicin are highly effective salvage regimens in r/r B-ALL.",
"affiliations": "Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany.;Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany.;Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany.;Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany.;Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany.;Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany.;Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany.;Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany.;Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany.;Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany.;Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany. Electronic address: matthias.stelljes@ukmuenster.de.",
"authors": "Stelmach|Patrick|P|;Wethmar|Klaus|K|;Groth|Christoph|C|;Wenge|Daniela V|DV|;Albring|Jörn|J|;Mikesch|Jan-Henrik|JH|;Schliemann|Christoph|C|;Reicherts|Christian|C|;Berdel|Wolfgang E|WE|;Lenz|Georg|G|;Stelljes|Matthias|M|",
"chemical_list": "D018033:Antibodies, Bispecific; C510808:blinatumomab; D000080045:Inotuzumab Ozogamicin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2020.05.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "20(10)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "AlloSCT; Antibody-drug conjugate; B-ALL; Bispecific T-cell engager; Salvage therapy",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000080045:Inotuzumab Ozogamicin; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012189:Retrospective Studies; D014184:Transplantation, Homologous; D055815:Young Adult",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e724-e733",
"pmc": null,
"pmid": "32646833",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
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"title": "Blinatumomab or Inotuzumab Ozogamicin as Bridge to Allogeneic Stem Cell Transplantation for Relapsed or Refractory B-lineage Acute Lymphoblastic Leukemia: A Retrospective Single-Center Analysis.",
"title_normalized": "blinatumomab or inotuzumab ozogamicin as bridge to allogeneic stem cell transplantation for relapsed or refractory b lineage acute lymphoblastic leukemia a retrospective single center analysis"
} | [
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"literaturereference": "STELLJES M.? STELMACH P.? WETHMAR K. ET AL.. BLINATUMOMAB OR INOTUZUMAB OZOGAMICIN AS BRIDGE TO ALLOGENEIC STEM CELL TRANSPLANTATION FOR RELAPSED OR REFRACTORY B?LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA: A RETROSPECTIVE SINGLE?CENTER ANALYSIS. CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA. 2020?1?9.E1",
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] |
{
"abstract": "Cytomegalovirus (CMV) infection is the most common infectious complication following solid organ transplantation. Ganciclovir (GCV)-resistant CMV infection may be fatal, and is difficult to treat while avoiding allograft rejection. A 31-year-old woman received a second ABO-incompatible kidney transplant, from her father. Induction therapy consisted of basiliximab and rituximab followed by maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and methylprednisolone. Her CMV serostatus was D(+) /R(-) at second transplant and she received prophylactic low-dose valganciclovir (VGCV). BK polyoma virus nephropathy (BKVN) developed 7 months after transplant concurrent with CMV hepatitis and retinitis. VGCV was increased to a therapeutic dose combined with reduced immunosuppression with minimal methylprednisolone (2 mg/day) and everolimus (0.5 mg/day). However, pp65 antigenaemia continued to increase for 6 weeks. Her CMV was defined as ganciclovir (GCV)-resistant. Foscarnet was therefore administered and her CMV disease resolved within 2 weeks. Kidney allograft dysfunction developed 9 months after transplant, and graft biopsy showed tubulointerstitial injury with crystal deposition suggesting foscarnet nephrotoxicity, with no findings of BKVN or rejection. Kidney function recovered after cessation of foscarnet and the patient had good graft function 18 months after transplant. This case demonstrates the successful use of foscarnet to treat GCV-resistant CMV infection after ABO-incompatible kidney transplant complicated with BKVN, without acute allograft rejection. This case further highlights the need to establish appropriate management for CMV D(+) /R(-) patients to avoid the acquisition of GCV-resistant gene mutations.",
"affiliations": "Department of Urology, Hokkaido University Hospital, Hokkaido, Japan.;Department of Surgical Pathology, Hokkaido University Hospital, Hokkaido, Japan.;Hokkaido Renal Pathology Center, Hokkaido, Japan.;Department of Urology, Hokkaido University Hospital, Hokkaido, Japan.;Department of Urology, Hokkaido University Hospital, Hokkaido, Japan.;Department of Urology, Hokkaido University Hospital, Hokkaido, Japan.;Department of Urology, Hokkaido University Hospital, Hokkaido, Japan.;Hokkaido Renal Pathology Center, Hokkaido, Japan.;Department of Urology, Hokkaido University Hospital, Hokkaido, Japan.",
"authors": "Iwami|Daiki|D|;Ogawa|Yayoi|Y|;Fujita|Hiromi|H|;Morita|Ken|K|;Sasaki|Hajime|H|;Oishi|Yuichiro|Y|;Higuchi|Haruka|H|;Hatanaka|Kanako|K|;Shinohara|Nobuo|N|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D017245:Foscarnet; D015774:Ganciclovir",
"country": "Australia",
"delete": false,
"doi": "10.1111/nep.12767",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1320-5358",
"issue": "21 Suppl 1()",
"journal": "Nephrology (Carlton, Vic.)",
"keywords": "BK polyoma virus nephropathy; cytomegalovirus; foscarnet-induced nephropathy; ganciclovir-resistant; kidney transplantation",
"medline_ta": "Nephrology (Carlton)",
"mesh_terms": "D000328:Adult; D064591:Allografts; D000998:Antiviral Agents; D001706:Biopsy; D003586:Cytomegalovirus Infections; D024882:Drug Resistance, Viral; D005260:Female; D017245:Foscarnet; D015774:Ganciclovir; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9615568",
"other_id": null,
"pages": "63-6",
"pmc": null,
"pmid": "26970406",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment with foscarnet for ganciclovir-resistant cytomegalovirus infection in a kidney transplant recipient: A case report.",
"title_normalized": "successful treatment with foscarnet for ganciclovir resistant cytomegalovirus infection in a kidney transplant recipient a case report"
} | [
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{
"abstract": "To describe a single institutional experience managing fetuses with supraventricular tachycardia (SVT) and to identify associations between patient characteristics and fetal and postnatal outcomes.\n\n\n\nSustained fetal SVT is associated with significant morbidity and mortality if untreated, yet the optimal management strategy remains unclear.\n\n\n\nRetrospective cohort study including fetuses diagnosed with sustained SVT (>50% of the diagnostic echocardiogram) between 1985 and 2018. Fetuses with congenital heart disease were excluded.\n\n\n\nSustained SVT was diagnosed in 65 fetuses at a median gestational age of 30 weeks (range, 14-37). Atrioventricular re-entrant tachycardia and atrial flutter were the most common diagnoses, seen in 41 and 16 cases, respectively. Moderate/severe ventricular dysfunction was present in 20 fetuses, and hydrops fetalis was present in 13. Of the 57 fetuses initiated on transplacental drug therapy, 47 received digoxin first-line, yet 39 of 57 (68%) required advanced therapy with sotalol, flecainide, or amiodarone. Rate or rhythm control was achieved in 47 of 57 treated fetuses. There were no cases of intrauterine fetal demise. Later gestational age at fetal diagnosis (odds ratio [OR], 1.1, 95% confidence interval [CI], 1.01-1.2, P = .02) and moderate/severe fetal ventricular dysfunction (OR, 6.1, 95% CI, 1.7-21.6, P = .005) were associated with postnatal SVT. Two postnatal deaths occurred.\n\n\n\nFetuses with structurally normal hearts and sustained SVT can be effectively managed with transplacental drug therapy with minimal risk of intrauterine fetal demise. Treatment requires multiple antiarrhythmic agents in over half of cases. Later gestational age at fetal diagnosis and the presence of depressed fetal ventricular function, but not hydrops, predict postnatal arrhythmia burden.",
"affiliations": "Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.;Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.;Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.;Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.;Harvard Medical School, Boston, Massachusetts.;Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.;Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.;Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.;Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.",
"authors": "O'Leary|Edward T|ET|0000-0001-8360-9820;Alexander|Mark E|ME|;Bezzerides|Vassilios J|VJ|;Drogosz|Monika|M|;Economy|Katherine E|KE|;Friedman|Kevin G|KG|;Pickard|Sarah S|SS|;Tworetzky|Wayne|W|;Mah|Douglas Y|DY|",
"chemical_list": "D000889:Anti-Arrhythmia Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/jce.14406",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1045-3873",
"issue": "31(5)",
"journal": "Journal of cardiovascular electrophysiology",
"keywords": "atrial flutter; fetal tachycardia; supraventricular tachycardia; therapy",
"medline_ta": "J Cardiovasc Electrophysiol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D005313:Fetal Death; D005315:Fetal Diseases; D005318:Fetal Heart; D005865:Gestational Age; D006340:Heart Rate, Fetal; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013617:Tachycardia, Supraventricular; D013997:Time Factors; D016896:Treatment Outcome; D016216:Ultrasonography, Prenatal; D055815:Young Adult",
"nlm_unique_id": "9010756",
"other_id": null,
"pages": "1105-1113",
"pmc": null,
"pmid": "32100356",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Low mortality in fetal supraventricular tachycardia: Outcomes in a 30-year single-institution experience.",
"title_normalized": "low mortality in fetal supraventricular tachycardia outcomes in a 30 year single institution experience"
} | [
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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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"reaction": [
{
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},
{
"reactionmeddrapt": "Foetal hypokinesia",
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},
{
"reactionmeddrapt": "Bradycardia foetal",
"reactionmeddraversionpt": "24.0",
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},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
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}
],
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"literaturereference": "O^LEARY ET, ALEXANDER ME, BEZZERIDES VJ, DROGOSZ M, ECONOMY KE, FRIEDMAN KG, ET AL. LOW MORTALITY IN FETAL SUPRAVENTRICULAR TACHYCARDIA: OUTCOMES IN A 30?YEAR SINGLE?INSTITUTION EXPERIENCE. J?CARDIOVASC?ELECTROPHYSIOL 2020?31(5):1105?1113.",
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},
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},
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}
] |
{
"abstract": "Hematologic abnormalities following solid organ transplantation are infrequently autoimmune in origin. We present a series of autoimmune cytopenias developing as a late complication of pediatric cardiac transplantation. Autoimmune cytopenias represented include autoimmune hemolytic anemia, acquired Glanzmann thrombasthenia, and idiopathic thrombocytopenic purpura. Standard therapies were used in each patient without sustainable results. Eventually, each patient was treated with and responded to rituximab. In this report, we review these cases, propose potential mechanisms for development of autoimmune cytopenias, and discuss our experience with rituximab in managing refractory autoimmune cytopenias.",
"affiliations": "Division of Hematology/Oncology, Children's Hospital Boston, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.",
"authors": "Tubman|Venée N|VN|;Smoot|Leslie|L|;Heeney|Matthew M|MM|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D001323:Autoantibodies; D016756:Immunoglobulins, Intravenous; D000069283:Rituximab; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.20761",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "48(3)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000741:Anemia, Aplastic; D000744:Anemia, Hemolytic, Autoimmune; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D001323:Autoantibodies; D001327:Autoimmune Diseases; D001402:B-Lymphocytes; D009202:Cardiomyopathies; D002313:Cardiomyopathy, Restrictive; D002648:Child; D003327:Coronary Disease; D004341:Drug Evaluation; D017809:Fatal Outcome; D005260:Female; D006330:Heart Defects, Congenital; D016027:Heart Transplantation; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D009203:Myocardial Infarction; D010322:Parvoviridae Infections; D011183:Postoperative Complications; D011241:Prednisone; D000069283:Rituximab; D013915:Thrombasthenia",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "339-44",
"pmc": null,
"pmid": "16435382",
"pubdate": "2007-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acquired immune cytopenias post-cardiac transplantation respond to rituximab.",
"title_normalized": "acquired immune cytopenias post cardiac transplantation respond to rituximab"
} | [
{
"companynumb": "US-ROCHE-1697418",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
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"drugcharacterization": "1",
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"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": "FOR 4 WEEKS",
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"drugindication": "AUTOIMMUNE HAEMOLYTIC ANAEMIA",
"drugintervaldosagedefinition": "803",
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"medicinalproduct": "RITUXIMAB"
}
],
"patientagegroup": null,
"patientonsetage": "9",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Varicella zoster virus infection",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": ", SMOOT L AND HEENEY M. ACQUIRED IMMUNE CYTOPENIAS POST-CARDIAC TRANSPLANTATION RESPOND TO RITUXIMAB. PEDIATR BLOOD CANCER 2007;48:339-344.",
"literaturereference_normalized": "acquired immune cytopenias post cardiac transplantation respond to rituximab",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170118",
"receivedate": "20170118",
"receiver": {
"receiverorganization": "FDA",
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},
"reporttype": "1",
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"transmissiondate": "20170428"
}
] |
{
"abstract": "Elderly patients who are injured from a low-level fall comprise an increasing percentage of trauma admissions. We sought to evaluate the prevalence of antithrombotic (anticoagulant or antiplatelet) agent use, injury patterns, and outcomes in this population, focusing on intracranial hemorrhage (ICH).\n\n\n\nWe retrospectively reviewed the trauma registry at an American College of Surgeons-verified Level I trauma center for all patients aged 65 y or older admitted between 2007 and 2016 following a low-level fall. Medical records of patients on antithrombotic agents were examined in detail. Patients were divided into four groups based on the presence/absence of ICH and presence/absence of preadmission antithrombotic medication use.\n\n\n\nThere were 4074 elderly patients admitted after a low-level fall, of which 1153 (28.3%) had a traumatic ICH, and 1238 (30.4%) were on antithrombotic agents. Notably, 35.9% of patients on antithrombotics had an ICH, as compared to 25.0% of 2836 patients not on antithrombotics other than aspirin (P < 0.001). The overall distribution of antithrombotic agent use differed significantly between the ICH and non-ICH groups; the ICH group had more coumadin usage. The mortality rate was significantly different across groups, with the group having ICH and a history of antithrombotics having the highest mortality at 14.2% (P < 0.001). Excluding the 27.8% of patients who were transferred into our hospital demonstrated that significantly more admissions on antithrombotics had ICH (22.4%) versus ICH admissions not on antithrombotics (14.7%, P < 0.001). The mortality rate was significantly different across groups, with the group having ICH and a history of antithrombotics having the highest mortality at 12.0% (P < 0.001). On multivariable analysis, anticoagulants, antiplatelets, and aspirin were all significantly associated with ICH; but only anticoagulants were significantly associated with mortality.\n\n\n\nAntithrombotic agent use was common in admitted elderly patients sustaining a low-level fall and is associated with an elevated rate of ICH. Anticoagulants were also associated with increased mortality.",
"affiliations": "Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York.;Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York.;Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York.;Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York.;Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York.;Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York.;Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York.;Division of Trauma, Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York. Electronic address: randeep.jawa@stonybrookmedicine.edu.",
"authors": "Meade|Michael J|MJ|;Tumati|Abhinay|A|;Chantachote|Chanak|C|;Huang|Emily C|EC|;Rutigliano|Daniel N|DN|;Rubano|Jerry A|JA|;Vosswinkel|James A|JA|;Jawa|Randeep S|RS|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jss.2020.08.047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-4804",
"issue": "258()",
"journal": "The Journal of surgical research",
"keywords": "Anticoagulants; Antiplatelet agents; Antithrombotics; Trauma",
"medline_ta": "J Surg Res",
"mesh_terms": "D000058:Accidental Falls; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D020198:Intracranial Hemorrhage, Traumatic; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "0376340",
"other_id": null,
"pages": "216-223",
"pmc": null,
"pmid": "33032140",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Antithrombotic Agent Use in Elderly Patients Sustaining Low-Level Falls.",
"title_normalized": "antithrombotic agent use in elderly patients sustaining low level falls"
} | [
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"companynumb": "US-BAYER-2020-229713",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
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"activesubstancename": "ASPIRIN"
},
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"activesubstancename": "WARFARIN SODIUM"
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{
"abstract": "GS2 is a rare autosomal recessive disease characterized by hypopigmentation, variable immunodeficiency with HLH. HSCT is the only curative treatment for GS2. We analyzed the outcome of 10 children with GS2 who underwent HSCT at our center between October 1997 and September 2013. The median age of the patients at transplant was 13.5 months (range, 6-58 months). All of the patients developed HLH before HSCT and received HLH 94 or HLH 2004 protocols. Donors were HLA-identical relatives in 8 patients, HLA-mismatched relatives in 2 patients. Engraftment was achieved in all except one patient. None of the patients developed acute GVHD. Chronic GVHD occurred in one and veno-occlusive disease occurred in four patients. Eight of the patients are under remission without any neurologic sequelae-median time of disease-free survival is 92.4 months. The present study shows successful transplant outcome without long-term neurologic sequelae in patients with GS2 who underwent HSCT from HLA-related donors.",
"affiliations": "Division of Bone Marrow Transplantation, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Immunology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Hematology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Immunology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Bone Marrow Transplantation, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Hematology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Immunology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Bone Marrow Transplantation, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.",
"authors": "Kuskonmaz|Baris|B|http://orcid.org/0000-0002-1207-4205;Ayvaz|Deniz|D|;Gokce|Muge|M|;Ozgur|Tuba Turul|TT|;Okur|Fatma V|FV|;Cetin|Mualla|M|;Tezcan|Ilhan|I|;Uckan Cetinkaya|Duygu|D|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "21(7)",
"journal": "Pediatric transplantation",
"keywords": "Griscelli syndrome; hemophagocytic lymphohistiocytosis; transplantation",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D016116:Piebaldism; D000081207:Primary Immunodeficiency Diseases; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28836324",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hematopoietic stem cell transplantation in children with Griscelli syndrome: A single-center experience.",
"title_normalized": "hematopoietic stem cell transplantation in children with griscelli syndrome a single center experience"
} | [
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] |
{
"abstract": "Talimogene laherparepvec (T-VEC) is approved for unresected stage III-IV malignant melanoma. T-VEC has a direct cytotoxic effect and enhances the antitumor immunity of host cells. Immune checkpoints inhibitors also enhance the immunity of host cells by increasing the recruitment of antigen-presenting cells or activation and restoration of T-cell functions. Both type of therapies can potentiate the effect of the other therapy. We are reporting a case of T-VEC rechallenge who initially progressed on T-VEC with pembrolizumab but then responded to T-VEC rechallenge after intervening ipilimumab/nivolumab. An 83-year-old man developed a subungual lesion of the left thumb and found to have AJCC V. 7 stage IIIb melanoma. Few months later, he developed axillary lymphadenopathy and multiple subcutaneous nodules (AJCC V. 7 stage IIIc). The patient was started on intralesional rose Bengal and pembrolizumab. After 4 cycles of pembrolizumab with rose Bengal, a positron-emission tomography/computerized tomography scan showed the progression of disease. He was started on T-VEC intralesional injections with concurrent pembrolizumab, however, after 3 T-VEC injections and 2 more cycles of pembrolizumab, there was the progression of disease. Subsequently, ipilimumab/nivolumab was started and patient responded partially. Ipilimumab/nivolumab was held due to toxicity. Eight weeks from the last dose of ipilimumab/nivolumab, he experienced locoregional progression and was rechallenged with T-VEC monotherapy. The patient showed a significant response after second T-VEC injection and continued to show response 6 months since rechallenge. After, initial progression on T-VEC with pembrolizumab, intervening immune checkpoints inhibitors may favorably modify the antitumor immunity and potentiate antitumor effect of T-VEC rechallenge.",
"affiliations": "Department of Hospital Medicine, Dartmouth-Hitchcock Medical Center.;Department of Hematology-Oncology, Norris Cotton Cancer Center, Lebanon, NH.",
"authors": "Afzal|Muhammad Z|MZ|;Shirai|Keisuke|K|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D001688:Biological Products; D000074324:Ipilimumab; C000629782:talimogene laherparepvec; D000077594:Nivolumab; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000265",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-9557",
"issue": "42(4)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D001688:Biological Products; D018259:Herpesvirus 1, Human; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D000077594:Nivolumab; D049268:Positron-Emission Tomography; D019233:Retreatment; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "136-141",
"pmc": null,
"pmid": "30933044",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Response to the Rechallenge With Talimogene Laherparepvec (T-VEC) After Ipilimumab/Nivolumab Treatment in Patient With Cutaneous Malignant Melanoma Who Initially Had a Progression on T-VEC With Pembrolizumab.",
"title_normalized": "response to the rechallenge with talimogene laherparepvec t vec after ipilimumab nivolumab treatment in patient with cutaneous malignant melanoma who initially had a progression on t vec with pembrolizumab"
} | [
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{
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}
] |